Consumer medicine information

Nab-Paclitaxel Juno

Paclitaxel, nab

BRAND INFORMATION

Brand name

Nab-Paclitaxel Juno

Active ingredient

Paclitaxel, nab

Schedule

SUMMARY CMI

Nab-PACLITAXEL JUNO

Consumer Medicine Information (CMI) summary

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

1. Why am I using Nab-PACLITAXEL JUNO?

Nab-PACLITAXEL JUNO contains the active ingredient paclitaxel. Nab-PACLITAXEL JUNO is used to treat cancer of the breast, non-small cell cancer of the lungs and pancreatic cancer.

For more information, see Section 1. Why am I using Nab-PACLITAXEL JUNO? in the full CMI.

2. What should I know before I use Nab-PACLITAXEL JUNO?

Do not use if you are allergic to paclitaxel or any of the ingredients listed at the end of this leaflet or if you have a very low white blood cell (WBC) count.

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

For more information, see Section 2. What should I know before I use Nab-PACLITAXEL JUNO? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Nab-PACLITAXEL JUNO and affect how it works. A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How is Nab-PACLITAXEL JUNO given?

Your doctor will decide what dose of Nab-PACLITAXEL JUNO you will receive. This depends on your condition and other factors. Nab-PACLITAXEL JUNO may be used alone or in combination with other anticancer agents. More instructions can be found in Section 4. How is Nab-PACLITAXEL JUNO given? in the full CMI.

5. What should I know while using Nab-PACLITAXEL JUNO?

Things you should do	Remind any doctor, dentist or pharmacist you visit that you are using Nab-PACLITAXEL JUNO. Tell your doctor immediately if you are pregnant or plan to become pregnant while taking this medicine. Tell your doctor if you experience any of the side effects listed in the CMI.
Things you should not do	Do not receive Nab-PACLITAXEL JUNO if you have an infection or high temperature, if you have severe liver damage or have a very low white blood cell (WBC) count.
Driving or using machines	Be careful driving or operating machinery until you know how Nab-PACLITAXEL JUNO affects you.
Looking after your medicine	Nab-PACLITAXEL JUNO 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.

For more information, see Section 5. What should I know while using Nab-PACLITAXEL JUNO? in the full CMI.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention. Some of the symptoms of a serious allergic reaction are: 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, yellowing of the skin or eyes.

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

FULL CMI

Nab-PACLITAXEL JUNO Powder for injection (suspension)

Active ingredient(s): Paclitaxel (pak‐li‐TAX‐el)

Consumer Medicine Information (CMI)

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

Where to find information in this leaflet:

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

1. Why am I using Nab-PACLITAXEL JUNO?

Nab-PACLITAXEL JUNO 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.

This medicine is used to treat:

Breast cancer
Lung Cancer
Pancreatic Cancer

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

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.

2. What should I know before I use Nab-PACLITAXEL JUNO?

Warnings

Do not receive Nab-PACLITAXEL JUNO 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.

Check with your doctor if you have or have had:

a very low white blood cell (WBC) count.
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.
severe liver damage. Tell your doctor you have liver disease or damage.
kidney 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)

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

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Like most cytotoxic medicines paclitaxel 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.

Paclitaxel 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 paclitaxel and for at least 12 weeks after you stop using it. Your doctor will discuss this with you.

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

The active ingredient in Nab-PACLITAXEL JUNO passes into breast milk and there is a possibility that your baby may be affected.

Do not breastfeed if you are taking this medicine.

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

3. What if I am taking other medicines?

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

Some medicines and paclitaxel may interfere with each other. Some medicines may be affected by paclitaxel 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.

4. How is Nab-PACLITAXEL JUNO given?

How and how much will be given

Nab-PACLITAXEL JUNO is usually given as an infusion (drip) into a vein over 30 minutes.

Your doctor will decide what dose of Nab-PACLITAXEL JUNO 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.

Nab-PACLITAXEL JUNO should given alone or in combination with other drugs.

Several courses of Nab-PACLITAXEL JUNO 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 Nab-PACLITAXEL JUNO you receive.

How long will it be given for

Breast Cancer:

Nab-PACLITAXEL JUNO 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:

Nab-PACLITAXEL JUNO 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:

Nab-PACLITAXEL JUNO 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 Nab-PACLITAXEL JUNO has been given.

Your doctor will decide how many of these cycles you will need.

If you use too much Nab-PACLITAXEL JUNO

As Nab-PACLITAXEL JUNO 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 or phone the Poisons Information Centre (by calling 13 11 26), or go to the Emergency Department at your nearest hospital. You should do this even if there are no signs of discomfort or poisoning.

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

5. What should I know while using Nab-PACLITAXEL JUNO?

Things you should do

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

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 Nab-PACLITAXEL JUNO 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 paclitaxel 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 nonbleaching 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.

Driving or using machines

Be careful driving or operating machinery until you know how Nab-PACLITAXEL JUNO affects you.

There is no known reason why you cannot continue driving or using machines between courses of Nab-PACLITAXEL JUNO 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.

Looking after your medicine

Nab-PACLITAXEL JUNO 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.

6. Are there any side effects?

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

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

Less serious side effects

Less serious side effects	What to do
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	Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effects

What to do

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
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

Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

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

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

Reporting side effects

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

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

7. Product details

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

What Nab-PACLITAXEL JUNO contains

Active ingredient (main ingredient)	Paclitaxel
Other ingredients (inactive ingredients)	Human albumin solution (containing sodium octanoate and N-acetyl-DL-tryptophan)

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

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

What Nab-PACLITAXEL JUNO looks like

Nab-PACLITAXEL JUNO is a white to yellow solid powder cake in a clear glass vial.

When it is reconstituted it will be a milky liquid. (AUST R 328527)

Sponsor

Cipla Australia Pty Ltd.,
Level 1/132‐136 Albert road,
South Melbourne Vic 3205
[email protected]
Phone: 1800‐569‐074

Who distributes Nab-PACLITAXEL JUNO

Juno Pharmaceuticals Pty Ltd
15‐17 Chapel Street
Cremorne VIC 3121

This leaflet was prepared in July 2024.

Published by MIMS March 2025

BRAND INFORMATION

Brand name

Nab-Paclitaxel Juno

Active ingredient

Paclitaxel, nab

Schedule

1 Name of Medicine

Nanoparticle albumin-bound paclitaxel.

2 Qualitative and Quantitative Composition

Nab-Paclitaxel Juno powder for suspension for infusion is an albumin nanoparticle form of paclitaxel with a mean particle size of approximately 130 nanometres. Paclitaxel exists in the nanoparticles in a non-crystalline, amorphous state. Each vial of Nab-Paclitaxel Juno 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. Nab-Paclitaxel Juno 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.
The active agent in Nab-Paclitaxel Juno is paclitaxel, a natural product with antitumour activity. Paclitaxel is obtained from Taxus species.

Excipient(s) with known effect.

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

3 Pharmaceutical Form

Nab-Paclitaxel Juno is supplied as a sterile white to yellow lyophilised cake or powder in a 50 mL USP Type I flint glass vial with 20 mm grey bromobutyl rubber stopper and 20 mm aluminium flip off seal.

4 Clinical Particulars

4.1 Therapeutic Indications

Metastatic breast cancer.

Nab-Paclitaxel Juno is indicated for the treatment of metastatic carcinoma of the breast after failure of anthracycline therapy.

Non-small cell lung cancer.

Nab-Paclitaxel Juno, 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.

Nab-Paclitaxel Juno, 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.
Nab-Paclitaxel Juno should be administered under the supervision of a physician experienced in the use of chemotherapeutic agents.
Nab-Paclitaxel Juno is for single use in one patient only. Discard any residue.
No premedication to prevent hypersensitivity reactions is required prior to administration of Nab-Paclitaxel Juno.

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 paclitaxel 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 Nab-Paclitaxel Juno 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 paclitaxel therapy should have dosage reduced to 220 mg/m² for subsequent courses of paclitaxel. For recurrence of severe neutropenia or severe peripheral neuropathy, additional dose reduction should be made to 180 mg/m². Paclitaxel 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 paclitaxel.

Missed dose in metastatic breast cancer.

Nab-Paclitaxel Juno 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 Nab-Paclitaxel Juno 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 paclitaxel administration. Day 1 is the only day of each 21-day cycle when carboplatin is used in combination with paclitaxel.
Dose adjustments during treatment for non-small cell lung cancer.

Haematologic toxicities in non-small cell lung cancer.

Nab-Paclitaxel Juno 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 paclitaxel, 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 Nab-Paclitaxel Juno 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 Nab-Paclitaxel Juno 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.

Nab-Paclitaxel Juno is a cytotoxic anticancer medicine and, as with other potentially toxic paclitaxel compounds, caution should be exercised in handling Nab-Paclitaxel Juno. The use of gloves is recommended. If Nab-Paclitaxel Juno (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 Nab-Paclitaxel Juno 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 Nab-Paclitaxel Juno 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 Nab-Paclitaxel Juno powder for suspension for infusion.

Preparation for intravenous administration.

Nab-Paclitaxel Juno 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 100 mg vial as follows: Inject 20 mL of 0.9% Sodium Chloride Injection.
2. 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.
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.
6. If foaming or clumping occurs, stand solution for at least 15 minutes until foam subsides.
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 Nab-Paclitaxel Juno suspension from the vial(s) into a syringe. Inject the appropriate amount of reconstituted Nab-Paclitaxel Juno 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 Nab-Paclitaxel Juno infusions. The use of medical devices containing silicone oil as a lubricant (i.e. syringes and IV bags) to reconstitute and administer Nab-Paclitaxel Juno may result in the formation of proteinaceous strands.
Visually inspect the reconstituted Nab-Paclitaxel Juno suspension in the IV bag prior to administration. If strands are observed, administer reconstituted Nab-Paclitaxel Juno 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

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

4.4 Special Warnings and Precautions for Use

Nab-Paclitaxel Juno 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. Paclitaxel powder for suspension for infusion is not clinically interchangeable with other paclitaxel formulations. If a decision is made to discontinue Paclitaxel powder for suspension for infusion 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. Paclitaxel 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 paclitaxel. Patients should not be retreated with subsequent cycles of paclitaxel 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 paclitaxel 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 paclitaxel. The occurrence of grade 1 or 2 peripheral neuropathy does not generally require dose modification. When paclitaxel 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 paclitaxel. For combination use of paclitaxel 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 paclitaxel and carboplatin (see Section 4.2 Dose and Method of Administration). For combination use of paclitaxel and gemcitabine, if Grade 3 or higher peripheral neuropathy develops, withhold paclitaxel; continue treatment with gemcitabine at the same dose. Resume paclitaxel 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 paclitaxel 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 paclitaxel 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 paclitaxel was used in combination with gemcitabine and has been reported at a rate of 1% when paclitaxel 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 paclitaxel 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 paclitaxel should not be re-challenged with the medicine.
Cross-hypersensitivity between paclitaxel 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 paclitaxel therapy.

Cardiotoxicity.

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

CNS metastases.

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

Gastrointestinal symptoms.

If patients experience nausea, vomiting and diarrhoea following administration of paclitaxel, 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. Paclitaxel is not recommended in patients that have a total bilirubin > 5 x ULN or AST > 10 x ULN. In addition, paclitaxel 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 paclitaxel, 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 paclitaxel.
A subsequent analysis was conducted in 981 patients receiving paclitaxel 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 paclitaxel 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 paclitaxel 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 paclitaxel 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 paclitaxel in combination with gemcitabine. Give special consideration to performance status, co-morbidities and increased risk of infections.

Paediatric use.

The safety and effectiveness of paclitaxel 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 paclitaxel and gemcitabine.

4.5 Interactions with Other Medicines and Other Forms of Interactions

A pharmacokinetic study was conducted with paclitaxel and carboplatin in non-small cell lung cancer patients. There were no clinically relevant pharmacokinetic interactions for paclitaxel on the pharmacokinetics of carboplatin and for carboplatin on the pharmacokinetics of paclitaxel when administered as paclitaxel.
Medicine interaction studies between albumin-bound paclitaxel 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 paclitaxel and inhibitors and inducers of either CYP2C8 or CYP3A4 have not been formally investigated. Therefore, caution should be exercised when administering paclitaxel 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 Pharmacokinetics 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 paclitaxel 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 paclitaxel 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 paclitaxel 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, paclitaxel may impair fertility in females and males of reproductive potential.
(Category D)
Do not use this medicine if pregnant or likely to become pregnant.
Paclitaxel 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 paclitaxel 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 paclitaxel. Females of reproductive potential should have a pregnancy test prior to starting treatment with Nab-Paclitaxel Juno.
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 paclitaxel.
Advise females of reproductive potential to use effective contraception during treatment with paclitaxel and for at least 6 months after the last dose.
Like other genotoxic cytostatics, paclitaxel can have genotoxic effects. Male patients treated with paclitaxel 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 paclitaxel therapy.

4.7 Effects on Ability to Drive and Use Machines

Paclitaxel has minor or moderate influence on the ability to drive and use machines. Paclitaxel 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)

Metastatic breast cancer.

See Table 7.

Adverse events in any trial with single agent paclitaxel.

Table 8 lists adverse effects associated with the administration of paclitaxel to patients from studies in which paclitaxel 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 paclitaxel 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 paclitaxel 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 paclitaxel 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.

Pneumonitis^1,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 paclitaxel 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 paclitaxel 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 paclitaxel 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 paclitaxel 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 paclitaxel 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 paclitaxel 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 paclitaxel/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 paclitaxel and gemcitabine or gemcitabine monotherapy. Within each system organ class grouping, adverse reactions are presented in order of decreasing frequency.

Adverse effects reported with paclitaxel/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 paclitaxel/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 paclitaxel/gemcitabine in clinical trials.

For paclitaxel 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 paclitaxel at a reduced dose. No patients treated with paclitaxel/gemcitabine had Grade 4 peripheral neuropathy.

Sepsis with paclitaxel/gemcitabine in clinical trials.

Sepsis was reported at a rate of 5% in patients with or without neutropenia who received paclitaxel 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 paclitaxel 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 paclitaxel/gemcitabine in clinical trials.

Pneumonitis has been reported at a rate of 4% with the use of paclitaxel in combination with gemcitabine. Of the 17 pneumonitis ADRs in the paclitaxel/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 paclitaxel 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 paclitaxel 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 paclitaxel 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 paclitaxel 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 paclitaxel as well as with other taxanes. CME can be expected to resolve after cessation of treatment.

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

There is no known antidote for paclitaxel 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 Nab-Paclitaxel Juno, 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 nanoparticle albumin-bound paclitaxel powder for suspension for infusion 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 nanoparticle albumin-bound paclitaxel powder for suspension for infusion 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 paclitaxel 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. paclitaxel 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 paclitaxel 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 paclitaxel 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 paclitaxel 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 paclitaxel/gemcitabine versus gemcitabine monotherapy as first-line treatment in patients with metastatic adenocarcinoma of the pancreas. Paclitaxel 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 paclitaxel/gemcitabine group and 2.8 months in the gemcitabine group. Nearly one-third (32%) of patients in the paclitaxel/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 paclitaxel/gemcitabine group and 85% in the gemcitabine group. The median relative dose intensity of paclitaxel was 81%. A higher median cumulative dose of gemcitabine was delivered in the paclitaxel/gemcitabine group (11,400 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 paclitaxel/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 paclitaxel 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 paclitaxel/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 paclitaxel powder for suspension for infusion, 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 paclitaxel powder for suspension for infusion were independent of the duration of intravenous administration.

Distribution.

Following paclitaxel 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 nanoparticle albumin-bound paclitaxel powder for suspension for infusion (6.2%) than with solvent-based paclitaxel (2.3%). This contributes to significantly higher exposure to unbound paclitaxel with nanoparticle albumin-bound paclitaxel powder for suspension for infusion 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 paclitaxel, 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'-phydroxypaclitaxel. 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 paclitaxel has not been investigated.

Pharmacokinetics in the elderly.

Population pharmacokinetic analysis for paclitaxel 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 C_max) 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 C_max) 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 paclitaxel 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 C_max.
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 paclitaxel 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 paclitaxel 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 C_max) 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 paclitaxel powder for suspension for infusion has not been studied.

6 Pharmaceutical Particulars

6.1 List of Excipients

Human albumin solution (containing sodium octanoate and N-acetyl-DL-tryptophan).

6.2 Incompatibilities

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

6.3 Shelf Life

Unopened vial.

2 Years.
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 Nab-Paclitaxel Juno 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 Nab-Paclitaxel Juno 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.

6.5 Nature and Contents of Container

Nab-Paclitaxel Juno is supplied as a white to yellow, sterile, lyophilised cake for reconstitution as follows:
100 mg per vial is supplied in a 50 mL clear Type I flint moulded glass vial with 20 mm grey, latex free, bromobutyl rubber stopper and 20 mm aluminium flip off seal, 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.
Nab-Paclitaxel Juno is free of solvents.

Pack size.

1 single vial in a carton.

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-1,7β-dihydroxy-9-oxotax-11-ene-2α, 4, 10β,13α-tetrayl 4,10-diacetate 2-benzoate 13[(2R,3S)-3-(benzoylamino)-2-hydroxy-3- phenylpropanoate]. Paclitaxel has the following chemical structure:

CAS number.

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

7 Medicine Schedule (Poisons Standard)

Prescription only medicine (Schedule 4).

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