Taxol

Package leaflet: Information for the user

TAXOL 6 mg/ml concentrate for solution for infusion

paclitaxel
Please read this leaflet carefully before using this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor.
• If you get any side effects, talk to your doctor. This includes any side effects not listed in this leaflet. See section 4.

Contents of this leaflet:

1. What TAXOL is and what it is used for
2. What you need to know before using TAXOL
3. How to use TAXOL
4. Possible side effects
5. How to store TAXOL
6. Contents of the pack and other information

1. What TAXOL is and what it is used for

Paclitaxel belongs to a group of anticancer medicines called taxanes. These agents inhibit the growth of cancer cells.

TAXOL is indicated for the treatment of:

Ovarian cancer:

• as first-line therapy (after initial surgery in combination with cisplatin, a platinum-containing medicine).
• after standard platinum-based treatments that have not been effective.

Breast cancer:

• as first-line therapy in advanced or metastatic disease (cancer that has spread to other parts of the body). TAXOL is combined either with anthracyclines (e.g., doxorubicin) or with a medicine called trastuzumab (in patients for whom anthracyclines are not indicated and whose tumour cells express a protein on their surface called HER2; see the trastuzumab package leaflet).
• after initial surgery, as additional treatment following therapy with anthracyclines and cyclophosphamide (AC).
• as second-line therapy in patients who have not responded to standard anthracycline-based treatments or for whom such treatment should not be used.

Advanced non-small cell lung cancer:

• in combination with cisplatin, when surgery and/or radiotherapy are not suitable.

AIDS-related Kaposi's sarcoma:

• when another treatment (e.g., liposomal anthracyclines) has been tried but was not effective.

2. What you should know before using TAXOL

Do not use TAXOL

• if you are allergic (hypersensitive) to paclitaxel or to any of the other ingredients of this medicine (listed in section 6), particularly to polyoxyethylated castor oil.
• if your white blood cell count is too low. Your doctor will request blood tests.
• if you are breastfeeding.
• if you have a severe and uncontrolled infection and TAXOL is used to treat Kaposi’s sarcoma.

If you are in any of these situations, inform your doctor before starting treatment with TAXOL.
The use of TAXOL is not recommended in children (under 18 years of age).
Warnings and precautions
Talk to your doctor before using TAXOL.
To minimize allergic reactions, you will be given other medicines before receiving TAXOL.

• if you experience severe allergic reactions (for example, difficulty breathing, shortness of breath, chest tightness, drop in blood pressure, dizziness, lightheadedness, skin reactions such as rash or swelling).
• if you have fever, shaking chills, sore throat or mouth ulcers (signs of myelosuppression).
• if you have numbness or weakness in arms and legs (signs of peripheral neuropathy); a dose reduction of TAXOL may be necessary.
• if you have severe liver problems; in this case, use of TAXOL is not recommended.
• if you have abnormalities in cardiac conduction.
• if you have severe or persistent diarrhoea, with fever and stomach pain, during or immediately after treatment with TAXOL. The colon may become inflamed (pseudomembranous colitis).
• if you have previously received radiation therapy to the chest (as it may increase the risk of pulmonary inflammation).
• if you have inflamed or red mouth (signs of mucositis) and are being treated for Kaposi’s sarcoma. You may require a lower dose. If you are in any of these situations, inform your doctor immediately.

TAXOL must always be administered intravenously. Administration of TAXOL into arteries can cause inflammation and result in pain, swelling, redness and warmth.
Other medicines and TAXOL
Inform your doctor if you are taking, have recently taken, or might take any other medicines, including those without a prescription.
This is because TAXOL or other medicines may not work as expected, or you may be more likely to experience side effects.
An interaction means that different medicines can affect each other.
Talk to your doctor when taking paclitaxel at the same time as any of the following:

• medicines used to treat infections (i.e., antibiotics such as erythromycin, rifampicin, etc.; consult your doctor, nurse or pharmacist if you are unsure whether the medicine you are taking is an antibiotic)
• medicines used to stabilize your mood, sometimes called antidepressants (e.g., fluoxetine)
• medicines used to treat seizures (epilepsy) (e.g., carbamazepine, phenytoin)
• medicines used to help lower blood fat levels (e.g., gemfibrozil)
• medicines used for heartburn or gastric ulcers (e.g., cimetidine)
• medicines used to treat HIV and AIDS (e.g., ritonavir, saquinavir, indinavir, nelfinavir, efavirenz, nevirapine)
• a medicine called clopidogrel used to prevent blood clots
• a medicine named rifampicin, an antibiotic used for tuberculosis. An increase in the TAXOL dose may be necessary.
• vaccines: inform your doctor if you have recently been vaccinated or plan to be vaccinated. Using TAXOL together with certain vaccines may cause serious complications
• cisplatin (anticancer agent): TAXOL should be administered before cisplatin. Kidney function may require more frequent monitoring.
• doxorubicin (anticancer agent): TAXOL should be administered 24 hours after doxorubicin to avoid high circulating levels of doxorubicin.

Pregnancy and breastfeeding
Inform your doctor if you are pregnant or think you might be pregnant before receiving treatment
with TAXOL. If there is any chance you could become pregnant, use an effective and reliable
contraceptive method during treatment. TAXOL must not be used during pregnancy unless strictly necessary. Female and male patients of reproductive age, and/or their partners, should use contraception for at least six months after treatment with paclitaxel.
Male patients should discuss sperm cryopreservation with their doctor prior to treatment with paclitaxel due to the possibility of infertility.
If you are breastfeeding, inform your doctor. Stop breastfeeding if you are using TAXOL. Do not resume breastfeeding without your doctor’s permission.
Driving and using machines
This medicine contains alcohol. For this reason, it may be unwise to drive immediately after a treatment cycle. In any case, do not drive if you feel dizzy or unsteady.
Important information about some excipients in TAXOL

• TAXOL contains castor oil (50% polyoxyethylated castor oil), which may cause severe allergic reactions. If you are allergic to castor oil, talk to your doctor before taking TAXOL.
• TAXOL contains approximately 50% ethanol (alcohol), e.g., up to 20 g per 300 mg/50 ml dose, equivalent to 450 ml of beer or 175 ml of wine. This may be harmful for alcoholics. This should be taken into account in pregnant or breastfeeding women and in high-risk groups such as patients with liver disease or epilepsy. The amount of alcohol in this medicine may alter the effects of other medicines. The amount of alcohol in this medicine may impair your ability to drive or use machines.

3. How to use TAXOL

• To minimize allergic reactions, you will be given other medications before TAXOL. These medications may be administered either as tablets, intravenous infusion, or both.
• You will receive TAXOL by slow intravenous infusion through an in-line filter into a vein. TAXOL will be administered by a healthcare professional. He or she will prepare the infusion solution before it is given to you. The dose you receive will also depend on the results of your blood tests. Depending on the type and severity of your tumor, you will receive TAXOL either as monotherapy or in combination with another antineoplastic agent.
• TAXOL must always be administered into a vein over a period of 3 or 24 hours. It is usually given every 2 or 3 weeks, unless otherwise directed by your doctor. Your doctor will inform you of the number of TAXOL cycles you will need.

If you have further questions about the use of this product, ask your doctor.
If you take more TAXOL than you should
There are no antidotes for TAXOL overdose. You will receive treatment for your symptoms.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone gets them.
Contact your doctor immediately if you notice any signs of allergic reactions. These may
include one or more of the following:

• Flushing,
• Skin reactions,
• Itching,
• Chest tightness,
• Shortness of breath or difficulty breathing,
• Swelling. These may all be signs of serious side effects.

Contact your doctor immediately:

• If you have fever, shaking chills, sore throat or mouth ulcers (signs of myelosuppression)
• If you experience numbness or weakness in the arms and legs (signs of peripheral neuropathy). These symptoms may persist for more than 6 months after stopping treatment.
• If you develop severe or persistent diarrhoea, with fever and stomach pain.

Very common side effects
(May affect more than 1 in 10 people):

• Minor allergic reactions such as flushing, rash, itching
• Infections: mainly upper respiratory tract infections, urinary tract infections
• Shortness of breath
• Sore throat or mouth ulcers, red and inflamed mouth, diarrhoea, feeling unwell (nausea, vomiting)
• Hair loss (most cases of hair loss occurred within less than one month from the start of paclitaxel treatment. When this occurs, hair loss is evident [over 50%] in most patients)
• Muscle pain, cramps, joint pain
• Fever, shaking chills, headache, dizziness, fatigue, paleness, increased tendency to bruising
• Numbness, tingling or weakness in the arms and legs (all symptoms of peripheral neuropathy)
• Tests may show: decreased platelet count, decreased number of white or red blood cells, low blood pressure

Common side effects
(May affect up to 1 in 10 people):

• Mild and transient changes in nails and skin, injection site reactions (local swelling, pain, and skin redness)
• Tests may show: slowed heart rate, marked increase in liver enzymes (alkaline phosphatase and AST - SGOT)

Uncommon side effects
(May affect up to 1 in 100 people):

• Shock due to infection (known as 'septic shock')
• Palpitations, heart disorders (AV block), increased heart rate, heart attack, respiratory distress
• Fatigue, sweating, fainting (syncope), significant allergic reactions, inflammation of veins caused by a blood clot (thrombophlebitis), swelling of the face, lips, mouth, tongue or throat
• Back pain, chest pain, pain in hands and feet, chills, abdominal pain (stomach)
• Tests may show: severe increase in bilirubin (jaundice), high blood pressure, blood clot

Rare side effects
(May affect up to 1 in 1,000 people):

• Decrease in white blood cells with fever and increased risk of infection (febrile neutropenia)
• Nerve involvement causing muscle weakness in arms and legs (motor neuropathy)
• Shortness of breath, pulmonary embolism, pulmonary fibrosis, interstitial pneumonia, dyspnoea, pleural effusion
• Intestinal obstruction, intestinal perforation, inflammation of the colon (ischaemic colitis), inflammation of the pancreas (pancreatitis)
• Itching, rash, skin redness (erythema)
• Blood infection (sepsis), peritonitis
• Pyrexia, dehydration, asthenia, oedema, malaise
• Severe and potentially fatal hypersensitivity reactions (anaphylactic reactions)
• Tests may show: increased creatinine in blood indicating kidney dysfunction

Very rare side effects
(May affect up to 1 in 10,000 people):

• Rapid and irregular heart rate (atrial fibrillation, supraventricular tachycardia)
• Sudden disturbance in blood cell formation (acute myeloid leukaemia, myelodysplastic syndrome)
• Optic nerve disorder and/or visual disturbances (scintillating scotoma)
• Loss or reduction in hearing (ototoxicity), ringing in the ears (tinnitus), dizziness
• Cough
• Blood clot in a vein of the abdomen and intestine (mesenteric thrombosis), inflammation of the colon sometimes with severe and persistent diarrhoea (pseudomembranous colitis, neutropenic colitis), oedema (ascites), oesophagitis, constipation
• Severe hypersensitivity reactions including fever, skin redness, joint pain and/or eye inflammation (Stevens-Johnson syndrome), localized skin peeling (epidermal necrolysis), red irregular spots (exudative) (erythema multiforme), skin inflammation with blisters and peeling (exfoliative dermatitis), urticaria, nail loss (patients undergoing treatment must protect hands and feet with sunscreen creams)
• Loss of appetite (anorexia)
• Severe and potentially fatal hypersensitivity reactions with shock (anaphylactic shock)
• Impaired liver function (hepatic necrosis, hepatic encephalopathy) (both have reported fatal cases)
• Confusional state

Side effects with unknown frequency (frequency cannot be estimated from the available data)

• Disseminated intravascular coagulation or "DIC" has been reported. This is a serious condition that makes people highly susceptible to bleeding, blood clot formation, or both
• Hardening/thickening of the skin (scleroderma)
• Metabolic complications after chemotherapy (tumour lysis syndrome)
• Eye disorders, such as thickening and swelling of the macula (macular oedema), flashes of light (photopsia), and spots, specks, dots, and "floaters" floating in your field of vision (floaters), increased tear secretion
• Inflammation of veins (phlebitis)
• Autoimmune disease with multiple symptoms such as red, scaly patches on the skin, joint pain or fatigue (systemic lupus erythematosus), or skin rashes and red, thick, often scaly sores that may burn or itch (cutaneous lupus erythematosus)
• Redness, swelling and pain on the palms of the hands and/or soles of the feet (hand-foot syndrome)
• Acute inflammatory reaction confined to previously irradiated areas triggered by administration of systemic agents after radiation therapy (recall phenomenon)
• Excessive sweating (hyperhidrosis)

Reporting of side effects
If you get any side effects, including those not listed in this leaflet, talk to your doctor. You can also report side effects directly via the national reporting system at https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse . By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store TAXOL

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the carton and vial.
The expiry date refers to the last day of that month.

Before dilution of TAXOL:
Store below 25°C.
Keep in the original packaging to protect the medicine from light.
Freezing does not adversely affect the closed vials.
From a microbiological standpoint, once opened, the product can be stored for a maximum of 28 days at 25°C. Any other storage periods and conditions are the responsibility of the user.

After dilution of TAXOL:
From a microbiological standpoint, the diluted product should be used immediately. If not used immediately, it should be stored in a refrigerator (2°C – 8°C) for no longer than 24 hours, unless the dilution was carried out under validated and controlled aseptic conditions. For further details on stability after dilution, see the section for healthcare professionals.

6. Package contents and other information

What TAXOL contains
The active substance is paclitaxel.
Each ml of concentrate contains 6 mg of paclitaxel.
Each vial contains 5 - 16.7 or 50 ml (corresponding to 30, 100 or 300 mg of paclitaxel, respectively).
The other ingredients are ethanol (alcohol) and polyoxyethylated castor oil.

Description of the appearance of TAXOL and package contents
TAXOL 6 mg/ml concentrate for solution for infusion is a clear, colorless to slightly yellow viscous solution, supplied in 5 ml, 16.7 ml, and 50 ml vials of concentrate for dilution.
The vials are individually packaged in cartons; boxes containing 10 cartons are also available. Not all pack sizes may be marketed.

Marketing Authorization Holder and Manufacturer
Marketing Authorization Holder
CHEPLAPHARM Arzneimittel GmbH
Ziegelhof 24
17489 Greifswald
Germany

Manufacturer
Latina Pharma S.P.A
Via Murillo, 7
04013 Sermoneta (Latina) - Italy

The following information is intended for healthcare professionals only:

Preparation of infusion solutions:

• Containers and infusion sets used with TAXOL must be DEHP-free. This will reduce the risk of patient exposure to the plasticizer DEHP [di-(2-ethylhexyl)phthalate], which may be leached from PVC containers or infusion sets. The use of filtered devices (e.g., IVEX-2) incorporating short PVC inlet and/or outlet components has not resulted in significant DEHP leaching.
• As with all cytotoxic agents, TAXOL must be handled with care. Always wear appropriate protective gloves when handling vials containing paclitaxel. Dilution of paclitaxel must be performed under aseptic conditions by trained personnel in a designated area. In case of skin contact, wash the affected area thoroughly with soap and water. In case of mucous membrane contact, flush copiously with water.
• Do not use the Chemo-Dispensing Pin or similar piercing devices that may cause the stopper to fall into the vial, resulting in loss of sterility.

Step 1: Dilute the concentrate
Prior to administration, TAXOL must be diluted with one of the following:

• 0.9% Sodium Chloride
• 5% Dextrose
• 5% Dextrose and 0.9% Sodium Chloride Injection
• 5% Dextrose in Ringer's Injection

The final paclitaxel solution concentration must be between 0.3 mg/mL and 1.2 mg/mL. DEHP-free containers and infusion devices must be used.
After dilution, solutions may appear slightly turbid due to the vehicle formulation; this turbidity is not removable by filtration. No significant loss of concentration has been observed during simulated administration of the solution through an intravenous infusion line equipped with an in-line filter.

Step 2: Administration of the infusion
Premedicate all patients with corticosteroids, antihistamines, and H-_2 antagonists prior to administration.
Do not re-administer TAXOL until neutrophil count is ≥ 1,500/mm³ (≥ 1,000/mm³ for patients with Kaposi's sarcoma) and platelet count is ≥ 100,000/mm³ (≥ 75,000/mm³ for patients with Kaposi's sarcoma).
Avoid precipitation of the infusion solution:

• Use as soon as possible after dilution
• Avoid excessive shaking, vibration, or agitation
• Infusion sets must be thoroughly cleaned before use
• Regularly inspect the solution visually and discontinue infusion if precipitates are observed

Chemical and physical stability of the solution has been demonstrated for 7 days at 5°C and 25°C when diluted with 5% dextrose injection, and for 14 days when diluted with 0.9% sodium chloride injection. From a microbiological standpoint, the diluted product should be used immediately or stored at 2°C–8°C for no more than 24 hours.

TAXOL must be administered using an appropriate in-line filter with a microporous membrane having a pore size ≤ 0.2 micrometers. DEHP-free containers and infusion sets must be used. The use of filters incorporating short PVC inlet and outlet components has not resulted in significant DEHP leaching.

Step 3: Disposal
Disposal of any unused material or waste must be carried out in accordance with regulations governing the handling of cytotoxic drugs.

Dosage:
The recommended doses for intravenous infusion of TAXOL are as follows:

Do not re-administer TAXOL until the neutrophil count is ≥ 1,500/mm³ (≥ 1,000/mm³ for patients with Kaposi's sarcoma) and the platelet count is ≥ 100,000/mm³ (≥ 75,000/mm³ for patients with Kaposi's sarcoma).
Patients who experience severe neutropenia (neutrophil count < 500/mm³ for one or more weeks) or severe peripheral neuropathy should receive a 20% dose reduction in subsequent cycles (25% for patients with Kaposi's sarcoma) (see Summary of Product Characteristics).
There are insufficient data to recommend dose adjustments in patients with mild to moderate hepatic impairment. Patients with severe hepatic impairment must not be treated with TAXOL (see Summary of Product Characteristics).
The use of TAXOL is not recommended in children under 18 years of age due to limited data on safety and efficacy.