Consumer medicine information

Paclitaxel Ebewe

Paclitaxel

BRAND INFORMATION

Brand name

Paclitaxel Ebewe

Active ingredient

Paclitaxel

Schedule

What is in this leaflet

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

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

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

Your doctor or pharmacist can provide you with more information about Paclitaxel Ebewe.

Keep this leaflet with the medicine. You may need to read it again.

What Paclitaxel Ebewe is used for

This medicine is used to treat:

Ovarian cancer
Breast cancer
Non-small cell lung cancer (NSCLC).

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

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

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

This medicine is not addictive.

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

Before you are given Paclitaxel Ebewe

When you must not be given it

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

any medicine containing paclitaxel
any of the ingredients listed at the end of this leaflet
any medicines containing PEG-35 castor oil such as ciclosporin 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 (WBC) count.

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

You must not be given this medicine if you are pregnant or plan to become pregnant. Like most cytotoxic medicines Paclitaxel Ebewe 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.

Male patients should seek advice regarding storage of sperm prior to treatment with paclitaxel due to the possibility of infertility.

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

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

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

The safety and effectiveness of Paclitaxel Ebewe in children has not been established.

Before you are given it

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

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

kidney disease
liver disease
heart problems
any blood disorder with a reduced number of red blood cells, white 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 ciclosporin, or other medicines used to treat cancer (including radiation therapy)
had a previous serious reaction to a similar drug to paclitaxel (called taxanes).

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

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 Ebewe may interfere with each other. These include:

cisplatin, doxorubicin or trastuzumab (Herceptin), or other medicines used to treat cancer
ketoconazole, a medicine used to treat fungal infections
erythromycin, trimethoprim and rifampicin, antibiotics used to treat some bacterial infections
gemfibrozol, 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 Ebewe 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 Ebewe is given

How much is given

Your doctor will decide what dose of Paclitaxel Ebewe 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 Ebewe, 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 Ebewe. This will minimize the risk of allergic reactions occurring.

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

Several courses of Paclitaxel Ebewe 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 Ebewe you receive.

How it is given

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

How long it will be given for

Paclitaxel Ebewe 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 take too much (overdose)

As Paclitaxel Ebewe 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 Ebewe 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 in Australia) for advice, or go to Accident and Emergency at your nearest hospital.

While you are being given Paclitaxel Ebewe

Things you must do

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

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

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

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

Things to be careful of

Be careful driving or operating machinery until you know how Paclitaxel Ebewe affects you. This medicine may cause dizziness or light-headedness in some people. If you have these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

Side effects

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

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

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

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

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

muscle or joint pain on the arms and legs
nausea and vomiting
coughing
easily tiring during physical activity
hair loss
indigestion, heartburn, diarrhoea or constipation
changes in skin or nail appearance
soreness or ulceration of the mouth.
irritation and inflammation of the mouth, throat, nose or vagina.

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

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

pain, swelling, irritation and redness at the injection site
flushing
light-headedness or dizziness (due to low blood pressure)
headaches, confusion and memory problems
stinging pain, numbness or tingling in the fingers, toes and/or skin
redness, tightness, cracking, flaking or peeling of the skin
thick calluses and blisters on the palms of your hands and soles of your feet
difficulty walking or using your hands
changes in vision
abdominal pain
weight loss.

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

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

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
extreme weakness or tiredness
seizures (fits), fainting
fast, slow or irregular heart beat
chest pain
palpitations
yellowing of the skin or eyes
unusual bleeding or bruising (including blood in your stools or urine)
fever, sore throat or other signs of infection.

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

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

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

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

After being given Paclitaxel Ebewe

Storage

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

Product description

What it looks like

Paclitaxel Ebewe is a clear to pale yellow solution, in a glass vial.

Ingredients

Active ingredient:

Each vial of Paclitaxel Ebewe 30 mg/5 mL contains 30 mg of paclitaxel.

Each vial of Paclitaxel Ebewe 100 mg/16.7 mL contains 100 mg of paclitaxel.

Each vial of Paclitaxel Ebewe 150 mg/25 mL contains 150 mg of paclitaxel.

Each vial of Paclitaxel Ebewe 300 mg/50 mL contains 300 mg paclitaxel.

Inactive ingredient:

PEG 35 castor oil
ethanol.

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

Not all strengths may be marketed in Australia.

Supplier

Paclitaxel Ebewe is distributed in Australia by:

Sandoz Pty Ltd
ABN 60 075 449 553
54 Waterloo Road
Macquarie Park, NSW 2113
Australia
Tel: 1800 726 369

Australian Register Number

Paclitaxel Ebewe 300 mg in 50 mL: AUST R 98551

This leaflet was revised in March 2023.

Published by MIMS April 2023

BRAND INFORMATION

Brand name

Paclitaxel Ebewe

Active ingredient

Paclitaxel

Schedule

1 Name of Medicine

Paclitaxel.

2 Qualitative and Quantitative Composition

1 mL of Paclitaxel Ebewe concentrated injection contains 6 mg of paclitaxel.

Excipient with known effect.

Ethanol.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Injection, concentrated.

4 Clinical Particulars

4.1 Therapeutic Indications

Primary treatment of ovarian cancer in combination with a platinum agent.
Treatment of metastatic ovarian cancer and metastatic breast cancer, after failure of standard therapy.
Treatment of non-small cell lung cancer (NSCLC).
Adjuvant treatment of node-positive breast cancer administered sequentially to doxorubicin and cyclophosphamide.
Treatment of metastatic cancer of the breast, in combination with trastuzumab (Herceptin), in patients who have tumours that overexpress HER-2 and who have not received previous chemotherapy for their metastatic disease.

4.2 Dose and Method of Administration

Dosage.

Product is for single use in one patient only.
All patients must be premedicated before paclitaxel is administered to prevent severe hypersensitivity reactions (see Section 4.4 Special Warnings and Precautions for Use). Such premedication may consist of dexamethasone 20 mg orally (or its equivalent), approximately 12 and 6 hours prior to starting the paclitaxel infusion; promethazine 25 mg or 50 mg intravenously or other suitable H1-antagonist, 30 minutes prior to starting the paclitaxel infusion; and cimetidine 300 mg or ranitidine 50 mg by intravenous infusion over 15 minutes, starting 30 minutes prior to the paclitaxel infusion.
Repeat courses of Paclitaxel Ebewe Injection Concentrate should not be administered to patients with solid tumors 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) or severe peripheral neuropathy should receive a dosage reduction by 20% for subsequent courses. The incidence of neurotoxicity and the severity of neutropenia increase with dose within a regimen.

For primary treatment of ovarian cancer.

It is recommended that paclitaxel be used at a dose of 135 mg/m², administered intravenously over three hours, followed by cisplatin 75 mg/m². The infusion should be repeated every three weeks.

For the treatment of metastatic ovarian cancer or metastatic breast cancer.

It is recommended that paclitaxel be used as a single agent at a dose of 175 mg/m². Paclitaxel should be administered as an intravenous infusion over three hours. The infusion should be repeated every three weeks as tolerated. Patients have tolerated treatment with up to nine cycles of paclitaxel therapy, but the optimal course of therapy remains to be established.

For primary or secondary treatment of NSCLC (non-small cell lung cancer).

The recommended dose of paclitaxel is 175 mg/m² administered intravenously over three hours with a three-week interval between courses.

For node-positive breast cancer.

The recommended dose of paclitaxel is 175 mg/m² administered intravenously over three hours every three weeks for four courses following doxorubicin and cyclophosphamide combination therapy.

For overexpression of HER-2 breast cancer.

Paclitaxel 175 mg/m² administered intravenously over three hours with a three-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 bodyweight.

Dosage adjustment.

Subsequent doses of paclitaxel should be administered according to individual patient tolerance. Repetition of a course of paclitaxel is not recommended until the patient's neutrophil count is at least 1.5 x 10⁹ cells/L (1,500 cells/mm³) and the platelet count is at least 100 x 10⁹ cells/L (100,000 cells/mm³). If there is severe neutropenia (neutrophil count less than 0.5 x 10⁹ cells/L for a minimum of 7 days) or severe peripheral neuropathy or severe mucositis during paclitaxel therapy, the dose of paclitaxel in subsequent courses should be reduced by 20% (see Section 4.4 Special Warnings and Precautions for Use). The incidence of neurotoxicity and the severity of neutropenia increase with dose within a regime.

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.

Method of administration.

For intravenous administration.
Preparation for intravenous administration. Avoid contact of paclitaxel solutions with plasticised polyvinyl chloride (PVC) equipment, infusion lines or devices used when preparing infusion solutions. Prepare and store diluted paclitaxel solutions in glass or polyethylene containers. These precautions are to avoid leaching of the plasticiser DEHP (di-[2-ethylhexyl] phthalate) from PVC infusion bags or sets.
Paclitaxel solutions should be administered through polyethylene lined administration sets (e.g. Gemini 20 giving set) using an IMED pump.
Paclitaxel Ebewe Injection Concentrate must be diluted prior to intravenous infusion. It should be diluted in glucose 5% or sodium chloride 0.9% intravenous infusion. Dilution should be made to a final concentration of 0.3 to 1.2 mg/mL.
After the final dilution of Paclitaxel Ebewe Injection Concentrate, the bottle should be swirled gently to disperse the paclitaxel. Do not shake.
To reduce microbiological hazard, use as soon as practicable after reconstitution/preparation. If storage is necessary, hold at 2-8°C for not more than 24 hours after preparation. Administration should be completed within 24 hours of preparation of the infusion and any residue discarded according to the guidelines for the disposal of cytotoxic medicines (see Handling and disposal, below).

Filtration.

A microporous membrane of 0.22 microns or less in size should be used as the in-line filter for all infusions of paclitaxel. The IMED 0.2 micron add-on filter set composed of polysulfone and the IVEX II 0.2 micron filter composed of cellulose have both been found to be suitable for Paclitaxel Ebewe Injection Concentrate.
Devices with spikes should not be used with vials of Paclitaxel Ebewe Injection Concentrate since they can cause the stopper to collapse, resulting in a loss of sterile integrity of the Paclitaxel Ebewe Injection Concentrate solution.
Preparation and administration precautions. Paclitaxel is a cytotoxic anti-cancer medicine 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 medicine administration.
Handling and disposal. Care must be taken whenever handling cytotoxic 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. (See Section 6.6 Special Precautions for Disposal.)

4.3 Contraindications

Patients who have exhibited hypersensitivity reactions to paclitaxel, other taxanes or to any excipient especially patients who have a history of hypersensitivity reactions to PEG-35 castor oil (Cremophor EL) or medicines formulated in PEG-35 castor oil (e.g. ciclosporin for injection concentrate, teniposide for injection concentrate).
Paclitaxel should not be administered to patients who have baseline neutrophils counts of < 1.5 x 10⁹ cells/L.
Paclitaxel is contraindicated during lactation (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy, Use in lactation).

4.4 Special Warnings and Precautions for Use

General.

Paclitaxel should be administered under the supervision of medical staff experienced in the use of cancer chemotherapeutic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are available.
Paclitaxel should be given before a platinum compound when it is given in combination with a platinum compound, e.g. cisplatin (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Premedication.

In order to minimise the possibility of hypersensitivity reactions due to histamine release, patients must be premedicated before every treatment cycle of paclitaxel. Premedication should include corticosteroids (e.g. dexamethasone), antihistamines (e.g. diphenhydramine or promethazine) and an H₂-receptor antagonist (e.g. cimetidine or ranitidine). (See Section 4.2 Dose and Method of Administration.) The characteristic symptoms of hypersensitivity reactions are dyspnoea and hypotension (both requiring treatment), angioedema and widespread urticaria. In clinical trials, 2% of patients treated with paclitaxel experienced severe hypersensitivity. One of these reactions was fatal in a patient treated without premedication. Paclitaxel Ebewe Injection Concentrate must not be used in patients who have exhibited hypersensitivity reactions to paclitaxel.

Neutropenia.

(See Section 4.8 Adverse Effects (Undesirable Effects)).
As the dose limiting toxicity of paclitaxel is dose related in bone marrow suppression (primarily neutropenia), paclitaxel should not be administered to patients with a pre-treatment neutrophil count of less than 1.5 x 10⁹ cells/L (1,500 cells/mm³) or platelet count of less than 100 x 10⁹ cells/L. Blood counts should be frequently monitored during treatment with paclitaxel. Further cycles of paclitaxel should not be administered until the patient's neutrophil count is greater than 1.5 x 10⁹ cells/L (1,500 cells/mm³) and the platelet count is greater than 100 x 10⁹ cells/L (100,000 cells/mm³).
If there is severe neutropenia during a course of paclitaxel (i.e. neutrophil count less than 0.5 x 10⁹ cells/L (500 cells/mm³) for seven or more days), the dose of paclitaxel in subsequent cycles should be reduced by 20%. Previous radiation therapy may induce more severe myelosuppression. There is little information available from such patients at doses above 135 mg/m².

Cardiovascular toxicity.

Hypotension, hypertension and bradycardia have been observed during Paclitaxel Ebewe Injection Concentrate administration, but generally do not require treatment. Frequent monitoring of vital signs, particularly during the first hour of Paclitaxel Ebewe Injection Concentrate infusion is recommended. (Also 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 infusion, appropriate therapy should be administered and continuous electrocardiographic monitoring should be commenced and performed during subsequent therapy with paclitaxel. (Also see Section 4.8 Adverse Effects (Undesirable Effects)). Severe cardiovascular events have been observed more frequently in patients with non-small cell lung cancer (NSCLC) than breast or ovarian cancer.
When paclitaxel injection concentrate 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).

Gastrointestinal toxicity.

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

Administration.

Paclitaxel is administered by intravenous infusion only; it must not be administered by the intracerebral, intrapleural or intraperitoneal routes. Paclitaxel must be diluted before intravenous infusion. 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 medicine. 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.

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 medicine administration.
Special care should be taken to avoid intra-arterial application of paclitaxel, since in animal studies testing for local tolerance severe tissue reactions were observed after intra-arterial application.

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 pretreatment.
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 re-challenged with the medicine. Minor hypersensitivity reactions such as flushing, skin reactions, etc., do not require interruption of therapy (also see Section 4.8 Adverse Effects (Undesirable Effects)).

Hypotension and bradycardia.

Patients may develop hypotension and bradycardia during paclitaxel treatment, but generally not to a level requiring treatment. Vital signs should be monitored frequently, particularly during the first hour of paclitaxel infusion. Only patients with serious conduction abnormalities require continuous cardiac monitoring (see Conduction abnormalities (above); see Section 4.8 Adverse Effects (Undesirable Effects)).

Nervous system.

The occurrence of peripheral neuropathy is frequent and the development of severe symptoms is dose-dependent.
Patients with pre-existing neuropathy should be carefully monitored. Peripheral neuropathy is frequently reported in patients receiving paclitaxel and the severity is dose dependent. A 20% reduction in paclitaxel dose for all subsequent courses of paclitaxel is recommended for patients who develop severe peripheral neuropathy during therapy (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, 402 mg/mL and consideration should be given to possible central nervous system and other effects of absolute ethanol.
For instance, children may be more sensitive than adults to the effects of absolute ethanol.

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.

The effect of hepatic impairment on the pharmacokinetics of paclitaxel has not been established. However, as the liver is thought to be the primary site for metabolism of the drug, paclitaxel should be given cautiously to patients with decreased liver function. Paclitaxel has been shown to cause a dose related elevation of liver enzymes.
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 impairment and dose adjustments should be considered. Patients with severe hepatic impairment must not be treated with paclitaxel.
Patients with hepatic impairment may be at increased risk of toxicity, particularly Grade 3-4 myelosuppression. When paclitaxel is given as a 24-hour infusion to patients with moderate to severe hepatic impairment, increased myelosuppression may be seen as compared to patients with mildly elevated liver function tests given 24-hour infusions. Patients should be monitored closely for the development of profound myelosuppression (see Section 4.2 Dose and Method of Administration). 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 randomised 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 medical survival than younger patients, but no other efficacy parameters favoured the younger group.

Paediatric use.

The safety and effectiveness of paclitaxel in children have 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 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 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

Cisplatin.

The recommended regimen of paclitaxel administration for the first-line chemotherapy of ovarian carcinoma is for paclitaxel to be given before cisplatin. When paclitaxel is given before cisplatin, the safety profile of paclitaxel is consistent with that reported for single-agent use. Administration of cisplatin prior to paclitaxel treatment leads to greater myelosuppression than that seen when paclitaxel is given prior to cisplatin. Pharmacokinetic data demonstrated a reduction in paclitaxel clearance of approximately 33% 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 gynaecological cancers.

Ketoconazole.

As ketoconazole may inhibit the metabolism of paclitaxel, patients receiving paclitaxel and ketoconazole should be closely monitored or the combination of these medicines should be avoided.

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 and are given closer in time. 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 three-hour paclitaxel infusion found no sequence effects on the pattern of toxicity.

Cimetidine.

Paclitaxel clearance is not affected by cimetidine premedication.

Medicines metabolised in the liver.

Caution should be exercised during concurrent administration of medicines, which are metabolised in the liver (e.g. erythromycin), as such medicines may inhibit the metabolism of paclitaxel.
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.
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).
Arthralgia or myalgia adverse events of paclitaxel appear to be of a higher incidence in patients being treated concurrently with filgrastim (granulocyte colony stimulating factor (G-CSF)).
Paclitaxel clearance is not affected by cimetidine premedication.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Following treatment with intravenous paclitaxel at a dose of 1 mg/kg (6 mg/m²), rats showed decreased fertility and toxicity in unborn offspring. Paclitaxel administered intravenously to rabbits during organogenesis at a dose of 3 mg/kg (33 mg/m²) was toxic to both mother and foetus.

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)
Paclitaxel Ebewe Injection Concentrate may cause foetal harm when administered to a pregnant woman. There is no adequate data from the use of paclitaxel in pregnant women. Studies have shown paclitaxel to be embryotoxic and foetotoxic in rabbits at an intravenous dose of 3 mg/kg (33 mg/m²) given during organogenesis. Paclitaxel is toxic to rat foetuses at a dose of 1 mg/kg (6 mg/m²) and produced low fertility and foetal toxicity in rats. As with other cytotoxic medicinal products, paclitaxel may cause foetal harm when administered to pregnant women. Therefore, paclitaxel should not be used during pregnancy unless clearly necessary. Examination revealed that no gross external, soft tissue or skeletal alterations occurred. There are no studies in pregnant women. Women of children-bearing potential should have a pregnancy test prior to starting treatment with Paclitaxtel Ebewe Injection Concentrate. These women should be strongly advised to use effective contraception throughout therapy and for at least six months after the last dose of Paclitaxel Ebewe Injection Concentrate. If Paclitaxel Ebewe Injection Concentrate is used during pregnancy, or if the patient becomes pregnant while receiving this medicine, the patient should be apprised of the potential hazard.
Females and males of reproductive potential.

Females.

Women of childbearing potential should be advised to use effective contraception in order to avoid become pregnant during treatment and for at least 6 months after the last dose of paclitaxel.

Males.

Based on findings in genetic toxicity and animal productive 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 Ebewe Injection Concentrate.
Paclitaxel is contraindicated during lactation (see Section 4.3 Contraindications). It is not known whether paclitaxel is excreted in human milk. The evidence from many medicines would suggest that paclitaxel could be excreted in breast milk, though this has not been established. Because of the potential for serious adverse effects in breastfeeding infants, it is recommended that breastfeeding be discontinued when receiving paclitaxel therapy.

4.7 Effects on Ability to Drive and Use Machines

It is not known whether paclitaxel interferes with the ability to drive and use machines; however, Paclitaxel Ebewe does contain alcohol. Patients should exercise caution and refrain from driving or using machines until they know that paclitaxel does not negatively affect these abilities.

4.8 Adverse Effects (Undesirable Effects)

Unless otherwise noted, 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 regimen. If other regimens 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 (non-small cell lung cancer). 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 and very rare: < 1/10,000.

Infections and infestations.

Very common: infection (mainly urinary tract and upper respiratory tract infections), with reported cases of fatal outcome.
Uncommon: Septic shock.
Rare: Sepsis, peritonitis, pneumonia.

Cardiovascular.

Very common: hypotension.
Common: bradycardia; ECG abnormalities (nonspecific repolarisation 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).
Very rare: Atrial fibrillation, supraventricular tachycardia.
Six severe cardiovascular events possibly related to paclitaxel administration occurred including asymptomatic ventricular tachycardia, tachycardia with bigeminy, atrioventricular block (two patients), and syncopal episodes (two 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.

Very common: myelosuppression, thrombocytopenia, leucopenia, 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 eleven days after paclitaxel administration).
Common: febrile neutropenia (associated with an infectious episode, including urinary tract infection (UTI) and upper respiratory tract infection (URTI)).
Rare: five septic episodes, which were associated with severe neutropenia attributable to paclitaxel administration, had a fatal outcome.
Very Rare: Acute myeloid leukaemia, myelodysplastic syndrome.
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).
Reports of thrombocytopenia after paclitaxel therapy are less frequent and less severe than neutropenia, with platelet nadir (< 50 x 10⁹ cells/L) observed eight or nine days after paclitaxel administration in 5% of patients. Haemorrhage has been reported in patients receiving paclitaxel but this does not appear to be related to thrombocytopenia. Patients (3%) may require platelet transfusions.

Hepatobiliary.

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

Immune system disorders.

Very common: minor hypersensitivity reactions (mainly flushing and rash).
Common: 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, hyperhydrosis, and hypertension were also noted.
Infections: Febrile neutropenia occurred in 5% of all courses and 30% of all courses were associated with an infectious episode. The most common infections involve the upper respiratory tract, urinary tract and blood (sepsis). In phase II clinical trials, five septic episodes resulted in death.
Rare: Anaphylactic reactions.
Very Rare: Anaphylactic shock.

Vascular disorders.

Very common: hypotension.
Uncommon: hypertension, thrombosis, thrombophlebitis.
Very Rare: Shock.
Not known: Phlebitis.

Metabolism and nutrition disorders.

Very Rare: Anorexia.
Not Known: Tumor lysis syndrome.

Gastrointestinal.

Very common: nausea; vomiting; diarrhoea; mucositis (these manifestations were usually mild to moderate at the recommended dose).
Rare: bowel obstruction, ischaemic colitis, pancreatitis, 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.
Very rare: Mesenteric thrombosis, pseudomembranous colitis, neutropenic colitis, ascites, oesophagitis, constipation.

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).
Not Known: Systemic lupus erythematosus.

Psychiatric disorders.

Very rare: Confusional state.

Neurological.

Very common: Neurotoxicity (mainly: 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. Neurological 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: Motor neuropathy (with resultant minor distal weakness).
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.
There is a report of a grand mal seizure in a patient receiving paclitaxel and the seizure recurred after treatment with paclitaxel was recommenced. There is also a second report of a grand mal seizure in a patient with significant hepatic impairment during infusion with paclitaxel.
Very rare: Grand mal seizures, autonomic neuropathy (resulting in paralytic ileus and orthostatic hypotension), encephalopathy, convulsions, dizziness, ataxia, headache.

Eye disorders.

Very rare: Optic nerve and/or visual disturbances (scintilating scotomata), particularly in patients who have received higher doses than recommended.

Ear and labyrinth disorders.

Very rare: Hearing loss, ototoxicity, tinnitus, vertigo.

Respiratory, thoracic and mediastinal disorders.

Rare: Respiratory failure, pulmonary embolism, lung fibrosis, interstitial pneumonia, dyspnoea, pleural effusion.
Very Rare: Cough.

Skin and appendages.

Very common: Alopecia.
Common: Transient and mild nail and skin changes.
Rare: Pruritus, rash, erythema, radiation recall dermatitis; recall dermatitis. Local effects: phlebitis following intravenous administration has been reported. Extravasation leading to oedema, pain, erythema and induration has been reported. On occasions, extravasation can lead to cellulitis. Skin discolouration may also occur.
Very Rare: Stevens-Johnson syndrome, epidermal necrolysis, erythema multiforme, exfoliative dermatitis, urticaria, onycholysis (patients on therapy should wear sun protection on hands and feet).
Not known: Scleroderma.
In some cases, the onset of the injection site reaction either occurred during a prolonged infusion or was delayed by a week to 10 days.

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, skin fibrosis and skin necrosis).
Rare: Pyrexia, dehydration, asthenia, oedema, malaise.
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 medicine administration.
Radiation pneumonitis has been reported in patients receiving concurrent radiotherapy.

Investigations.

Common: Severe elevation in AST (SGOT), severe elevation in alkaline phosphatase.
Uncommon: Severe elevation in bilirubin.
Rare: Increase in blood creatinine.

Combination treatment.

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, diarrhoea, 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.

Post-marketing experience.

The following additional adverse effects have been identified during post-approval use of Paclitaxel Ebewe Injection Concentrate. Because their 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 medicine exposure.

Infections and infestations.

Pneumonia, sepsis.

Cardiac disorders.

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

Hematological 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.

Metabolic and nutrition disorders.

Anorexia, Tumour Lysis Syndrome.

Psychiatric disorder.

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, pseudoemembranous 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), pruritus, rash, erythema, phlebitis, cellulitis, skin exfoliation, necrosis, fibrosis, cutaneous lupus erythematosus, palmar-plantar erythrodysesthesia syndrome.

Musculoskeletal, connective tissue and bone disorders.

Systemic lupus erythematosus, scleroderma.

Investigations.

Increase in blood creatinine.

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 www.tga.gov.au/reporting-problems (Australia) or https://nzphvc.otago.ac.nz/reporting/ (New Zealand).

4.9 Overdose

There is no known antidote for paclitaxel overdose. At present, there is no specific treatment for paclitaxel overdosage. In case of overdose, the patient should be closely monitored.
Probable consequences of an overdose are mucositis, severe bone marrow suppression and peripheral neurotoxicity and treatment should be supportive.
Overdosage 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 131126 (Australia) and 0800 POISON or 0800 764766 (New Zealand).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Paclitaxel is a natural product with anti-tumour activity.

Mechanism of action.

Paclitaxel is an antimicrotubule antineoplastic agent. It promotes microtubule assembly by enhancing the polymerisation of tubulin, the protein subunit of spindle microtubules, even in the absence of the mediators normally required for microtubule assembly (e.g. guanosine triphosphate (GTP)), thereby inducing the formation of stable, nonfunctional microtubules. While the precise mechanism of action of the drug is not completely known, paclitaxel disrupts the dynamic equilibrium within the microtubule system and blocks cells in the late G2 phase and M phase of the cell cycle, inhibiting cell replication and impairing function of nervous tissue.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Absorption.

After paclitaxel is administered intravenously, its plasma concentration declines biphasically. The first phase shows rapid decline, representing distribution of paclitaxel to the peripheral compartment and elimination. This initial phase is followed by a relatively slow elimination of paclitaxel from the peripheral compartment.

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. The serum protein binding of paclitaxel is 89%. The presence of cimetidine, ranitidine, dexamethasone or diphenhydramine does not affect protein binding of paclitaxel.

Metabolism.

The liver is thought to be the primary site of metabolism for paclitaxel.

Excretion.

In patients treated with doses of 135 and 175 mg/m² as 3- and 24-hour infusions of paclitaxel. Mean terminal half-life: 3.0 to 52.7 hours; total body clearance: 11.6 to 24.0 L/hour/m². Following a three-hour infusion of 175 mg/m² paclitaxel. Mean terminal half-life: 9.9 hours; mean total body clearance: 12.4 L/hour/m².
The mean cumulative urinary recovery of unchanged paclitaxel has been reported to be 1.8 to 12.6% of the dose, indicating extensive non-renal clearance.

5.3 Preclinical Safety Data

Genotoxicity.

In vitro studies (chromosome abnormalities in human lymphocytes) and in vivo (micronucleus test using mice) mammalian test systems have shown paclitaxel to be mutagenic. When tested using the Ames test or the CHO/HGPRT (Chinese hamster ovary/ hypoxanthine-guanine phosphoribosyl transferase) gene mutation assay, paclitaxel did not induce mutagenicity.

Carcinogenicity.

No studies have examined the carcinogenic potential of paclitaxel; however, medicines similar to paclitaxel are carcinogens.

6 Pharmaceutical Particulars

6.1 List of Excipients

Absolute ethanol, PEG-35 castor oil.

6.2 Incompatibilities

For information on interactions with other medicines and other forms of interactions, see Section 4.2 Dose and Method of Administration, Preparation for intravenous administration; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

6.3 Shelf Life

Compounding centres, 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 14 days at 2 to 8°C (refrigerate; do not freeze) to paclitaxel solutions, which have been diluted with glucose 5% or sodium chloride 0.9% for intravenous infusion and stored in glass or polyethylene containers. Diluted 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 medicines.
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 Ebewe 30 mg/5 mL injection, concentrated vial - glass vial: Pack of 1 or 5 vials.
Paclitaxel Ebewe 100 mg/16.7 mL injection, concentrated vial - glass vial: Pack of 1 vial.
Paclitaxel Ebewe 150 mg/25 mL injection, concentrated vial - glass vial: Pack of 1 vial.
Paclitaxel Ebewe 300 mg/50 mL injection solution vial - glass vial: Pack of 1 vial.
Not all strengths or presentations may be marketed in Australia.
Vial stopper is not made with natural rubber latex.

6.6 Special Precautions for Disposal

The published guidelines related to procedures for the proper handling and disposal of cytotoxic medicines should be followed.
In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Paclitaxel is a white to off-white crystalline powder that is extremely highly lipophilic and practically insoluble in water. Paclitaxel is partially soluble in ethanol and is therefore formulated with PEG-35 castor oil and absolute ethanol.

Chemical structure.

Chemical name: (2S,5R,7S,10R,13S)-10,20-bis(acetoxy)-2-benzoyloxy-1,7- dihydroxy-9-oxo-5,20-epoxytax-11-en-13-yl (3S)-3- benzoylamino-3-phenyl-D-lactate.
Molecular formula: C₄₇H₅₁NO₁₄.
Molecular weight: 853.9.

CAS number.

33069-62-4.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

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