Consumer medicine information

Paclitaxel Accord

Paclitaxel

BRAND INFORMATION

Brand name

Paclitaxel Accord

Active ingredient

Paclitaxel

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Paclitaxel Accord.

What is in this leaflet

This leaflet answers some common questions about Paclitaxel Accord. It does not contain all the available information. It does not take the place of talking to your doctor.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking this medicine against the benefits they expect it will have for you.

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

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

What Paclitaxel Accord is used for

Paclitaxel Accord is used to treat cancer of the ovary, the breast, and non small cell cancer of the lung. Paclitaxel Accord may be used alone or in combination with other anticancer agents.

Paclitaxel Accord is not recommended for use in children as its safety and effectiveness in patients under 18 years of age has not been established.

Ask your doctor if you have any questions about why Paclitaxel Accord was prescribed for you.

How Paclitaxel Accord works

Paclitaxel Accord belongs to a class of anticancer agents known as taxanes. These agents prevent the division of cells, particularly cancer cells.

The use of Paclitaxel Accord to treat your cancer can lead to side-effects, which are discussed below.

Before Receiving Paclitaxel Accord

When Paclitaxel Accord must not be given

You have an allergy to:

  • Any medicine containing paclitaxel or other medicines similar to paclitaxel called taxanes
  • Any of the ingredients listed at the end of this leaflet
  • Any medicines containing PEG-35 castor oil such as cyclosporin injection or teniposide injection.

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 count.

Tell your doctor if you have an infection or high temperature. Your doctor may decide to delay your treatment until the infection has 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 are pregnant or plan 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. 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.

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

If you take this medicine after the expiry date has passed, it may not work as well (or it may make you feel sick).

Before you receive Paclitaxel Accord

Before you receive Paclitaxel Accord for the first time you should tell your doctor if:

  • If you are taking any other medicines or treatment
  • If you have ever been anaemic or suffered from other problems with your blood
  • If you have had kidney or liver problems
  • If you have received radiation therapy
  • If you have high or low blood pressure
  • If you have a heart problem
  • 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
  • If you have ever suffered from neuropathy (numbness, tingling and pain in feet or hands)
  • If you have had a previous serious reaction to a similar drug to paclitaxel (called taxanes).

Tell your doctor if you are pregnant or plan to become pregnant or are breast-feeding. Your doctor can discuss with you the risks and benefits involved.

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

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 paclitaxel may interfere with each other. These include:

  • cisplatin and doxorubicin, medicines used to treat cancer
  • erythromycin, trimethoprim and rifampicin, antibiotics used to treat some bacterial infections
  • gemfibrozil, a medicine used to lower high cholesterol levels
  • deferasirox, a medicine used to treat iron overload
  • filgrastim, a medicine used for white blood cell disorders
  • fluoxetine, a medicine used to treat depression
  • carbamazepine, phenytoin and phenobarbital (phenobarbitone), medicines used for epilepsy
  • efavirenz and nevirapine, medicines used to treat HIV (Human Immunodeficiency Virus) infection
  • herbal medicines containing St John's wort.

These 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.

How Paclitaxel Accord is given

How much is given

Your doctor will decide what dose of Paclitaxel Accord 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.

Before you are given Paclitaxel Accord, you must take some other medicines to prevent allergic reactions occurring during your treatment.

You will need to take dexamethasone tablets 12 hours and 6 hours before your treatment, which your doctor will prescribe for you. You will also be given 2 different injections 30 to 60 minutes prior to receiving Paclitaxel Accord. This will minimize the risk of allergic reactions occurring.

Paclitaxel Accord may be given alone or in combination with other drugs.

Several courses of Paclitaxel Accord 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 Paclitaxel Accord you receive.

How it is given

Paclitaxel Accord is usually given as an infusion (drip) into a vein over 3 hours.

How long it will be given for

Paclitaxel Accord is usually given once every three weeks. Each infusion is called one ‘cycle’ of chemotherapy. Your doctor will decide how many of these cycles you will need.

If you are given too much (overdose)

As Paclitaxel Accord 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 a Paclitaxel Accord overdose include the side effects listed below in the ‘Side Effects’ section, but are usually of a more severe nature.

If you experience severe side effects tell your doctor immediately, telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice or go to Accident and Emergency at the nearest hospital. You may need urgent medical attention.

Receiving Paclitaxel Accord

Things you must do

If you are about to be started on any new medicine, tell your doctor and pharmacist that you are receiving Paclitaxel Accord.

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.

Tell all of the doctors, dentists and pharmacists who are treating you that you are receiving treatment with Paclitaxel Accord.

You must tell your doctor immediately if you become pregnant while receiving Paclitaxel Accord treatment.

Keep follow-up appointments with your doctor. It is important to have your follow-up cycles of Paclitaxel Accord 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 Accord 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 nonbleaching 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

Paclitaxel Accord contains absolute ethanol (alcohol). You should not drive, operate machinery, or do anything else that could be dangerous after receiving treatment with Paclitaxel Accord.

You should wear sun protection on your hands and feet after receiving treatment.

Side Effects

Tell your doctor as soon as possible if you do not feel well while you are receiving Paclitaxel Accord.

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

Common side effects
The most common side effects include:

  • Infections, including of the lungs, upper respiratory tract, inner lining of the abdomen, blood and urinary tract
  • flushing and rash
  • itchiness
  • bone marrow suppression (primarily neutropenia)
  • thrombocytopenia (reduced numbers of the white blood cells that are responsible for blood clotting)
  • leucopenia (low numbers of white blood cells)
  • bleeding, blood clots
  • fever
  • anaemia (reduced numbers of red blood cells)
  • hypotension (low blood pressure)
  • disturbances of heart rate and rhythm
  • heart problems which can cause shortness of breath or ankle swelling
  • chest pain
  • increased sweating
  • nausea and vomiting
  • diarrhoea
  • mucositis (inflammation on the lining of the mouth or throat)
  • arthralgia (pain in the joints) and myalgia (muscle pain)
  • peripheral neuropathy (numbness, tingling and pain in feet and hands)
  • abnormal liver blood tests
  • alopecia (hair loss)
  • seizures and convulsions
  • headache
  • visual disturbances
  • hearing loss
  • weight loss
  • nail loss
  • reactions at the injection site including localised swelling, pain, redness, hardening of the skin and skin discolouration.

Tell your doctor immediately, or go to accident and emergency at your nearest hospital if you notice any of the following:

  • swelling to the face, lips, tongue or throat which may cause difficulty in swallowing or breathing
  • severe and sudden onset of pinkish, itchy swellings
  • gastrointestinal bleeding (blood in your stool)
  • blistering of the skin, mouth, eyes and genitals.

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

  • fever
  • chest pain
  • seizures (fits)
  • disturbances of heart rate and rhythm
  • numbness, tingling and pain in feet and hands
  • unexpected bleeding
  • abdominal pain.

The use of Paclitaxel Accord is also associated with a reduction in certain types of blood cells in the body:

  • a reduction in red blood cells, which may result in fatigue or dizziness
  • a reduction in white blood cells, which are used to fight infection
  • a reduction in cells that help your blood to clot after injury.

These are serious side effects. You may need urgent medical attention or hospitalisation.

Other side effects not listed above may also occur in some patients. Tell your doctor if you notice anything else that is making you feel unwell.

Storage

Paclitaxel Accord should be stored below 25°C. Protected from light.

Product Description

What it looks like

Paclitaxel Accord is a clear to slightly yellow solution for injection.

Ingredients

Active Ingredient: paclitaxel

Inactive Ingredients: PEG-35 castor oil and absolute ethanol.

Name and Address of the Sponsor

Accord Healthcare Pty Ltd
Level 24, 570 Bourke Street
Melbourne, VIC, 3000
Australia

Australian Register numbers

30 mg/5 mL: AUST R 219554

100 mg/16.7 mL: AUST R 219555

300 mg/50 mL: AUST R 219556

Date of Preparation

This leaflet was prepared on 11 December 2020.

Published by MIMS February 2021

BRAND INFORMATION

Brand name

Paclitaxel Accord

Active ingredient

Paclitaxel

Schedule

S4

 

1 Name of Medicine

Paclitaxel.

2 Qualitative and Quantitative Composition

1 mL contains 6 mg paclitaxel.
1 vial of 5 mL concentrated injection for infusion contains 30 mg paclitaxel.
1 vial of 16.7 mL concentrated injection for infusion contains 100 mg paclitaxel.
1 vial of 50 mL concentrated injection for infusion contains 300 mg paclitaxel.

Excipients with known effect.

Absolute ethanol (49.5% v/v). For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Paclitaxel Accord Concentrate for Intravenous Infusion is supplied as a nonaqueous solution intended for dilution with 0.9% sodium chloride injection or 5% glucose injection prior to intravenous infusion.

4 Clinical Particulars

4.1 Therapeutic Indications

1. Paclitaxel is indicated for the primary treatment of ovarian cancer in combination with a platinum agent.
2. Paclitaxel is indicated for the treatment of metastatic carcinoma of the ovary after failure of standard therapy.
3. Paclitaxel is indicated for the treatment of metastatic carcinoma of the breast after failure of standard therapy.
4. Paclitaxel is indicated for adjuvant treatment of node-positive breast cancer administered sequentially to doxorubicin and cyclophosphamide.
5. Paclitaxel is indicated for the treatment of metastatic cancer of the breast, in combination with trastuzumab (Herceptin), in patients who have tumours that over-express HER-2 and who have not received previous chemotherapy for their metastatic disease.
6. Paclitaxel, in combination with gemcitabine (Gemzar), is indicated for the treatment of patients with unresectable, locally recurrent or metastatic breast cancer who have relapsed following adjuvant/neoadjuvant chemotherapy. Prior chemotherapy should have included an anthracycline unless clinically contraindicated.
7. Paclitaxel is indicated for the treatment of non-small cell lung cancer (NSCLC).

4.2 Dose and Method of Administration

All patients must be premedicated prior to paclitaxel administration [to prevent severe hypersensitivity reactions]. Such premedication may consist of dexamethasone 20 mg orally (or its equivalent), approximately 12 and 6 hours before paclitaxel, promethazine 25 mg or 50 mg IV (or other suitable H1 - antagonist) 30 to 60 minutes prior to paclitaxel, and cimetidine (300 mg) or ranitidine (50 mg) IV (over 15 minutes) 30 minutes before paclitaxel.
1. The recommended dose of paclitaxel for the primary treatment of ovarian cancer is:
(a) 175 mg/m2 administered over 3 hours, followed by cisplatin 75 mg/m2, with a 3 week interval between courses.
(b) 135 mg/m2 administered intravenously over 24 hours, followed by cisplatin 75 mg/m2, with a 3 week interval between courses.
2. The recommended dose of paclitaxel for the secondary treatment of ovarian or breast cancer is 175 mg/m2 administered intravenously over 3 hours every three weeks. Patients have tolerated treatment with up to 9 cycles of paclitaxel therapy, but the optimal course of therapy remains to be established.
3. Primary or secondary treatment of NSCLC:
The recommended dose of paclitaxel is 175 mg/m2 administered intravenously over 3 hours, with a 3 week interval between courses.
4. Node-positive breast cancer:
Paclitaxel 175 mg/m2 administered intravenously over 3 hours every 3 weeks for 4 courses following doxorubicin and cyclophosphamide combination therapy.
5. Overexpressed HER-2 breast cancer:
Paclitaxel 175 mg/m2 administered intravenously over 3 hours with a 3 week interval between courses for six cycles. Herceptin 2 mg/kg administered intravenously once a week until progression of disease after an initial loading dose of 4 mg/kg body weight. Paclitaxel infusion may be started the day following the first dose of trastuzumab or immediately after the subsequent doses of trastuzumab if the preceding dose of trastuzumab was well tolerated.
6. Metastatic breast cancer:
Paclitaxel 175 mg/m2 administered intravenously over 3 hours on Day 1 followed by gemcitabine 1250 mg/m2 as a 30-minute intravenous infusion on Days 1 and 8 of each 21 day cycle. Dose reduction each cycle or within a cycle may be applied based upon the amount of toxicity experienced by the patient.
Subsequent doses of paclitaxel should be administered according to individual patient tolerance. Repeat courses of paclitaxel should not be administered to patients with solid tumours until the neutrophil count is at least 1.5 x 109 cells/L and the platelet count is at least 100 x 109 cells/L. Patients who experience severe neutropenia (< 0.5 x 109 cells/L for a minimum of 7 days) or severe peripheral neuropathy or severe mucositis should receive a dosage reduced by 20% for subsequent courses. The incidence of neurotoxicity and the severity of neutropenia increase with dose within a regimen.
Patients receiving gemcitabine in combination with paclitaxel for breast cancer should have an absolute granulocyte count of at least 1.5 (x109/L) and a platelet count of ≥ 100 (x109/L) prior to initiation cycle. Table 1 presents appropriate gemcitabine dose adjustments within a cycle for haematologic toxicities.

Hepatic impairment.

Inadequate data are available to recommend dosage alterations in patients with mild, moderate and severe hepatic impairments (see Section 4.4 Special Warnings and Precautions for Use).

Paediatric population.

Paclitaxel is not recommended for use in children below 18 years due to lack of data on safety and efficacy.
Paclitaxel should be administered through an in-line filter with a microporous membrane not greater than 0.22 microns. (See Preparation for intravenous administration and Note below.) The IMED 0.2 micron add on filter set composed of cellulose have both been found to be suitable for Paclitaxel Accord Injection concentrate.

Note.

Contact of the undiluted concentrate with plasticised PVC (polyvinyl chloride) equipment or devices used to prepare solutions for infusion is not recommended. In order to minimise patient exposure to the plasticiser DEHP [di-(2-ethylhexyl) phthalate], which may be leached from PVC infusion bags or sets, diluted paclitaxel solutions should preferably be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and be administered through polyethylene-lined administration sets. See Preparation for intravenous administration. Use of filter devices such as IVEX-2 filters which incorporate short inlet and outlet PVC-coated tubing has not resulted in a significant leaching of DEHP.

Preparation and administration precautions.

Paclitaxel is a cytotoxic anticancer drug and, as with other potentially toxic compounds, caution should be exercised in handling paclitaxel. The use of gloves is recommended. Following topical exposure, tingling, burning and redness have been observed. If paclitaxel solution contacts the skin, wash the skin immediately and thoroughly with soap and water. If paclitaxel contacts mucous membranes, the membranes should be flushed thoroughly with water. Upon inhalation, dyspnoea, chest pain, burning eyes, sore throat and nausea have been reported. Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug administration.

Preparation for intravenous administration.

Paclitaxel must be diluted prior to infusion. Paclitaxel should be diluted in 5% glucose injection or 0.9% sodium chloride injection, to a final concentration of 0.3 to 1.2 mg/mL. Although these solutions for infusion are physically and chemically stable for up to 72 hours at ambient temperature (approximately 25°C), to reduce the microbial hazard it is recommended that the solution for infusion should be administered as soon as practicable after preparation as it does not contain an antimicrobial agent. The infusion should be completed within 24 hours of preparation of the solution and any residue discarded. If not used immediately, diluted solutions should be stored at 2-8°C.
Product is for single use in one patient only. Discard any residue.
Compounding centers which are licensed by the TGA to reconstitute and/or further dilute cytotoxic products, and have validated aseptic procedure and regular monitoring of aseptic technique, may apply a shelf life of 7 days at 2 to 8°C (refrigerate; do not freeze) or at 25°C to paclitaxel solutions which have been reconstituted with glucose 5% for intravenous infusion and stored in glass bottles. For paclitaxel solutions which have been reconstituted with sodium chloride 0.9% for intravenous infusion and stored in glass bottles, a shelf life of 14 days at both 2 to 8°C (refrigerate; do not freeze) and room temperature (25°C) may be applied. Reconstituted solutions prepared this way have been shown to be chemically stable for these periods. Administration should be completed within 24 hours of the start of the infusion and any residue discarded according to the guidelines for the disposal of cytotoxic drugs.
Upon preparation, solutions may show haziness, which is attributed to the formulation vehicle. No significant losses in potency have been noted following simulated delivery of the solution through IV. tubing containing an in-line 0.22 micron filter.
When dilutions of paclitaxel are prepared in PVC containers, extractable plasticiser DEHP [di-(2-ethylhexyl) phthalate] levels increase with time and paclitaxel concentration. Consequently, the use of plasticized PVC containers and administration sets is not recommended. Paclitaxel solutions should be prepared and stored in glass, polypropylene, or polyolefin containers. Non-PVC containing administration sets, such as those which are polyethylene-lined, should be used.
Devices with spikes should not be used with vials of paclitaxel since they can cause the stopper to collapse, resulting in a loss of sterile integrity of the paclitaxel solution.

Stability.

Unopened single dose vials of paclitaxel Injection for dilution are stable until the date indicated on the package when stored in the original package below 25°C. (Freezing does not adversely affect the product.)

4.3 Contraindications

Paclitaxel is contraindicated in patients who have a history of hypersensitivity reactions to paclitaxel or other taxanes.
Paclitaxel must not be used in patients who have a history of hypersensitivity reactions to PEG 35 castor oil or other drugs formulated with PEG-35 castor oil (e.g. cyclosporin for injection concentrate and teniposide for injection concentrate) or any of the other excipients.
Paclitaxel should not be administered to patients who have baseline neutrophil counts of < 1.5 x 109 cells/L.

4.4 Special Warnings and Precautions for Use

General.

Paclitaxel 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.
Paclitaxel should be administered as a diluted infusion. Patients must be pretreated with corticosteroids, antihistamines and H2 antagonists (such as dexamethasone, promethazine and cimetidine or ranitidine) before receiving paclitaxel (see Section 4.2 Dose and Method of Administration). Paclitaxel is administered by intravenous infusion only; it should not be administered by intracerebral, intrapleural or intraperitoneal.
Paclitaxel should be given before a platinum compound when it is given in combination with a platinum compound.

Gastrointestinal (GI) toxicity.

In patients receiving paclitaxel who complain of abdominal pain with other signs and symptoms, bowel perforation should be excluded.

Anaphylaxis and severe hypersensitivity reactions.

Severe hypersensitivity (anaphylactoid reactions characterised by dyspnoea and hypotension requiring treatment, angioedema, and generalised urticaria have occurred rarely in pre-medicated patients receiving paclitaxel.
Rare fatal reactions have occurred in patients despite pre-treatment. 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.
Since significant hypersensitivity reactions may occur, appropriate supportive equipment should be available. Patients receiving paclitaxel should be under continuous observation for at least the first 30 minutes following the start of the infusion and frequently thereafter. In case of a severe hypersensitivity reaction, paclitaxel infusion should be discontinued immediately and appropriate treatment given as indicated for anaphylaxis. The patient should not be rechallenged with the drug. Minor hypersensitivity reactions such as flushing, skin reactions etc do not require interruption of therapy (see Section 4.8 Adverse Effects (Undesirable Effects)).

Haematologic toxicity.

Bone marrow suppression (primarily neutropenia) is the dose-limiting toxicity. Frequent monitoring of blood counts should be instituted during paclitaxel treatment. Paclitaxel should not be administered to patients until the baseline neutrophil count is at least 1.5 x 109 cells/L and the platelet count is at least 100 x 109 cells/L. In the case of severe neutropenia (< 0.5 x 109 cells/L) during a course of paclitaxel, a 20% reduction in dose for subsequent courses of therapy is recommended. (See Section 4.8 Adverse Effects (Undesirable Effects)).

Cardiovascular toxicity.

Hypotension, hypertension and bradycardia have been observed during paclitaxel administration, but generally do not require treatment. Frequent monitoring of vital signs, particularly during the first hour of paclitaxel infusion is recommended. (See Section 4.8 Adverse Effects (Undesirable Effects)).
Electrocardiographic monitoring is recommended for patients with serious conduction abnormalities, and should be commenced for patients who develop abnormal cardiovascular symptoms or signs during monitoring of vital signs.
Severe cardiac conduction abnormalities have been reported rarely during paclitaxel therapy. If patients develop significant conduction abnormalities during paclitaxel administration, appropriate therapy should be administered and continuous electrocardiographic monitoring should be commenced and performed during subsequent therapy with paclitaxel. (See Section 4.8 Adverse Effects (Undesirable Effects)). Severe cardiovascular events were observed more frequently in patients with NSCLC than breast or ovarian cancer.
When paclitaxel is used in combination with trastuzumab or doxorubicin for treatment of metastatic breast cancer, monitoring of cardiac function is recommended. When patients are candidates for treatment with paclitaxel in these combinations, they should undergo baseline cardiac assessment including history, physical examination, ECG, echocardiogram, and/or MUGA scan. Cardiac function should be further monitored during treatment (e.g. every 3 months). Monitoring may help to identify patients who develop cardiac dysfunction and treating physicians should carefully assess the cumulative dose (mg/m2) of anthracycline administered when making decisions regarding frequency of ventricular function assessment. When testing indicates deterioration in cardiac function, even asymptomatic, treating physicians should carefully assess the clinical benefits of further therapy against the potential for producing cardiac damage, including potentially irreversible damage. If further treatment is administered, monitoring of cardiac function should be more frequent (e.g. every 1-2 cycles).

Administration.

Prior to intravenous infusion of paclitaxel, it must be ensured that the indwelling catheter is in the correct position as extravasation, necrosis and/or thrombophlebitis may result with incorrect administration (see Section 4.2 Dose and Method of Administration).
Patients receiving paclitaxel should be under continuous observation for at least the first 30 minutes following the start of the infusion and frequently thereafter. In case of a severe hypersensitivity reaction, paclitaxel infusion should be discontinued immediately and appropriate treatment given as indicated for anaphylaxis. The patient should not be rechallenged with the drug. Minor hypersensitivity reactions such as flushing, skin reactions, etc, do not require interruption of therapy (see Section 4.8 Adverse Effects (Undesirable Effects)).
In some patients, temporary discontinuation of the infusion is sufficient to resolve the symptoms. Other patients may require therapy with bronchodilators, adrenaline, antihistamines and corticosteroids, either alone or in combination.

Nervous system.

Patients with pre-existing neuropathy should be carefully monitored. The occurrence of peripheral neuropathy is frequent and the severity is dose dependent. Patients with pre-existing neuropathy should be carefully monitored. In severe cases, all subsequent doses of paclitaxel should be reduced by 20% (see Section 4.8 Adverse Effects (Undesirable Effects)).
In NSCLC patients, the administration of paclitaxel in combination with cisplatin, resulted in a greater incidence of neurotoxicity than usually seen in patients receiving single agent paclitaxel.
Paclitaxel contains absolute ethanol, 391 mg/mL; consideration should be given to possible CNS and other effects of alcohol.
Children may be more sensitive than adults to the effects of ethanol.

Injection site reaction.

A specific treatment for extravasation reactions is unknown at this time. Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug administration.

Interstitial pneumonia.

Paclitaxel in combination with radiation of the lung, irrespective of their chronological order, may contribute to the development of interstitial pneumonia.

Pseudomembranous colitis.

Pseudomembranous colitis has been reported in patients who have not been concomitantly treated with antibiotics. This reaction should be considered in the differential diagnosis of cases of severe or persistent diarrhoea occurring during or shortly after treatment with paclitaxel.

Mucositis.

Severe mucositis has been reported which requires dose reduction (see Section 4.2 Dose and Method of Administration).

Ophthalmology.

There have been reports of reduced visual acuity due to cystoid macular oedema (CMO) during treatment with paclitaxel as well as with other taxanes (see Section 4.8 Adverse Effects (Undesirable Effects)). Patients with visual impairment during paclitaxel treatment should seek a prompt and complete ophthalmologic examination. Paclitaxel should be discontinued if a CMO diagnosis is confirmed.

Use in hepatic impairment.

There is evidence that the toxicity of paclitaxel is enhanced in patients with elevated liver enzymes. Caution should be exercised when administering paclitaxel to patients with moderate to severe hepatic impairment and dose adjustments should be considered. Patients should be monitored closely for the development of profound myelosuppression.
Patients with hepatic impairment may be at increased risk of toxicity, particularly Grade 3-4 myelosuppression. There is no evidence that the toxicity of paclitaxel is increased when given as a 3-hour infusion to patients with mildly abnormal liver function. When paclitaxel is given as a greater than 3-hour infusion, increased myelosuppression may be seen in patients with moderate to severe hepatic impairment. Inadequate data are available to recommend dosage alterations in patients with mild to moderate hepatic impairments (see Section 5.2 Pharmacokinetic Properties). Patients with severe hepatic impairment must not be treated with paclitaxel.

Use in renal impairment.

The effect of renal impairment on the pharmacokinetics of paclitaxel has not been established.

Use in the elderly.

Of 2228 patients who received paclitaxel in eight clinical studies evaluating its safety and efficacy in the treatment of advanced ovarian cancer, breast carcinoma, or NSCLC, and 1570 patients who were randomized to receive paclitaxel in the adjuvant breast cancer study, 649 patients (17%) were 65 years or older, including 49 patients (1%) 75 years or older. In most studies, severe myelosuppression was more frequent in elderly patients; in some studies, severe neuropathy was more common in elderly patients. In two clinical studies in NSCLC, the elderly patients treated with paclitaxel had a higher incidence of cardiovascular events. Estimates of efficacy appeared similar in elderly patients and in younger patients; however, comparative efficacy cannot be determined with confidence due to the small number of elderly patients studied. In a study of first-line treatment of ovarian cancer, elderly patients had a lower median survival than younger patients, but no other efficacy parameters favoured the younger group.

Paediatric use.

The safety and effectiveness of paclitaxel in paediatric patients has not been established. There have been reports of central nervous system (CNS) toxicity (rarely associated with death) in a clinical trial in paediatric patients in which paclitaxel was infused intravenously over 3 hours at doses ranging from 350 mg/m2 to 420 mg/m2. The toxicity is most likely attributable to the high dose of the ethanol component of the paclitaxel vehicle given over a short infusion time. The use of concomitant antihistamines may intensify this effect. Although a direct effect of the paclitaxel itself cannot be discounted, the high doses used in this study (over twice the recommended adult dosage) must be considered in assessing the safety of paclitaxel for use in this population.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Effect of other drugs on paclitaxel.

Cisplatin.

In a dose-finding trial in which paclitaxel was administered as a 24-hour infusion and cisplatin was administered as a 1 mg/min infusion, myelosuppression was more profound when paclitaxel was given after cisplatin than when paclitaxel was given before cisplatin. Pharmacokinetic data demonstrated a reduction in paclitaxel clearance of approximately 20% when paclitaxel was administered following cisplatin. Patients treated with paclitaxel and cisplatin may have an increased risk of renal failure as compared to cisplatin alone in gynecological cancers.

Substrates, inducers, inhibitors of cytochrome P450 2C8 and 3A4.

The metabolism of paclitaxel is catalysed by cytochrome P450 isoenzymes CYP2C8 and CYP3A4.
Clinical studies have demonstrated that CYP2C8 mediated metabolism of paclitaxel, to 6α-hydroxypaclitaxel, is the major metabolic pathway in humans. Concurrent administration of ketoconazole, a known potent inhibitor of CYP3A4, does not inhibit the elimination of paclitaxel in patients; thus, both medicinal products may be administered together without dosage adjustment. Further data on the potential of drug interactions between paclitaxel and CYP2C8 and 3A4 substrates/inhibitors are limited. Therefore, caution should be exercised when administering paclitaxel concomitantly with medicines known to inhibit (e.g. erythromycin, fluoxetine, gemfibrozil, deferasirox, trimethoprim) or induce (e.g. rifampicin, carbamazepine, phenytoin, phenobarbital, efavirenz, nevirapine, St John's wort) either CYP2C8 or 3A4.
Medications concomitantly administered with paclitaxel (eg: corticosteroids, antihistamines, and H2 antagonists) did not appear to interact adversely.

Effect of paclitaxel on other drugs.

Doxorubicin.

Sequence effects characterised by more profound neutropenic and stomatitis episodes have been observed with combination use of paclitaxel and doxorubicin when paclitaxel was administered before doxorubicin and using longer than recommended infusion times (paclitaxel administered over 24 hours; doxorubicin over 48 hours).
Plasma levels of doxorubicin (and its active metabolite doxorubicinol) may be increased when paclitaxel and doxorubicin are used in combination. Paclitaxel for initial treatment of metastatic breast cancer should be administered 24 hours after doxorubicin (see Section 4.2 Dose and Method of Administration).
However, data from a trial using bolus doxorubicin and 3-hour paclitaxel infusion found no sequence effects on the pattern of toxicity.

Trastuzumab.

In the clinical trial of paclitaxel in combination with trastuzumab (Herceptin), mean serum trough concentration of trastuzumab were consistently elevated 1.5 fold as compared with serum concentrations of trastuzumab in combination with anthracycline plus cyclophosphamide (AC).

Other effects.

Paclitaxel clearance is not affected by cimetidine premedication.
Arthralgia or myalgia adverse events of paclitaxel appear to be of a higher incidence in patients being treated concurrently with filgrastim (granulocyte colony stimulating; G-CSF).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

At a dose of 1 mg/kg (6 mg/m2) paclitaxel produced low fertility and foetal toxicity in rats. Paclitaxel has also been shown to be embryotoxic and foetotoxic in rabbits receiving the drug at an IV dose of 3 mg/kg (33 mg/m2) during organogenesis.

Infertility in females and males.

Based on findings in animal studies, paclitaxel may impair fertility in females and males of reproductive potential. Male patients should seek advice regarding cryoconservation of sperm prior to treatment with paclitaxel because of the possibility of infertility.
(Category D)
Drugs which have caused, are suspected to have caused or may be expected to cause, an increased incidence of human fetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects. Accompanying texts should be consulted for further details.
Paclitaxel may cause foetal harm when administered to a pregnant woman. Paclitaxel has also been shown to be embryotoxic and foetotoxic in rabbits receiving the drug at an IV dose of 3 mg/kg (33 mg/m2) during organogenesis. At a dose of 1 mg/kg (6 mg/m2) paclitaxel produced low fertility and foetotoxicity in rats. No gross external, soft tissue or skeletal alterations occurred.
There are no studies in pregnant women. Women of childbearing potential should have a pregnancy test prior to starting treatment with paclitaxel. These women should be strongly advised to use effective contraception throughout therapy and for at least six months after the last dose of paclitaxel. If paclitaxel is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard.
Females and males of reproductive potential.

Males.

Based on findings in genetic toxicity and animal reproduction studies, males should be advised to use effective contraception in order to avoid fathering a child during treatment and for at least three months after the last dose of paclitaxel.

Females.

Women of childbearing potential should be advised to use effective contraception in order to avoid becoming pregnant during treatment and for at least six months after the last dose of paclitaxel.
 It is not known whether paclitaxel is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, it is recommended that nursing be discontinued when receiving paclitaxel therapy.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration. Patients should refrain from driving or using machines until they know that paclitaxel does not negatively affect these abilities. It should be noted that paclitaxel contains ethanol.

4.8 Adverse Effects (Undesirable Effects)

The following is based on the experience of 812 patients treated in Phase II and III clinical trials. The frequency and severity of adverse effects are generally similar between patients receiving paclitaxel for the treatment of ovarian, breast or lung cancer. None of the observed effects were clearly influenced by age. Unless stated otherwise percent figures, where given, are based on observed incidence when using the recommended dosing regime. If other regimes are used, the incidence of reaction may be higher.
Safety of the paclitaxel/platinum combination has been investigated in a large randomised trial in ovarian cancer and in two Phase III trials in NSCLC. Unless otherwise mentioned the combination of paclitaxel with platinum agents did not result in any clinically relevant changes to the safety profile of single agent paclitaxel.
Adverse effects reported were those occurring during or following the first course of therapy, and have, where possible, been grouped by frequency according to the following criteria.
Very common: ≥ 1/10; common: ≥ 1/100 and < 1/10; uncommon: ≥ 1/1,000 and < 1/100; rare: ≥ 1/10,000 and < 1/1,000; very rare: < 1/10,000.

Infections and infestation.

Very common: Infection.
Uncommon: Septic shock.

Cardiac disorders.

Common: Bradycardia; ECG abnormalities (non-specific re-polarisation and sinus tachycardia).
Uncommon: ECG abnormalities (premature beats), cardiomyopathy.
Rare: Myocardial infarction; congestive heart failure (typically in patients who have received other chemotherapy, notably anthracyclines).
Six severe cardiovascular events possibly related to paclitaxel administration occurred including asymptomatic ventricular tachycardia, tachycardia with bigeminy, atrioventricular block (2 patients), and syncopal episodes (2 patients - in one associated with severe hypotension and coronary stenosis resulting in death). Severe hypotensive reactions have been associated with serious hypersensitivity reactions and have required intervention. Cardiac failure and sinus bradycardia have also been observed.

Haematological disorders.

Very common: Myelosuppression, thrombocytopenia, leucopoenia, fever, bleeding, anaemia; neutropenia (overall, 52% of the patients experienced severe Grade IV neutropenia and 56% had Grade III/IV severe neutropenia on their first course. Neutrophil nadirs occurred at a median of 11 days after paclitaxel administration).
Infectious episodes occurred very commonly and were fatal in 1% of all patients, and included sepsis, pneumonia and peritonitis. Urinary tract infections and upper respiratory tract infections were the most frequently reported infectious complications. The use of supportive therapy, including G-CSF, is recommended for patients who have experienced severe neutropenia.
Common: Febrile neutropenia (associated with an infectious episode, including UTI and URTI). Neutropenia, the most important haematologic toxicity, was dose and schedule dependant and was generally rapidly reversible.
Rare: Five septic episodes, which were associated with severe neutropenia attributable to paclitaxel administration, had a fatal outcome.
Patients who have received prior radiation or cisplatin therapy exhibit more frequent myelosuppression, which is generally of greater severity (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Immune system disorders.

Very common: Minor hypersensitivity reactions (mainly flushing and rash).
Common: Hypersensitivity reactions (dyspnoea; hypotension; chest pains; tachycardia).
Uncommon: Significant hypersensitivity reactions requiring therapy (e.g. hypotension, angioneurotic oedema, bronchospasm, respiratory distress, generalised urticaria, oedema, back pain, pain in extremities, chills, diaphoresis). The most frequent symptoms observed during severe reactions were dyspnoea, flushing, chest pain and tachycardia. Abdominal pain, pain in the extremities, hyperhidrosis and hypertension were also noted.
Rare: Anaphylactic reactions (with fatal outcome).
Very rare: Anaphylactic shock.

Vascular disorders.

Very common: Hypotension.
Uncommon: Hypertension, thrombosis, thrombophlebitis.

Gastrointestinal disorders.

Very common: Nausea; vomiting; diarrhoea; mucositis (these manifestations were usually mild to moderate at the recommended dose).
Rare: Bowel perforation (there have been several cases of bowel perforation associated with patients receiving paclitaxel. Patients receiving paclitaxel, who complain of abdominal pain with other signs and symptoms, should have bowel perforation excluded).
Neutropenic enterocolitis has been reported.

Musculoskeletal, connective tissue and bone disorders.

Very common: Arthralgia; myalgia (the symptoms were usually transient occurring two to three days after paclitaxel administration and resolving within a few days).

Neurological disorders.

Very common: Peripheral neuropathy (peripheral neuropathy occurs and is dose dependent with 60% of patients experiencing Grade I toxicity, 10% Grade II and 2% Grade III at the recommended doses. Neuropathy was present in 87% of patients at higher doses. Severity of symptoms also increased with dose; 4% of patients experienced severe symptoms at the recommended dose versus 10% at higher doses. Neurologic symptoms may occur following the first course and symptoms may worsen with increasing exposure to paclitaxel. Peripheral neuropathy was the cause of paclitaxel discontinuation in 2% of patients. Sensory symptoms have usually improved or resolved within several months of paclitaxel discontinuation).
Rare: Optic nerve and/or visual disturbances (scintillating scotomata) particularly in patients who have received higher doses than recommended; these effects generally have been reversible.
Motor neuropathy with resultant minor distal weakness and autonomic neuropathy resulting in paralytic ileus and orthostatic hypotension.

Hepatobiliary disorders.

Very common: Elevated alkaline phosphatase; elevated AST; elevated ALT.
Common: Elevated bilirubin.
Rare: Hepatic necrosis (leading to death); hepatic encephalopathy (leading to death).

Skin and subcutaneous tissue disorders.

Very common: Alopecia.
Common: Nail and skin changes (mild and transient).
Rare: Radiation-recall dermatitis; recall dermatitis.

General disorders and administration site conditions.

Very common: Mucosal inflammation.
Common: Injection site reactions (including localised oedema, pain, erythema, induration, on occasion extravasation can result in cellulitis).
Injection site reactions, including reactions secondary to extravasation, were usually mild and consisted of erythema, tenderness, skin discolouration, or swelling at the injection site. These reactions have been observed more frequently with the 24-hour infusion than with the 3-hour infusion. Recurrence of skin reactions at a site of previous extravasation following administration of paclitaxel at a different site, i.e. 'recall', has been reported rarely.
Rare reports of more severe events such as phlebitis, cellulitis, induration, skin exfoliation, necrosis and fibrosis have been received as part of the continuing surveillance of paclitaxel safety. In some cases the onset of the injection site reaction either occurred during a prolonged infusion or was delayed by a week to ten days.
A specific treatment for extravasation reactions is unknown at this time. Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug administration.
Radiation pneumonitis has been reported in patients receiving concurrent radiotherapy.

Combination treatment with trastuzumab.

When paclitaxel was administered as a 3-hour infusion in combination with trastuzumab for the first line treatment of patients with metastatic breast cancer, the following events (regardless of relationship to paclitaxel or trastuzumab) were reported more frequently than with single agent paclitaxel: heart failure, infection, chills, fever, cough, rash, arthralgia, tachycardia, diarrhea, hypertonia, epistaxis, acne, herpes simplex, accidental injury, insomnia, rhinitis, sinusitis and injection site reaction. Some of these frequency differences may be due to the increased number and duration of treatments with paclitaxel/trastuzumab combination vs single agent paclitaxel. Severe events were reported at similar rates for paclitaxel/trastuzumab and single agent paclitaxel.
Administration of trastuzumab in combination with paclitaxel in patients previously treated with anthracyclines resulted in an increased frequency and severity of cardiac dysfunction in comparison with patients treated with paclitaxel single agent and rarely has been associated with death. In all but these rare cases, patients responded to appropriate medical treatment.

Post marketing experience.

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

Infections and infestations.

Pneumonia, sepsis.

Cardiac disorders.

Atrial fibrillations, supraventricular tachycardia, reduction of left ventricular ejection fraction, ventricular failure.

Haematological disorders.

Acute myeloid leukaemia, myelodysplastic syndrome.

Immune system disorders.

Anaphylactic reactions (with fatal outcome), anaphylactic shock, cross-hypersensitivity between paclitaxel and other taxanes has been reported.

Metabolism and nutrition disorders.

Anorexia, tumour lysis syndrome.

Psychiatric disorders.

Confusional state.

Vascular disorders.

Shock.

Respiratory, thoracic and mediastinal disorders.

Dyspnoea, pleural effusion, respiratory failure, interstitial pneumonia, lung fibrosis, pulmonary embolism, cough.

Gastrointestinal disorders.

Bowel obstruction, bowel perforation, ischemic colitis, pancreatitis, mesenteric thrombosis, pseudomembranous colitis, oesophagitis, constipation, ascites.

Neurological disorders.

Autonomic neuropathy (resulting in paralytic ileus and orthostatic hypotension), grand mal seizures, convulsions, encephalopathy, dizziness, headache, ataxia, paresthesia, hyperesthesia.

Eye disorders.

Photopsia, visual floaters, cystoid macular oedema, macular oedema.

Ear and labyrinth disorders.

Hearing loss, tinnitus, vertigo, ototoxicity.

Skin and subcutaneous tissue disorders.

Stevens-Johnson syndrome, epidermal necrolysis, erythema multiforme, exfoliative dermatitis, urticaria, onycholysis (patients on therapy should wear sun protection on hands and feet), scleroderma, pruritus, rash, erythema, phlebitis, cellulitis, skin exfoliation, necrosis, fibrosis and palmar-plantar erythrodysesthesia syndrome.

Musculoskeletal, connective tissue and bone disorders.

Systemic lupus erythematosus, scleroderma.

Investigations.

Increase in blood creatine.

General disorders and administration site conditions.

Asthenia, malaise, pyrexia, dehydration, oedema.

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

4.9 Overdose

There is no known antidote for paclitaxel overdosage. At present, there is no specific treatment for paclitaxel overdosage. In case of overdose, the patient should be closely monitored. The primary anticipated complications of overdosage would consist of severe bone marrow suppression, peripheral neurotoxicity and mucositis and treatment should be supportive.
Overdoses in paediatric patients may be associated with acute ethanol toxicity. Treatment is symptomatic and supportive.
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 is a novel antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers. It stabilises microtubules by preventing depolymerisation resulting in the inhibition of the normal dynamic reorganisation of the microtubule network essential for cellular functions. Paclitaxel also induces abnormal arrays or "bundles" of microtubules throughout the cell cycle and multiple asters of microtubules during mitosis. This can result in arrest of cell division and impaired function of nervous tissue.

Clinical trials.

Ovarian carcinoma.

The safety and efficacy of paclitaxel in the first-line treatment of ovarian cancer was investigated in two major, randomised, controlled trials. The first was a prospective, randomised trial in first line ovarian cancer; Protocol (CA 139-022 or GOG-111) compared the use of paclitaxel (135 mg/m2 over 24 hours)/cisplatin (75 mg/m2) to cyclophosphamide/ cisplatin (standard therapy) in 410 patients with suboptimal stage III and stage IV epithelial ovarian carcinoma. Known prognostic factors were similar in the two treatment groups. Among 219 women with measurable disease, 67% in the paclitaxel/cisplatin group responded to therapy, as compared with 55% in the cyclophosphamide/cisplatin group (p=0.074). The frequency of surgically verified complete response was similar in the two groups. Progression-free survival was significantly longer (P=0.0008) in the paclitaxel/cisplatin group than the cyclophosphamide/cisplatin group (median 16.6 vs 13 months). Survival was also significantly longer (P=0.0002) in the paclitaxel/cisplatin group (median 35.5 vs 24.2 months).
The second was a multicentre randomised, controlled trial in which 342 patients received paclitaxel (175 mg/m2 over 3 hours) in combination with cisplatin (75 mg/m2) every 3 weeks and 338 received cyclophosphamide plus cisplatin, demonstrated significantly increased time to progression (15.3 vs 11.5 months) and significantly increased overall survival (35.6 vs. 25.9 months) in favour of the paclitaxel/cisplatin combination.
Although both dosage regimens have not been studied in a direct comparison, they have both been compared to cyclophosphamide/cisplatin regimen and demonstrate comparable efficacy results.
Although the 175 mg/m2/3 hr regimen may be associated with greater neurotoxicity compared to the 135 mg/m2/24 hr regimen, this is offset by reduced haematological toxicity.

Non-small cell lung carcinoma.

Four open label phase 2 studies were conducted in 224 patients with advanced NSCLC and no prior chemotherapy; 131 received paclitaxel and 93 received investigational agents in a randomised Phase 2 trial. In the earliest two trials (CA139-027 and CA139-029), paclitaxel was administered as a 24-hour infusion at initial doses of 200 mg/m2 and 250 mg/m2 respectively. The response rates in both trials were 19% and 17% respectively, with one-year survival of 33% and 40% respectively. The median survival was 8.1 months (95% CI 4.8-13.0 months) and 4.4 months (95% CI 3.0-16.2 months). In the later two trials (CA139-127 and CA139-201), paclitaxel was administered as a 3-hour infusion at initial doses of 200 mg/m2 and 225 mg/m2, respectively. The response rates were 20% and 19%, with one-year survival of 43% and 35%, respectively. The median survival was 11.7 months (95% CI 7.3-16.8 months) and 9.0 months (95% CI 5.9-11.4 months), respectively. The response rates were similar to those for other single agent therapies.
Two prospective multicentre trials were conducted in patients with advanced NSCLC and no prior chemotherapy. Five hundred and sixty-five patients were randomised to receive paclitaxel followed by cisplatin in these studies. The majority of patients had stage IV NSCLC and approximately two thirds had an impaired performance status (ECOG PS 1 or 2). In a study conducted by the European Organization for Research and Treatment of Cancer (EORTC), patients were randomised to either paclitaxel (T) 175 mg/m2 as a 3-hour infusion followed by cisplatin (c) 80 mg/m2 or cisplatin (c) 80 mg/m2 on day 1 followed by teniposide (VM) 100 mg/m2 on day 1, 3 and 5 (control). In a study conducted by the Eastern Cooperative Oncology Group (ECOG), patients were randomised to either paclitaxel (T) 135 mg/m2 as a 24-hour infusion followed by cisplatin (c) 75 mg/m2, paclitaxel (T) 250 mg/m2 as a 24-hour infusion followed by cisplatin (c) 75 mg/m2 with G-CSF support, or cisplatin (c) 75 mg/m2 on day 1, followed by etoposide (VP) 100 mg/m2 on days 1, 2 and 3 (control). Response rates, median time to progression, median survival and one-year survival rates for the two studies and respective treatment arms are given in Table 2. The paclitaxel combinations showed improvement in response rates (> 20%) and median time to progression (> 4 months), but no significant increase in survival.

Breast carcinoma.

A randomised Phase 3 intergroup multicenter, 3 x 2 factorial study of the adjuvant use of paclitaxel was conducted in 3170 women with histologically positive lymph nodes following either a mastectomy or segmental mastectomy and nodal dissections. The 3 x 2 factorial study was designed to assess the efficacy and safety of three different dose levels of doxorubicin and to evaluate the effect of the addition of paclitaxel administered following the completion of doxorubicin and cyclophosphamide (AC) therapy. Patients were randomised, after stratification for the number of positive lymph nodes, to receive cyclophosphamide at a dose of 600 mg/m2 and doxorubicin at doses of either 60 mg/m2 (on day 1), 75 mg/m2 (in two divided doses on days 1 and 2), or 90 mg/m2 (in two divided doses on days 1 and 2 with prophylactic G-CSF support and ciprofloxacin) every 3 weeks for four courses and either paclitaxel 175 mg/m2 as a 3-hour infusion every 3 weeks for four additional courses or no additional chemotherapy. Patients whose tumours were positive or of unknown hormone receptor status were to receive subsequent tamoxifen treatment (20 mg daily for 5 years); patients who received segmental mastectomies prior to study were to receive breast irradiation after recovery from treatment-related toxicities.
The primary analyses of disease-free survival and overall survival used multivariate Cox models which included paclitaxel administration, doxorubicin dose, number of positive lymph nodes, tumour size, menopausal status, and oestrogen receptor status as factors. Based on the model for disease free survival, patients receiving AC followed by paclitaxel had a 22% reduction in the risk of disease recurrence compared to patients randomised to AC alone (Hazard Ratio=0.78 with 95% CI: 0.67-0.91, p=0.0022). They also had a 26% reduction in the risk of death (Hazard Ratio=0.74 with 95% CI: 0.60-0.92, p=0.0065). The absolute increases in disease-free survival and overall survival were 4% and 2% respectively. Doxorubicin dose had no effect on either disease-free survival or overall survival. The overall median follow-up was 30.1 months.
Subset analysis revealed that adjunctive treatment with paclitaxel is most beneficial in patients with hormone receptor-negative disease (see Table 3).
The safety and efficacy of paclitaxel were studied in a randomised controlled multinational study of chemotherapy alone and in combination with Herceptin (trastuzumab). Patients with previously untreated metastatic breast cancer were treated with an anthracycline (doxorubicin 60 mg/m2 or epirubicin 75 mg/m2) plus cyclophosphamide (600 mg/m2) with (H+AC) or without (AC alone) Herceptin or paclitaxel (175 mg/m2 infused over three hours every three weeks) with (H+P) or without (P alone) Herceptin. Patients were treated with paclitaxel for six cycles, and could be treated with Herceptin until progression of disease. Patients who had previously received anthracycline based adjuvant therapy were treated with paclitaxel whereas those who were anthracycline naive were treated with an anthracycline plus cyclophosphamide. Patients in the Herceptin treatment groups received a 4 mg/kg intravenous loading dose of Herceptin on day 0. From day 7, patients received weekly infusions of Herceptin 2 mg/kg, which they could continue to receive until evidence of disease progression. Patients in both treatment groups were eligible to receive Herceptin in an open label study following disease progression.
The prospectively defined primary intent to treat analysis indicated that the combination of chemotherapy and Herceptin significantly prolonged the time to disease progression (progression free survival) compared with chemotherapy alone as first line treatment of women with metastatic breast cancer who had tumours that over-expressed HER-2. The addition of Herceptin to chemotherapy extended the median time to disease progression by 2.8 months representing a 61% increase (p=0.0001).
Both AC treated and paclitaxel treated patients benefited from Herceptin treatment, although the effect appeared to be greater in the paclitaxel stratum. See Table 4.
One year survival rates (the prospectively defined survival endpoint) were significantly better for chemotherapy + Herceptin versus chemotherapy arms (79 versus 68%; p=0.008). With a median follow-up of approximately two years, overall survival is improved for patients initially treated with chemotherapy and Herceptin compared with those receiving chemotherapy alone (25.4 versus 20.3 months; p=0.025) with a relative risk of death of 0.769 (95% CI 0.607 to 0.973; p=0.028).
The relative overall survival advantage with the addition of Herceptin was observed in both subgroups: AC (26.8 months (H=AC) versus 22.8 months (AC alone); p=0.052) and paclitaxel (22.1 months (H+P) versus 18.4 months (P alone); p=0.273). The analysis of overall survival was, however, greatly confounded by subsequent Herceptin treatment of each of the control arms' patients, following disease progression, in the open label extension study, H0659 g (59% of patients in the AC alone group, and 75% of patients in the paclitaxel alone group subsequently received Herceptin). Hence, the survival advantage seen above, for chemotherapy + Herceptin treatment versus chemotherapy alone (which includes patients who subsequently received Herceptin) may underestimate the benefit to patients.
Importantly, the efficacy described above was obtained without a significant negative impact on the quality of life. Global quality of life decreased equally in both the chemotherapy alone group and the chemotherapy + Herceptin group and was most likely related to the effects of cytotoxic chemotherapy. However, at weeks 20 and 32, the global quality of life score had returned to baseline or better than baseline in the group receiving chemotherapy plus Herceptin, while it remained low in the chemotherapy only arm.
The safety and efficacy of paclitaxel were studied in a randomised controlled multinational study of chemotherapy alone and in combination with Gemzar (gemcitabine).
A total of 529 patients with unresectable, recurrent or metastatic breast cancer were randomised to receive gemcitabine plus paclitaxel (GT) combination therapy (n=267) or paclitaxel (T) monotherapy (n=262). In the GT arm gemcitabine (1250 mg/m2) was administered intravenously over 30 to 60 minutes on Days 1 and 8 of 21-day cycle and paclitaxel (175 mg/m2) was administered intravenously over 3 hours before gemcitabine on Day 1 of a 21-day cycle. In the T arm paclitaxel (175 mg/m2) was administered intravenously over 3 hours on Day 1 of a 21-Day cycle. Patients were included in the trial if they had relapsed after receiving either one anthracycline-based chemotherapy in the adjuvant/neoadjuvant setting or a non-anthracycline based regimen in the adjuvant/neoadjuvant setting if use of an anthracycline was clinically contraindicated.
The primary endpoint of the planned interim analysis was time to documented progression of disease (TtDPD). Patients who died without evidence of disease progression were excluded from this analysis. Estimates of median TtDPD were 5.4 months (95% CI, 4.6 to 6.1 months) on the GT therapy arm and 3.5 months (95% CI, 2.9 to 4.0 months) on the T arm using the earlier of the dates of disease progression, derived from either the investigator's or the independent reviewers' assessment. The difference between the two treatment arms was statistically significant (p=0.0013). GT also significantly improved progression-free survival by a similar amount. This endpoint accounts for not only patients with documented disease progression but also patients who die without evidence of progression.
The overall response rates, according to the investigator assessment were 39.3% (95% CI, 33.5% to 45.2%) on the GT arm and 25.6% (95% CI, 20.3% to 30.9%) on the T arm, which was statistically significant (p=0.0007).
There were no significant treatment differences in the patient-assessed quality-of-life measures, Brief Pain Inventory and Rotterdam Symptom Checklist.

5.2 Pharmacokinetic Properties

Absorption.

The pharmacokinetics of paclitaxel have been evaluated over a wide range of doses, up to 300 mg/m2, and infusion schedules, ranging from 3 to 24 hours.
Following intravenous administration, paclitaxel exhibits a biphasic decline in plasma concentrations. The initial rapid decline represents distribution to the peripheral compartment and elimination; the later phase is due, in part, to a relatively slow efflux of paclitaxel from the peripheral compartment. Maximum plasma concentrations are related to dose. In patients treated with doses of 135 and 175 mg/m2 given as 3 and 24 hour infusions, mean terminal half-life has ranged from 3.0 to 52.7 hours, and total body clearance has ranged from 11.6 to 24.0 L/h/m2.

Distribution.

Mean steady state volume of distribution following single dose infusion of 135 and 175 mg/m2 has ranged from 198 to 688 L/m2, indicating extensive extravascular distribution and/or tissue binding. The volume of distribution is reduced in female subjects. Following 3 hour infusions of 175 mg/m2, mean terminal half-life was estimated to be 9.9 hours; mean total body clearance was 12.4 L/h/m2.
Variability in systemic paclitaxel exposure, as measured by AUC (0-4) for successive treatment courses was minimal; there was no evidence of accumulation of paclitaxel with multiple treatment courses.
Some studies indicate that the pharmacokinetics of paclitaxel may be non-linear. There is evidence of a disproportionately large increase in Cmax and AUC with increasing dose, and total body clearance appears to decrease with higher plasma concentrations of paclitaxel. These findings were most readily observed in patients in whom high plasma concentrations of paclitaxel were achieved. Saturable processes in elimination/metabolism may account for these findings.
On average, 89% of drug is bound to serum proteins; the presence of cimetidine, ranitidine, dexamethasone, or diphenhydramine does not affect protein binding of paclitaxel. Premedication with this combination of drugs reduces the total body clearance from 14.2 L/hr/m2 to 8.6 L/hr/m2.

Metabolism.

Preliminary animal/ ex vivo data indicate that ketoconazole may inhibit the metabolism of paclitaxel. Likewise, preliminary reports suggest that plasma levels of doxorubicin (and its active metabolite doxorubicinol) may be increased when paclitaxel and doxorubicin are used in combination. The mechanism for this interaction is unknown. The pharmacodynamic consequences of this interaction are unclear. (See Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.)
Hepatic metabolism has been demonstrated in animals. Hydroxylated metabolites isolated in bile have been demonstrated to be the principal metabolites. Hepatic metabolism and biliary clearance may be the principal mechanism for disposition of paclitaxel. The effect of renal or hepatic dysfunction on the disposition of paclitaxel has not been investigated.

Excretion.

The disposition of paclitaxel has not been fully elucidated in humans. Mean values for cumulative urinary recovery of unchanged drug have ranged from 1.8 to 12.6% of the dose, indicating extensive non-renal clearance.

5.3 Preclinical Safety Data

Genotoxicity.

Paclitaxel has been shown to be mutagenic in vitro (chromosome aberrations in human lymphocytes) and in vivo (micronucleus test in mice). It did not induce mutagenicity in the Ames test or mammalian cells.

Carcinogenicity.

The carcinogenic potential of paclitaxel has not been studied, however, drugs similar to paclitaxel are carcinogens.

6 Pharmaceutical Particulars

6.1 List of Excipients

PEG-35 castor oil, absolute ethanol.

6.2 Incompatibilities

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

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Store below 25°C. Protect from light.

6.5 Nature and Contents of Container

Paclitaxel Accord is available in single dose glass vials in cartons of 1 vial containing paclitaxel 30 mg/5 mL, 100 mg/16.7 mL and 300 mg/50 mL.

6.6 Special Precautions for Disposal

Handling and disposal.

Procedures for proper handling and disposal of anticancer drugs 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.
Care must be taken whenever handling cytostatic products. Always take steps to prevent exposure. This includes appropriate equipment, such as, wearing gloves, and washing hands with soap and water after handling such products.

6.7 Physicochemical Properties

Paclitaxel is a white to off-white crystalline powder that is highly lipophilic and insoluble in water.
Paclitaxel injection contains paclitaxel, a natural product with antitumour activity. Paclitaxel is the first of a new class of anticancer agents known as taxanes.

Chemical structure.

Paclitaxel has the following structural formula:
Molecular Formula: C47H51NO14.
Molecular Weight: 853.929.

CAS number.

33069-62-4.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes