Consumer medicine information

Abraxane

Paclitaxel, nab

BRAND INFORMATION

Brand name

Abraxane

Active ingredient

Paclitaxel, nab

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Abraxane.

What is in this leaflet

This leaflet answers some common questions about ABRAXANE. 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 being given ABRAXANE against the benefits they expect it will have for you.

If you have any concerns about being given this medicine, ask your doctor. Your doctor or pharmacist can provide you with more information about ABRAXANE.

Keep this leaflet You may need to read it again.

What ABRAXANE is used for

This medicine is used to treat:

  • Breast cancer
  • Lung Cancer
  • Pancreatic Cancer

This medicine belongs to a group of medicines called antineoplastic or cytotoxic medicines. You may also hear of these being called chemotherapy medicines.

It works by killing cancer cells and stopping them from multiplying.

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

This medicine is not addictive.

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

Before you are given ABRAXANE

When you must not be given it

You must not be given ABRAXANE if you have an allergy to:

  • any medicine containing paclitaxel
  • 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 or difficulty breathing; swelling of the face, lips, tongue or other parts of the body; rash, itching or hives on the skin.

You must not be given this medicine if you have a very low white blood cell (WBC) count.

Tell your doctor if you have an infection or high temperature. Your doctor may decide to delay your treatment until the infection is gone. A mild illness, such as a cold, is not usually a reason to delay treatment.

You must not be given this medicine if you have severe liver damage. Tell your doctor you have liver disease or damage.

You must not be given this medicine if you are pregnant or plan to become pregnant. Like most cytotoxic medicines ABRAXANE is not recommended for use during pregnancy. If there is any need to consider this medicine during your pregnancy, your doctor will discuss with you the benefits and risks of using it.

Males: tell your doctor if your partner plans to become pregnant while you are being treated with this medicine or shortly after you have stopped treatment with it. ABRAXANE may cause birth defects if either the male or female is being treated with it at the time of conception. It is recommended that you use some kind of birth control while you are being treated with ABRAXANE and for at least 12 weeks after you stop using it. Your doctor will discuss this with you.

Do not breast-feed if you are taking this medicine. The active ingredient in ABRAXANE passes into breast milk and there is a possibility that your baby may be affected.

If you are not sure whether you should be given this medicine, talk to your doctor.

The safety and effectiveness of ABRAXANE in children (under 18 years) has not been established.

Before you are given it

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

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

  • kidney disease
  • liver disease
  • heart problems
  • any blood disorder with a reduced number of blood cells, or platelets
  • any disease of the nerves
  • lowered immunity due to diseases such as HIV/AIDS
  • lowered immunity due to treatment with medicines such as cyclosporine, or other medicines used to treat cancer (including radiation therapy)

If you have not told your doctor about any of the above, tell him/her before you start taking ABRAXANE.

Taking other medicines

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

Some medicines and ABRAXANE may interfere with each other. Some medicines may be affected by ABRAXANE 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 this medicine.

How to take ABRAXANE

How much is given

Your doctor will decide what dose of ABRAXANE you will receive. This depends on your condition and other factors, such as your weight, kidney function and other chemotherapy medicines you are being given.

ABRAXANE may be given alone or in combination with other drugs.

Several courses of ABRAXANE therapy may be needed depending on your response to treatment.

Additional treatment may not be repeated until your blood cell numbers return to acceptable levels and any uncontrolled effects have been controlled.

Ask your doctor if you want to know more about the dose of ABRAXANE you receive.

How it is given

ABRAXANE is usually given as an infusion (drip) into a vein over 30 minutes.

How long it will be given for

Breast Cancer:
ABRAXANE is usually given once every three weeks (i.e. on day 1 of a 21-day cycle). Each infusion is called one 'cycle' of chemotherapy. Your doctor will decide how many of these cycles you will need.

Lung Cancer:
ABRAXANE is given every week (i.e. on days 1, 8 and 15 of each 21-day cycle). Another medicine called carboplatin is also given on day 1 only of each 21-day cycle. Your doctor will decide how many of these cycles you will need.

Pancreatic Cancer:
ABRAXANE is given every week (i.e. on days 1, 8 and 15 of each 28-day cycle). Every 28 days is called one ‘cycle’ of chemotherapy.

Another medicine called gemcitabine is also given on days 1, 8 and 15 after ABRAXANE has been given. Your doctor will decide how many of these cycles you will need.

Overdose

As ABRAXANE is given to you under the supervision of your doctor, it is very unlikely that you will receive too much. However, if you experience severe side effects after being given this medicine, tell your doctor or nurse immediately. You may need urgent medical attention.

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

While you are being given ABRAXANE

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are being treated with ABRAXANE.

Tell any other doctors, dentists, and pharmacists who are treating you that you are being given this medicine.

If you are going to have surgery, tell the surgeon or anaesthetist that you are being treated with this medicine. It may affect other medicines used during surgery.

If you become pregnant while you are being treated with this medicine, tell your doctor immediately.

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 cycles of ABRAXANE at the appropriate times to get the best effects from your treatments.

This medicine 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.

Your body breaks down ABRAXANE and uses it to fight cancer. The breakdown products may be excreted in body fluids and waste, including blood, urine, faeces, vomitus and semen.

In general, precautions to protect other people should be taken while you are receiving chemotherapy and for one week after the treatment period by:

  • Flushing the toilet twice to dispose of any body fluids and waste.
  • Wearing gloves to clean any spill of body fluid or waste. Use paper towels or old rags, a strong solution of non-bleaching detergent and large amounts of water to mop up the spill. Discard the towels or rags into a separate waste bag and dispose of fluids in the toilet.
  • Wash linen or clothing that is heavily contaminated by body fluids or waste separately from other items. Use a strong solution of non-bleaching detergent and large amounts of water.
  • Place soiled disposable nappies and other pads in a plastic bag, seal and dispose into the garbage.
  • For sexual intercourse, use a barrier method such as a condom.

Things to be careful of

Be careful driving or operating machinery until you know how ABRAXANE affects you. There is no known reason why you cannot continue driving or using machines between courses of ABRAXANE unless you feel tired or dizzy.

If you are given other medication as part of your treatment, you should ask your doctor for advice on driving and using machines.

Side effects

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

Like other medicines that treat cancer, ABRAXANE may have unwanted side effects, some of which may be serious. You may need medical treatment if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

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

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

  • muscle or joint pain on the arms and legs
  • nausea and vomiting
  • hair loss
  • diarrhoea
  • changes in skin or nail appearance
  • soreness or ulceration of the mouth
  • tiredness

The above list includes the more common side effects of your medicine.

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

  • pain, swelling, irritation and redness at the injection site
  • flushing
  • light-headedness, dizziness or fainting (due to low blood pressure)
  • numbness or tingling in the fingers and/or toes
  • changes in vision
  • abdominal pain

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

If any of the following happen, tell your doctor or nurse immediately, or if you are not in hospital, go to an Accident and Emergency Room at your nearest hospital:

  • shortness of breath, coughing, wheezing or difficulty breathing
  • swelling of the face, lips, tongue, or other parts of the body
  • rash, itching or hives on the skin
  • extreme weakness or tiredness
  • seizures (fits)
  • fast, slow or irregular heart beat
  • chest pain
  • yellowing of the skin or eyes
  • unusual bleeding or bruising (including blood in your stools or urine)
  • fever, sore throat or other signs of infection

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation.

Tell your doctor, nurse or pharmacist if you notice anything that is making you feel unwell.

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

The benefits and side effects of ABRAXANE may take some time to occur. Therefore, even after you have finished receiving your treatment, you should tell your doctor immediately if you notice any of the side effects listed in this section.

After being given ABRAXANE

Storage

ABRAXANE will be stored in the pharmacy or on the ward. The injection is kept in a cool, dry place, protected from light, where the temperature stays below 25°C.

Product description

What it looks like:

ABRAXANE is a white to yellow solid powder cake in a clear glass vial.

When it is reconstituted it will be a milky liquid.

Ingredients

Each vial of ABRAXANE contains either 100 mg or 250 mg of paclitaxel as the active ingredient, and human albumin solution (which contains sodium, sodium octanoate and sodium acetyltryptophanate).

This medicine does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

Manufacturer

ABRAXANE is manufactured in the USA by: Abraxis BioScience, LLC.

Sponsor

In Australia:

Abraxis BioScience Australia Pty Ltd
Level 2, 17 Cotham Road
Kew, Victoria 3101

Distributed by Specialised
Therapeutics Australia Pty Ltd
Ph: 1300 798 820
Fax: 1800 798 829
www.stbiopharma.com

In New Zealand:

Specialised Therapeutics Limited
Level 1, The Lane,
Botany Town Centre,
588 Chapel Road,
East Tamaki
AUCKLAND 2013
Ph: +64 9801 0299
Fax: +64 9801 0118

100 mg vial AUST R 133500

250 mg vial AUST R 297973

The 250 mg presentation is not approved by Medsafe and is therefore not marketed in New Zealand.

Abraxis BioScience Australia Pty Ltd is an indirect subsidiary of Celgene Corporation

This leaflet was prepared in November 2018.

Published by MIMS February 2019

BRAND INFORMATION

Brand name

Abraxane

Active ingredient

Paclitaxel, nab

Schedule

S4

 

1 Name of Medicine

Nanoparticle albumin-bound paclitaxel.

2 Qualitative and Quantitative Composition

Abraxane (nanoparticle albumin-bound paclitaxel) powder for injection (suspension) is an albumin nanoparticle form of paclitaxel with a mean particle size of approximately 130 nanometre. Paclitaxel exists in the nanoparticles in a non-crystalline, amorphous state. Each vial of Abraxane contains paclitaxel and human albumin in the ratio of 1:9. The paclitaxel is contained within nanoparticles that consist of a majority of paclitaxel bound to human albumin.
Each single-use vial contains the following: paclitaxel 100 mg or 250 mg. Abraxane is free of solvents.

100 mg vial.

The reconstituted medicinal product contains approximately 85 mg sodium per vial when reconstituted with 0.9% sodium chloride.

250 mg vial.

The reconstituted medicinal product contains approximately 213 mg sodium per vial when reconstituted with 0.9% sodium chloride.
The active agent in Abraxane is paclitaxel, a natural product with antitumour activity. Paclitaxel is obtained from Taxus media.

Excipient(s) with known effect.

Not applicable. For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Abraxane is supplied as a white to yellow, sterile, lyophilised powder in the following presentations:
100 mg paclitaxel in a 50 mL glass vial;
250 mg paclitaxel in a 100 mL glass vial.

4 Clinical Particulars

4.1 Therapeutic Indications

Metastatic breast cancer.

Abraxane is indicated for the treatment of metastatic carcinoma of the breast after failure of anthracycline therapy.

Non-small cell lung cancer.

Abraxane, in combination with carboplatin, is indicated for the first-line treatment of non-small cell lung cancer in patients who are not candidates for potentially curative surgery and/or radiation.

Metastatic adenocarcinoma of the pancreas.

Abraxane, in combination with gemcitabine, is indicated for the first-line treatment of patients with metastatic adenocarcinoma of the pancreas.

4.2 Dose and Method of Administration

The reconstituted suspension is milky and homogenous without visible particles.
Abraxane should be administered under the supervision of a physician experienced in the use of chemotherapeutic agents.
Abraxane is for single use in one patient only. Discard any residue.
No premedication to prevent hypersensitivity reactions is required prior to administration of Abraxane.

Patients with hepatic impairment.

For patients with mild hepatic impairment (total bilirubin > 1 to ≤ 1.5 x ULN and aspartate aminotransferase [AST] ≤ 10 x ULN, no dosage adjustments are required, regardless of indication. Treat with same doses as patients with normal hepatic function.
For patients with moderate to severe hepatic impairment (total bilirubin > 1.5 to ≤ 5 x ULN and AST ≤ 10 x ULN), a 20% reduction in dose is recommended for indications of metastatic breast cancer and non-small cell lung cancer.
The reduced dose may be escalated to the dose for patients with normal hepatic function if the patient is tolerating the treatment for at least two cycles.
There are insufficient data to permit dosage recommendations for patients with metastatic adenocarcinoma of the pancreas that have moderate to severe hepatic impairment.
For patients with total bilirubin > 5 x ULN or AST > 10 x ULN, there are insufficient data to permit dosage recommendations regardless of indication.

Patients with impaired renal function.

Adjustment of the starting Abraxane dose is not required for patients with mild to moderate renal impairment (estimated creatinine clearance ≥ 30 to < 90 mL/min). There are insufficient data to permit dosage recommendations in patients with severe renal impairment or end stage renal disease (estimated creatinine clearance, < 30 mL/min). See Section 5.2 Pharmacokinetic Properties.

Metastatic breast cancer.

The recommended dose for Abraxane is 260 mg/m2 administered intravenously over 30 minutes every 3 weeks.

Dose adjustments during treatment for metastatic breast cancer.

Patients who experience severe neutropenia (neutrophil < 0.5 x 109/L for a week or longer) or severe peripheral neuropathy during Abraxane therapy should have dosage reduced to 220 mg/m2 for subsequent courses of Abraxane. For recurrence of severe neutropenia or severe peripheral neuropathy, additional dose reduction should be made to 180 mg/m2. Abraxane should not be administered until neutrophil counts recover to > 1.5 x 109/L. For grade 3 peripheral neuropathy hold treatment until resolution to grade 1 or 2, followed by a dose reduction for all subsequent courses of Abraxane.

Missed dose in metastatic breast cancer.

Abraxane is administered every three weeks. In the event that the next scheduled dose is missed, dosing should occur as soon as possible, consistent with good medical practice, after the missed dose.

Non-small cell lung cancer.

The recommended dose of Abraxane is 100 mg/m2 administered as an intravenous infusion over 30 minutes on Days 1, 8, and 15 of each 21-day cycle. The recommended dose of carboplatin is AUC = 6 mg.min/mL on Day 1 only of each 21-day cycle, beginning immediately after the end of Abraxane administration. Day 1 is the only day of each 21-day cycle when carboplatin is used in combination with Abraxane.

Dose adjustments during treatment for non-small cell lung cancer.

Haematologic toxicities in non-small cell lung cancer.

Abraxane should not be administered on Day 1 of a cycle until absolute neutrophil count (ANC) is ≥ 1.5 x 109/L and platelet count is ≥ 100 x 109/L. For each subsequent weekly dose of Abraxane, patients must have an ANC ≥ 0.5 x 109/L and platelets > 50 x 109/L or the dose is to be withheld until counts recover. When counts recover, resume dosing the following week according to the criteria in Table 1. Reduce subsequent dose only if criteria in Table 1 are met. Weekly pre-dose full blood counts should be performed (see Section 4.4 Special Warnings and Precautions for Use, Haematology).

Nonhaematologic toxicities in non-small cell lung cancer.

Guidelines for implementing dose reductions for nonhaematologic toxicities are provided in Table 2. For Grade 2 or 3 cutaneous toxicity, Grade 3 mucositis, or Grade 3 diarrhoea, interrupt treatment until the toxicity improves to ≤ Grade 1, then restart treatment according to the guidelines in Table 2. For ≥ Grade 3 peripheral neuropathy, withhold treatment until resolution ≤ Grade 1. Treatment may be resumed at the next lower dose level in subsequent cycles according to the guidelines in Table 2. For any other Grade 3 or 4 nonhaematologic toxicity excluding alopecia, interrupt treatment until the toxicity improves to ≤ Grade 2, then restart treatment according to the guidelines in Table 2.

Metastatic adenocarcinoma of the pancreas.

The recommended dose of Abraxane is 125 mg/m2 administered as an intravenous infusion over 30 minutes on Days 1, 8 and 15 of each 28-day cycle. The recommended dose of gemcitabine is 1000 mg/m2 as an intravenous infusion over 30 minutes beginning immediately after the completion of Abraxane administration on Days 1, 8 and 15 of each 28-day cycle.

Dose adjustment.

Dose level reductions for patients with metastatic adenocarcinoma of the pancreas are provided in Table 3. Table 3 should be used in combination with the recommended dose modifications for neutropenia and/or thrombocytopenia that are given in Table 4 and the dose modifications for other toxicities (including neuropathy) that are given in Table 5.
Dose recommendation and modifications for neutropenia and thrombocytopenia at the start of a cycle or within a cycle for patients with metastatic adenocarcinoma of the pancreas are provided in Table 4.
Dose modifications for other adverse drug reactions in patients with metastatic adenocarcinoma of the pancreas are provided in Table 5.

Preparation and administration precautions.

Abraxane is a cytotoxic anticancer medicine and, as with other potentially toxic paclitaxel compounds, caution should be exercised in handling Abraxane. The use of gloves is recommended. If Abraxane (lyophilised cake or reconstituted suspension) contacts the skin, wash the skin immediately and thoroughly with soap and water. Following topical exposure to paclitaxel, events may include tingling, burning and redness. If Abraxane contacts mucous membranes, the membranes should be flushed thoroughly with water.
Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during medicine administration. Limiting the infusion of Abraxane to 30 minutes, as directed, reduces the likelihood of infusion-related reactions.
Each mL of the reconstituted formulation will contain 5 mg/mL paclitaxel.
Calculate the exact total dosing volume of 5 mg/mL suspension required for the patient:
Dosing volume (mL) = Total dose (mg)/5 (mg/mL).
Do not mix any other medicines with the Abraxane infusion.

Preparation for intravenous administration.

Abraxane is supplied as a sterile lyophilised powder for reconstitution before use.
Avoid errors, read entire preparation instructions prior to reconstitution. See Table 6.
1. Aseptically, reconstitute each vial as follows:
100 mg vial: inject 20 mL of 0.9% Sodium Chloride Injection;
250 mg vial: inject 50 mL of 0.9% Sodium Chloride Injection.
2. 100 mg vial: Slowly inject the 20 mL of 0.9% Sodium Chloride Injection over a minimum of 1 minute, using the sterile syringe to direct the solution flow onto the inside wall of the vial.
250 mg vial: Slowly inject the 50 mL of 0.9% Sodium Chloride Injection over a minimum of 1 minute, using the sterile syringe to direct the solution flow onto the inside wall of the vial.
3. Do not inject the 0.9% Sodium Chloride Injection directly onto the lyophilised cake as this will result in foaming.
4. Once the injection is complete, allow the vial to stand for a minimum of 5 minutes to ensure proper wetting of the lyophilised cake/powder.
5. Gently swirl and/or invert the vial slowly for at least 2 minutes until complete dissolution of any cake/powder occurs. Avoid generation of foam.
The reconstituted sample should be milky and homogenous without visible particulates. If particulates or settling are visible, the vial should be gently inverted again to ensure complete resuspension prior to use. Discard the reconstituted suspension if precipitates are observed. Discard any unused portion.
Slowly withdraw the dosing volume of the reconstituted Abraxane suspension from the vial(s) into a syringe. Inject the appropriate amount of reconstituted Abraxane into an empty, sterile intravenous bag [plasticised polyvinyl chloride (PVC) containers or non-PVC type intravenous bag]. The use of specialised DEHP-free solution containers or administration sets is not necessary, but may be used if desired to prepare or administer Abraxane infusions. The use of medical devices containing silicone oil as a lubricant (i.e. syringes and IV bags) to reconstitute and administer Abraxane may result in the formation of proteinaceous strands.
Visually inspect the reconstituted Abraxane suspension in the IV bag prior to administration. If strands are observed, administer reconstituted Abraxane suspension through a 15 micrometre filter. Do not use a filter with a pore size less than 15 micrometre.
Parenteral medicine products should be inspected visually for particulate matter and discolouration prior to administration whenever solution and container permit.

4.3 Contraindications

Abraxane should not be used in patients who have baseline neutrophil counts of < 1.5 x 109/L.
Patients who have exhibited hypersensitivity reactions to Abraxane or human albumin should not be treated with Abraxane.
Abraxane is contraindicated during pregnancy and lactation.

4.4 Special Warnings and Precautions for Use

Abraxane should be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available.

Interchangeability.

An albumin form of paclitaxel may substantially affect a medicine's functional properties relative to those of medicine in solution. Abraxane is not clinically interchangeable with other paclitaxel formulations. If a decision is made to discontinue Abraxane and to begin treatment with other paclitaxel formulations (or vice versa), there should be careful consideration of the differences between these products in indication, pharmacokinetics, dosing, administration, safety profile, and monitoring requirements.

Haematology.

Bone marrow suppression is dose dependent and a dose limiting toxicity. Abraxane therapy should not be administered to patients with baseline neutrophil counts of less than 1.5 x 109/L. In order to monitor the occurrence of myelotoxicity, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving Abraxane. Patients should not be retreated with subsequent cycles of Abraxane until neutrophils recover to a level > 1.5 x 109/L and platelets recover to a level > 100 x 109/L. In the case of severe neutropenia (< 0.5 x 109/L for seven days or more) during a course of Abraxane therapy, a dose reduction for subsequent courses of therapy is recommended (see Section 4.2 Dose and Method of Administration).

Peripheral neuropathy.

Peripheral neuropathy is a dose-dependent, dose-limiting toxicity. Peripheral neuropathy occurs frequently with Abraxane. The occurrence of grade 1 or 2 peripheral neuropathy does not generally require dose modification. When Abraxane is used as monotherapy, if grade 3 peripheral neuropathy develops, treatment should be withheld until resolution to grade 1 or 2 followed by a dose reduction for all subsequent courses of Abraxane. For combination use of Abraxane and carboplatin, if grade 3 or higher peripheral neuropathy develops, treatment should be withheld until improvement to grade 0 or 1 followed by a dose reduction for all subsequent courses of Abraxane and carboplatin (see Section 4.2 Dose and Method of Administration). For combination use of Abraxane and gemcitabine, if Grade 3 or higher peripheral neuropathy develops, withhold Abraxane; continue treatment with gemcitabine at the same dose. Resume Abraxane at reduced dose when peripheral neuropathy improves to Grade 0 or 1 (see Section 4.2 Dose and Method of Administration).

Sepsis in metastatic adenocarcinoma of the pancreas.

Sepsis was reported at a rate of 5% in patients with or without neutropenia who received Abraxane in combination with gemcitabine. Complications due to the underlying pancreatic cancer, especially biliary obstruction or presence of biliary stent, were identified as significant contributing factors. Sepsis was more common in the older age group (median age of those with sepsis was 61 years). Two deaths occurred as a result of infection in the ≥ 75-year old age group. If a patient becomes febrile (regardless of neutrophil count), initiate treatment with broad spectrum antibiotics. For febrile neutropenia, withhold Abraxane and gemcitabine until fever resolves and ANC ≥ 1.5 x 109/L, then resume treatment at reduced dose levels (see Section 4.2 Dose and Method of Administration).

Pneumonitis.

Pneumonitis has been reported at a rate of 4% when Abraxane was used in combination with gemcitabine and has been reported at a rate of 1% when Abraxane was used as monotherapy. Monitor patients closely for signs and symptoms of pneumonitis. After ruling out infectious aetiology and upon making a diagnosis of pneumonitis, permanently discontinue treatment with Abraxane and gemcitabine and promptly initiate appropriate treatment and supportive measures.

Hypersensitivity.

Rare occurrences of severe hypersensitivity reactions, including very rare events of anaphylactic reactions with fatal outcome, have been reported. Patients who experience a severe hypersensitivity reaction to Abraxane should not be re-challenged with the medicine.
Cross-hypersensitivity between Abraxane and other taxane products has been reported and may include severe reactions such as anaphylaxis. Patients with a previous history of hypersensitivity to other taxanes should be closely monitored during initiation of Abraxane therapy.

Cardiotoxicity.

Uncommon events of congestive heart failure and left ventricular dysfunction have been observed among individuals receiving Abraxane. Most of the individuals were previously exposed to cardiotoxic medicines, such as anthracyclines, or had underlying cardiac history. Thus patients receiving Abraxane should be vigilantly monitored by physicians for the occurrence of cardiac events.

CNS metastases.

The effectiveness and safety of Abraxane in patients with CNS metastases has not been established.

Gastrointestinal symptoms.

If patients experience nausea, vomiting and diarrhoea following administration of Abraxane, they may be treated with commonly used anti-emetics and antidiarrhoeals.

Use in hepatic impairment.

Patients with hepatic impairment may be at increased risk of toxicity, particularly from myelosuppression; such patients should be closely monitored for development of profound myelosuppression. Abraxane is not recommended in patients that have a total bilirubin > 5 x ULN or AST > 10 x ULN. In addition, Abraxane is not recommended in patients with metastatic adenocarcinoma of the pancreas that have moderate to severe hepatic impairment (total bilirubin > 1.5 x ULN and AST ≤ 10 x ULN). See Section 4.2 Dose and Method of Administration.

Use in the elderly.

Metastatic breast cancer.

Of the 229 patients in the randomised study who received Abraxane, 13% were at least 65 years of age and < 2% were 75 years or older. No toxicities occurred notably more frequently among elderly patients at least 65 years of age who received Abraxane.
A subsequent analysis was conducted in 981 patients receiving Abraxane monotherapy for metastatic breast cancer; 15% were ≥ 65 years old and 2% were ≥ 75 years old. A higher incidence of epistaxis, diarrhoea, dehydration, fatigue and peripheral oedema was found in patients ≥ 65 years.

Non-small cell lung cancer.

Of the 514 patients in the randomised study who received Abraxane and carboplatin, 31% were 65 years or older and 3.5% were 75 years or older. Myelosuppression events, peripheral neuropathy events, and arthralgia were more frequent in patients 65 years or older compared to patients younger than 65 years old. No additional dose reductions, other than those recommended for all patients, are necessary for patients 65 years or older (see Section 4.2 Dose and Method of Administration).

Metastatic adenocarcinoma of the pancreas.

Patients 65 years and older.

In the randomised study, of the 431 patients with metastatic adenocarcinoma of the pancreas who received Abraxane in combination with gemcitabine, 41% were 65 years and older. Diarrhoea, decreased appetite, dehydration and epistaxis were more frequent in patients 65 years or older compared with patients younger than 65 years old.

Patients 75 years and older.

Of the 431 patients with metastatic adenocarcinoma of the pancreas who received Abraxane in combination with gemcitabine, 10% were 75 years and older. In patients 75 years and older, there was a higher incidence of serious adverse reactions and adverse reactions that led to treatment discontinuation. Carefully assess patients 75 years and older for their ability to tolerate Abraxane in combination with gemcitabine. Give special consideration to performance status, co-morbidities and increased risk of infections.

Paediatric use.

The safety and effectiveness of Abraxane in paediatric patients have not been established.

Effects on laboratory tests.

Interactions with laboratory tests have not been established.

Other.

Although limited data is available, no clear benefit in terms of prolonged overall survival has been demonstrated in patients with metastatic adenocarcinoma of the pancreas who have normal CA 19-9 levels prior to start of treatment with Abraxane and gemcitabine.

4.5 Interactions with Other Medicines and Other Forms of Interactions

A pharmacokinetic study was conducted with Abraxane and carboplatin in non-small cell lung cancer patients. There were no clinically relevant pharmacokinetic interactions for Abraxane on the pharmacokinetics of carboplatin and for carboplatin on the pharmacokinetics of paclitaxel when administered as Abraxane.
Medicine interaction studies between Abraxane and other medicines have not been conducted.

Medicines metabolised in the liver.

The metabolism of paclitaxel is catalysed, in part, by cytochrome P450 isoenzymes CYP2C8 and CYP3A4. Clinical interaction studies between Abraxane and inhibitors and inducers of either CYP2C8 or CYP3A4 have not been formally investigated. Therefore, caution should be exercised when administering Abraxane concomitantly with medicines known to inhibit (e.g. erythromycin, ketoconazole, fluoxetine, imidazole antifungals, gemfibrozil, clopidogrel, cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir) or induce (e.g. rifampicin, carbamazepine, phenytoin, efavirenz, nevirapine) either CYP2C8 or CYP3A4 (see Section 5.2 Pharmacokinetic Properties).
In vitro studies using rat and human liver slices and liver microsomes have shown that the metabolism of paclitaxel is inhibited by a large number of medicines, including CYP2C8 and CYP3A4 substrates, and quinidine, PEG-35 castor oil, quercetin, clozapine, morin, and resveratrol.
Paclitaxel and gemcitabine do not share a common metabolic pathway. Paclitaxel clearance is primarily determined by cytochrome P450 2C8 and 3A4 mediated metabolism followed by biliary excretion, while gemcitabine is inactivated by cytidine deaminase followed by urinary excretion. Pharmacokinetic interactions between Abraxane and gemcitabine have not been evaluated in humans.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Administration of paclitaxel prior to and during mating produced impairment of fertility in male and female rats at doses equal to or greater than 1 mg/kg/day (about 0.04 the daily maximum recommended human dose on a mg/m2 basis).
Administration of Abraxane to male rats on a weekly basis for 11 weeks prior to mating with untreated female rats was associated with testicular atrophy/degeneration and reduced fertility accompanied by decreased pregnancy rates and increased loss of embryos in mated females. Testicular atrophy/degeneration has also been observed in single dose toxicology studies in rodents administered Abraxane at 6 mg/kg (54 mg/m2) and dogs administered 8.75 mg/kg (175 mg/m2).

Infertility.

Females and males.

Based on findings in animals, Abraxane may impair fertility in females and males of reproductive potential.
(Category D)
Abraxane is a cytotoxic agent. Cytotoxic agents can produce spontaneous abortion, foetal loss and birth defects, including serious birth defects when administered to a pregnant woman. Administration of Abraxane to female rats on gestation days 7 to 17 daily at doses of 6 mg/m2 (approximately 2% of the daily maximum recommended human dose on a mg/m2 basis) caused embryo- and foetotoxicity, as indicated by intrauterine mortality, increased resorptions, reduced numbers of live foetuses, reduction in foetal body weight and increase in foetal abnormalities. Foetal abnormalities included skeletal and soft tissue malformations, such as eye bulge, folded retina, and dilation of brain ventricles.
There are no adequate and well-controlled studies in pregnant women using Abraxane. Females of reproductive potential should have a pregnancy test prior to starting treatment with Abraxane.
If this medicine is used during pregnancy, or if the patient becomes pregnant while receiving this medicine, the patient should be apprised of the potential hazard to the foetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with Abraxane.
Advise females of reproductive potential to use effective contraception during treatment with Abraxane and for at least 6 months after the last dose.
Like other genotoxic cytostatics, Abraxane can have genotoxic effects. Male patients treated with Abraxane are advised to use effective contraception and to avoid fathering a child during and up to six months after treatment.
Paclitaxel and/or its metabolites were excreted into the milk of lactating rats. Following intravenous administration of radiolabeled paclitaxel to rats on days 9 to 10 postpartum, concentrations of radioactivity in milk were higher than in plasma and declined in parallel with the plasma concentrations. Because many medicines are excreted in human milk and because of the potential for serious adverse reactions in breastfeeding infants, breastfeeding must be discontinued when receiving Abraxane therapy.

4.7 Effects on Ability to Drive and Use Machines

Abraxane has minor or moderate influence on the ability to drive and use machines. Abraxane may cause adverse reactions such as tiredness (very common) and dizziness (common) that may affect the ability to drive and use machinery. Patients should be advised not to drive and use machines if they feel tired or dizzy.

4.8 Adverse Effects (Undesirable Effects)

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

Metastatic breast cancer.

See Table 7.

Adverse events in any trial with single agent Abraxane.

Table 8 lists adverse effects associated with the administration of Abraxane to patients from studies in which Abraxane has been administered as a single agent at any dose in any indication (N = 789). The frequency of adverse effects listed in Table 8 is defined using the following convention: Very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000); very rare (< 1/10,000).

Non-small cell lung cancer.

Table 9 provides the frequency and severity of adverse reactions by system organ class/preferred term that have been reported in ≥ 5% of 514 patients with advanced non-small cell lung cancer who received Abraxane and carboplatin and 524 patients with advanced non-small cell lung cancer who received solvent-based paclitaxel and carboplatin. Within each system organ class grouping, adverse reactions are presented in order of decreasing frequency.
The frequency estimates for adverse reactions are defined as: Very common (≥ 1/10); Common (≥ 1/100 to < 1/10); Uncommon (≥ 1/1,000 to < 1/100); Rare (≥ 1/10,000 to < 1/1,000); Very rare (< 1/10,000); and Not known (cannot be estimated from available data - spontaneous reports).
Additional clinically relevant adverse reactions that were reported in ≥ 1% and < 5% of the non-small cell lung cancer patients who received Abraxane and carboplatin included:

Blood and lymphatic system disorders.

Lymphopenia, febrile neutropenia.

Skin and subcutaneous tissue disorders.

Nail disorder, pruritus.

Gastrointestinal disorders.

Dyspepsia, abdominal pain, dysphagia.

Investigations.

Blood alkaline phosphatase increased.

Musculoskeletal and connective tissue disorders.

Back pain, pain in extremity, musculoskeletal pain.

Metabolic and nutrition disorders.

Dehydration.

Infections and infestations.

Bronchitis, upper respiratory tract infection, urinary tract infection.

Vascular disorders.

Hypotension, hypertension.

Eye disorders.

Vision blurred.

Hepatobiliary disorders.

Hyperbilirubinaemia.
Additional clinically relevant adverse reactions that were reported in < 1% of the non-small cell lung cancer patients who received Abraxane and carboplatin included:

Blood and lymphatic system disorders.

Pancytopenia.

Skin and subcutaneous tissue disorders.

Dermatitis allergic, urticaria, skin exfoliation.

General disorders and administration site conditions.

Mucosal inflammation, infusion site extravasation, infusion site inflammation, infusion site rash.

Respiratory thoracic and mediastinal disorders.

Pneumonitis1,a.

Infections and infestations.

Oral candidiasis, sepsis.

Vascular disorders.

Flushing.

Immune system disorders.

Drug hypersensitivity, hypersensitivity.
1 Pneumonitis evaluated using the MedDRA v14.0 Standardised MedDRA Query (SMQ) interstitial lung disease. a SMQ is a grouping of several MedDRA preferred terms to capture a medical concept.

Summary of the safety profile in combination with carboplatin in non-small cell lung cancer trials.

In the non-small cell lung cancer study, significantly less ≥ grade 3 neuropathy, neutropenia, arthralgia, and myalgia occurred in the Abraxane arm, while less thrombocytopenia and anaemia occurred in the paclitaxel arm.

Peripheral neuropathy in combination with carboplatin in non-small cell lung cancer trials.

In the non-small cell lung cancer study, peripheral neuropathy was graded by the investigator according to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0. For Abraxane and carboplatin, the median time to first occurrence of grade 3 peripheral neuropathy was 121 days, and the median time to improvement from grade 3 peripheral neuropathy to grade 1 was 38 days. No patients treated with Abraxane and carboplatin had grade 4 peripheral neuropathy.
Patient-reported taxane toxicity was assessed using the 4 subscales of the Functional Assessment of Cancer Therapy (FACT)-Taxane questionnaire. Using repeated measure analysis, 3 of the 4 subscales (peripheral neuropathy, pain hands/feet, and hearing) favoured Abraxane and carboplatin (p ≤ 0.002). For the other subscale (oedema), there was no difference in the treatment arms.

Metastatic adenocarcinoma of the pancreas.

Adverse reactions resulting in death within 30 days of the last dose of study medicine were reported for 4% of patients in the Abraxane and gemcitabine group and for 4% of patients in the gemcitabine group.

Clinical trial experience in metastatic adenocarcinoma of the pancreas.

Adverse reactions were assessed in 421 Abraxane plus gemcitabine-treated patients and 402 gemcitabine monotherapy-treated patients receiving first-line systemic treatment for metastatic adenocarcinoma of the pancreas in a multicentre, multinational, randomised, controlled, open-label trial.
Table 10 provides the frequency and severity of haematologic laboratory-detected abnormalities for the Abraxane/gemcitabine group and the gemcitabine group.
Table 11 provides the frequency and severity of adverse reactions by system organ class/preferred term that have been reported in ≥ 10% of patients with metastatic adenocarcinoma of the pancreas who received Abraxane and gemcitabine or gemcitabine monotherapy. Within each system organ class grouping, adverse reactions are presented in order of decreasing frequency.

Adverse effects reported with Abraxane/gemcitabine in clinical trials.

Additional clinically relevant adverse reactions that were reported in at least one patient but in < 10% of the patients with metastatic adenocarcinoma of the pancreas who received Abraxane/gemcitabine are listed in Table 12.
The frequency of adverse effects listed in Table 12 is defined using the following convention: Very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000); very rare (< 1/10,000).

Peripheral neuropathy with Abraxane/gemcitabine in clinical trials.

For Abraxane and gemcitabine, the median time to first occurrence of Grade 3 peripheral neuropathy was 140 days. Of the patients who experienced Grade 3 peripheral neuropathy, 63% improved by ≥ 1 grade and 43% had a resolution from Grade 3 to Grade 0 or 1 and the median time to improvement was 29 days. Of the patients with treatment interrupted due to peripheral neuropathy, 44% (31/70 patients) were able to resume Abraxane at a reduced dose. No patients treated with Abraxane/gemcitabine had Grade 4 peripheral neuropathy.

Sepsis with Abraxane/gemcitabine in clinical trials.

Sepsis was reported at a rate of 5% in patients with or without neutropenia who received Abraxane in combination with gemcitabine. Complications due to the underlying pancreatic cancer, especially biliary obstruction or presence of biliary stent, were identified as significant contributing factors. If a patient becomes febrile (regardless of neutrophil count), initiate treatment with broad spectrum antibiotics. For febrile neutropenia, withhold Abraxane and gemcitabine until fever resolves and ANC ≥ 1.5 x 109/L, then resume treatment at reduced dose levels (see Section 4.2 Dose and Method of Administration).

Pneumonitis with Abraxane/gemcitabine in clinical trials.

Pneumonitis has been reported at a rate of 4% with the use of Abraxane in combination with gemcitabine. Of the 17 pneumonitis ADRs in the Abraxane/gemcitabine arm, 2 had a fatal outcome. Monitor patients closely for signs and symptoms of pneumonitis. After ruling out infectious aetiology and upon making a diagnosis of pneumonitis, permanently discontinue treatment with Abraxane and gemcitabine and promptly initiate appropriate treatment and supportive measures.

Use in patients ≥ 65 years old.

Of the 421 patients in the randomised study who received Abraxane and gemcitabine, 41% were 65 years or older and 10% were 75 years or older. Diarrhoea, decreased appetite, dehydration and epistaxis were more frequent in patients 65 years or older compared with patients younger than 65 years old. In patients 75 years and older who received Abraxane and gemcitabine, there was a higher incidence of serious adverse reactions and adverse reactions that led to treatment discontinuation. Carefully assess patients 75 years and older for their ability to tolerate Abraxane in combination with gemcitabine. Give special consideration to performance status, co-morbidities and increased risk of infections.

Post-marketing experience.

See Table 13.

Cystoid macular oedema.

There have been rare reports (< 1/1000 patients) of reduced visual acuity due to cystoid macular oedema (CME) during treatment with Abraxane as well as with other taxanes. CME can be expected to resolve after cessation of treatment.

4.9 Overdose

There is no known antidote for Abraxane overdosage. The primary anticipated complications of overdosage would consist of bone marrow suppression, sensory neurotoxicity and 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.

Paclitaxel, the active pharmaceutical ingredient in Abraxane, is an antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers and stabilises microtubules by preventing depolymerisation. This stability results in the inhibition of the normal dynamic reorganisation of the microtubule network that is essential for vital interphase and mitotic cellular functions. Paclitaxel induces abnormal arrays or "bundles" of microtubules throughout the cell cycle and multiple asters of microtubules during mitosis.

Clinical trials.

Metastatic breast carcinoma.

In a multi-centre trial, patients with metastatic breast cancer were randomised to receive paclitaxel every 3 weeks, either in a solvent-based form at 175 mg/m2 in a 3-hour intravenous infusion (n=227) or as Abraxane 260 mg/m2 in a 30-minute intravenous infusion (n=233). Premedication was given with solvent-based paclitaxel to prevent hypersensitivity. The treatments were not blinded. Two patients randomised to solvent-based paclitaxel and four to Abraxane did not receive any treatment.
Sixty-four percent of patients had impaired performance status (ECOG 1 or 2) at study entry; 79% had visceral metastases; and 76% had > 3 sites of metastases. Fourteen percent of the patients had not received prior chemotherapy; 27% had received chemotherapy in the adjuvant setting only, 40% in the metastatic setting only, and 19% in both metastatic and adjuvant settings. Fifty-nine percent received study medicine as second or greater than second-line therapy. Seventy-seven percent of the patients had been previously exposed to anthracyclines.
Table 14 shows the results of the intent-to-treat analysis.

Non-small cell lung cancer.

Randomised comparative study.

A multicentre, randomised, open-label study was conducted in 1052 chemonaive patients with Stage IIIb/IV non-small cell lung cancer to compare Abraxane in combination with carboplatin versus solvent-based paclitaxel in combination with carboplatin as first-line treatment in patients with advanced non-small cell lung cancer. Patients with evidence of active brain metastases, including leptomeningeal involvement, were excluded from the study. Abraxane was administered to patients (N=521) as an intravenous infusion over 30 minutes at a dose of 100 mg/m2 on Days 1, 8, and 15 of each 21-day cycle without any steroid premedication and without granulocyte colony stimulating factor prophylaxis. Beginning immediately after the end of Abraxane administration, carboplatin at a dose of AUC = 6 mg.min/mL was administered intravenously on Day 1 only of each 21-day cycle. Solvent-based paclitaxel was administered to patients (N=531) at a dose of 200 mg/m2 as an intravenous infusion over 3 hours with standard premedication, immediately followed by carboplatin administered intravenously at AUC = 6 mg.min/mL, each medicine was administered on Day 1 of each 21-day cycle. The differences in paclitaxel dose and schedule between the two arms may independently influence the study results and limit direct comparison of dose and schedule-dependent clinical outcomes and adverse reactions. Treatment was administered until disease progression or development of an unacceptable toxicity.
Patient demographics of the intent-to-treat population are shown in Table 15. The demographics and disease characteristics were well balanced.
Patients received a median of 6 cycles of treatment in both study arms. For the treated population, the median cumulative paclitaxel dose and the median average paclitaxel dose intensity were higher with Abraxane administered weekly (1325.0 mg/m2 and 81.9 mg/m2/week, respectively) relative to solvent-based paclitaxel administered every 3 weeks (1125.0 mg/m2 and 65.1 mg/m2/week, respectively). The median cumulative carboplatin dose and the median average carboplatin dose intensity were lower for the Abraxane and carboplatin regimen (3140.5 mg and 166.1 mg/week, respectively) relative to the solvent based paclitaxel and carboplatin regimen (3315.0 mg and 203.6 mg/week, respectively).
The primary efficacy endpoint was overall response rate defined as the percentage of patients who achieved an objective confirmed complete response or partial response based on an independent, central, blinded radiological review using RECIST guidelines (Version 1.0). Results for overall response rate, progression-free survival, and overall survival are shown in Table 16.
The effect of prognostic factors on the primary efficacy endpoint of overall response rate was pre-specified. Two prognostic factors showed a significant interaction (defined as p ≤ 0.10) with treatment effect on overall response rate: (1) time interval from primary diagnosis to randomisation and (2) histology (see Table 17). There was no interaction between the variable and the treatment effect as measured by overall response rate for the following baseline factors: region, gender, race, age, smoking status, baseline ECOG status, stage at primary diagnosis, time from date of first documented metastasis/relapse to date of study entry, stage at current diagnosis, and number of lesions.

Metastatic adenocarcinoma of the pancreas.

Randomised comparative study.

A multicentre, multinational, randomised, open label study was conducted in 861 patients to compare Abraxane/gemcitabine versus gemcitabine monotherapy as first-line treatment in patients with metastatic adenocarcinoma of the pancreas. Abraxane was administered to patients (N=431) as an intravenous infusion over 30 minutes at a dose of 125 mg/m2 followed by gemcitabine as an intravenous infusion over 30 minutes at a dose of 1000 mg/m2 given on Days 1, 8 and 15 of each 28-day cycle. In the comparator treatment group, gemcitabine monotherapy was administered to patients (N=430) as 1000 mg/m2 given weekly for 7 weeks followed by a 1-week rest period in Cycle 1 and in Cycle 2 and onwards was administered on Days 1, 8 and 15 of a 28-day cycle (consistent with the label recommended dose and regimen). Treatment was administered until disease progression or development of an unacceptable toxicity.
Patient demographics and disease characteristics of the intent-to-treat population were well balanced between the two treatment groups.
In the intent-to-treat (all-randomised) population, the median age was 63 years, 58% were men, 93% were White, 44% were Karnofsky Performance Status (KPS) 90 and 32% were KPS 80, 46% had baseline CA 19-9 value ≥ 59 x ULN, 43% had primary tumour located in pancreas head, 84% had liver metastases and 39% had lung metastases.
Patients received a median treatment duration of 3.9 months in the Abraxane/gemcitabine group and 2.8 months in the gemcitabine group. Nearly one-third (32%) of patients in the Abraxane/gemcitabine group compared with 15% of patients in the gemcitabine group received 6 or more months of treatment.
For the treated population, the median relative protocol dose intensity for gemcitabine was 75% in the Abraxane/gemcitabine group and 85% in the gemcitabine group. The median relative dose intensity of Abraxane was 81%. A higher median cumulative dose of gemcitabine was delivered in the Abraxane/gemcitabine group (11400 mg/m2) when compared with the gemcitabine group (9000 mg/m2).
The primary efficacy endpoint was overall survival (OS). The key secondary endpoints were progression-free survival (PFS) and overall response rate (ORR), both assessed by independent, central, radiological review, blinded to the treatment allocation, using RECIST guidelines (Version 1.0).
Results for overall survival, progression free survival, and overall response rate are shown in Table 18.
There was a statistically significant improvement in OS for patients treated with Abraxane/gemcitabine versus gemcitabine alone, with 1.8 months increase in median OS, 28% overall reduction in risk of death, 59% improvement in 1-year survival, and 125% improvement in 2-year survival rates.
OS, PFS and ORR results were also consistent across the prespecified subgroups.
Of the 431 patients in the randomised study who received Abraxane and gemcitabine, 41% were 65 years or older and 10% were 75 years or older. The Kaplan-Meier curve for Overall Survival by treatment group is presented in Figure 1.
There was a statistically significant improvement in PFS for patients treated with Abraxane/gemcitabine versus gemcitabine alone, with 1.8 months increase in median PFS, 31% overall reduction in risk of progression or death, 76% improvement in 6 month risk of progression or death, and 78% improvement in 12-month risk of progression or death.
The Kaplan-Meier curve for Progression-free Survival by Independent Radiological Review is presented in Figure 2. Also see Table 19.

5.2 Pharmacokinetic Properties

Absorption.

Following intravenous administration of Abraxane, paclitaxel plasma concentrations declined in a biphasic manner, the initial rapid decline representing distribution to the peripheral compartment and the slower second phase representing medicine elimination. The medicine exposure (AUC) was dose proportional over 80 to 300 mg/m2 and the pharmacokinetics of paclitaxel for Abraxane were independent of the duration of intravenous administration.

Distribution.

Following Abraxane administration to patients with solid tumours, paclitaxel is evenly distributed into blood cells and plasma and is highly bound to plasma proteins (94%). In a within-patient comparison study, the fraction of unbound paclitaxel in plasma was significantly higher with Abraxane (6.2%) than with solvent-based paclitaxel (2.3%). This contributes to significantly higher exposure to unbound paclitaxel with Abraxane compared with solvent-based paclitaxel, when the total exposure is comparable.
In vitro studies of binding to human serum proteins, using paclitaxel concentrations ranging from 0.1 to 50 microgram/mL, indicate that the presence of cimetidine, ranitidine, dexamethasone, or diphenhydramine did not affect protein binding of paclitaxel.
Based on population pharmacokinetic analysis, the total volume of distribution is approximately 1741 L; the large volume of distribution indicates extensive extravascular distribution and/or tissue binding of paclitaxel.

Metabolism and excretion.

At the clinical dose range of 80 to 300 mg/m2, the mean total clearance of paclitaxel ranged from 13 to 30 L/h/m2 and the mean terminal half-life ranged from 13 to 27 hours in patients with metastatic breast cancer, advanced non-small cell lung cancer, or other solid tumours.
After a 30-minute infusion of 260 mg/m2 doses of Abraxane, the mean values for cumulative urinary recovery of unchanged medicine (4%) indicated extensive non-renal clearance. Less than 1% of the total administered dose was excreted in urine as the metabolites 6α-hydroxypaclitaxel and 3'-p-hydroxypaclitaxel. Faecal excretion was approximately 20% of the total dose administered. Hepatic metabolism has been demonstrated in animals. The pharmacokinetics of paclitaxel may also be altered in vivo as a result of interactions with compounds that are substrates, inducers, or inhibitors of CYP2C8 and/or CYP3A4 (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). The effect of renal or hepatic dysfunction on the disposition of Abraxane has not been investigated.

Pharmacokinetics in the elderly.

Population pharmacokinetic analysis for Abraxane included patients with ages ranging from 24 to 85 years old and show that age does not significantly influence the maximum elimination rate and systemic exposure (AUC and Cmax) of paclitaxel.

Pharmacokinetics in renal impairment.

Population pharmacokinetic analysis included patients with normal renal function (n=65), and pre-existing mild (n=61), moderate (n =23) or severe (n=1) renal impairment (according to draft FDA guidance criteria 2010). Mild to moderate renal impairment (creatinine clearance ≥ 30 to < 90 mL/min) has no clinically important effect on the maximum elimination rate and systemic exposure (AUC and Cmax) of paclitaxel.
Pharmacokinetic data are insufficient for patients with severe renal impairment and not available for patients with end stage kidney disease.

Pharmacokinetics in hepatic impairment.

The effect of hepatic impairment on population pharmacokinetics of Abraxane was studied in patients with advanced solid tumours. This analysis included patients with normal hepatic function (n=130), and pre-existing mild (n=8), moderate (n=7) or severe (n=5) hepatic impairment (according to NCI Organ Dysfunction Working Group criteria). The results show that mild hepatic impairment (total bilirubin > 1 to ≤ 1.5 x ULN) has no clinically important effect on pharmacokinetics of paclitaxel. Patients with moderate (total bilirubin > 1.5 to ≤ 3 x ULN) or severe (total bilirubin > 3 to ≤ 5 x ULN) hepatic impairment have a 22% to 26% decrease in the maximum elimination rate of paclitaxel and approximately 20% increase in mean paclitaxel AUC compared with patients with normal hepatic function. Hepatic impairment has no effect on mean paclitaxel Cmax.
In addition, elimination of paclitaxel shows an inverse correlation with total bilirubin and a positive correlation with serum albumin.
Pharmacokinetic/pharmacodynamic modelling indicates that there is no correlation between hepatic function (as indicated by the baseline albumin or total bilirubin level) and neutropenia after adjusting for Abraxane exposure.
Pharmacokinetic data are not available for patients with total bilirubin > 5 x ULN or for patients with metastatic adenocarcinoma of the pancreas.
See Section 4.2 Dose and Method of Administration for dose recommendations.

Other intrinsic factors.

Population pharmacokinetic analyses for Abraxane show that body weight (40 to 143 kg), body surface area (1.3 to 2.4 m2), gender, race (Asian vs White), and type of solid tumours do not have a clinically important effect on the maximum elimination rate and systemic exposure (AUC and Cmax) of paclitaxel.

5.3 Preclinical Safety Data

Genotoxicity.

Paclitaxel has been shown to be clastogenic in vitro (chromosome aberrations in human lymphocytes) and in vivo (micronucleus test in mice). Paclitaxel was not mutagenic in the Ames test or the CHO/HGPRT gene mutation assay.

Carcinogenicity.

The carcinogenic potential of Abraxane has not been studied.

6 Pharmaceutical Particulars

6.1 List of Excipients

Human albumin solution (containing sodium, sodium octanoate and sodium acetyltryptophanate).

6.2 Incompatibilities

This medicine must not be mixed with other medicines except those mentioned, see Section 4.2 Dose and Method of Administration.

6.3 Shelf Life

Unopened vial.

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. Unopened vials of Abraxane are stable until the date indicated on the package when stored between 20°C to 25°C, in the original package. Neither freezing nor refrigeration adversely affects the stability of the product.

Storage conditions after reconstitution.

Stability of reconstituted suspension in the vial.

Reconstituted Abraxane should be used immediately, but may be refrigerated at 2°C to 8°C (36°F to 46°F) for a maximum of 8 hours if necessary. If not used immediately, each vial of reconstituted suspension should be replaced in the original carton to protect it from bright light. Discard any unused portion.

Stability of the reconstituted suspension in the infusion bag.

The suspension for infusion prepared as recommended in an infusion bag should be used immediately. To reduce microbiological hazard, use as soon as practicable after dilution. If storage is necessary, hold at 2 - 8°C for not more than 8 hours.

6.4 Special Precautions for Storage

Store the vials in original cartons below 25°C. Protect from light.
For storage conditions after reconstitution of the medicine, please see Section 6.3 Shelf Life.

6.5 Nature and Contents of Container

Abraxane is supplied as a white to yellow, sterile, lyophilised cake for reconstitution as follows:

100 mg presentation.

50 mL clear Type I glass vial with either a latex free, bromobutyl or chlorobutyl rubber stopper, individually packaged in a carton. Each single use vial contains 100 mg of paclitaxel formulated as albumin-bound nanoparticles.
After reconstitution with 20 mL of 0.9% Sodium Chloride Injection each millilitre (mL) of reconstituted suspension contains 5 mg of paclitaxel.

250 mg presentation.

100 mL clear Type I glass vial with either a latex free, bromobutyl or chlorobutyl rubber stopper, individually packaged in a carton. Each single use vial contains 250 mg of paclitaxel formulated as albumin-bound nanoparticles.
After reconstitution with 50 mL of 0.9% Sodium Chloride Injection each millilitre (mL) of reconstituted suspension contains 5 mg of paclitaxel.
Abraxane is free of solvents.

Pack size.

1 single vial in a carton.
Abraxane 100 mg: AUST R 133500.
Abraxane 250 mg: AUST R 297973.
The 250 mg presentation is not currently marketed in Australia.
The 250 mg presentation is not approved by Medsafe and is therefore not marketed in New Zealand.

6.6 Special Precautions for Disposal

Procedures for proper handling and disposal of anticancer medicines should be considered. Several guidelines on this subject have been published. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

6.7 Physicochemical Properties

Chemical structure.

The empirical formula for paclitaxel is C47H51NO14. The chemical name for paclitaxel is 5β,20-Epoxy-1,2α,4, 7β,10β,13α-hexahydroxytax-11-en-9-one 4,10-diacetate 2-benzoate 13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine. Paclitaxel has the following chemical structure:

CAS number.

The CAS Number for paclitaxel is 33069-62-4.

7 Medicine Schedule (Poisons Standard)

S4 / Prescription Medicine.

Summary Table of Changes