nogen Pharma

PACKAGE LEAFLET: INFORMATION FOR THE USER

Paclitaxel 6mg/ml concentrate for solution for infusion

Read all of this leaflet carefully before you start taking this medicine because it contains important information foryou.

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

•    If you have any further questions, ask your doctor or pharmacist or nurse.

•    This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.

•    If you get any side effects, talk to your doctor, or pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet:

1.    What Paclitaxel is and what it is used for

2.    What you need to know before you use Paclitaxel

3.    How to use Paclitaxel

4.    Possible side effects

5.    How to store Paclitaxel

6.    Contents of the pack and other information

Paclitaxel Concentrate for Solution for Infusion is given only by a doctor. They can answer any questions you may have after reading this leaflet.

1. WHATPACLITAXEL ISANDWHAT IT IS USED FOR

Paclitaxel belongs to a group of compounds

called taxenes, which are anti-cancer drugs.

It works by stopping cells dividing and is

used to prevent the growth of cancer cells.

Paclitaxel is used for the treatment of

•    Ovarian cancer - either as initial therapy in combination with cisplatin, or as second-line treatment when platinum-containing medicines have not worked

•    Breast cancer - as initial therapy for advanced or spreading breast cancer. It may be used in combination with an anthracycline medicine or in combination with a medicine called trastuzumab. It may also be used as treatment for breast cancer after the patient has had treatment with anthracycline and cyclophosamide.

•    Non-small cell lung cancer - will be used in combination with cisplatin in patients who cannot have curative surgery and/or radiotherapy.

•    AIDs(Acquired Immuno Deficiency Syndrome)-related Kaposi's sarcoma -may be used where other treatments have not worked (e.g. liposomal anthracyclines)

erythromycin, fluoxetine, gemfibrozil, rifampicin, carbamazepine, phenytoin, efavirenz, and nevirapine and for HIV patients receiving protease inhibitors (ritonavir, nelfinavir) as concomitant therapy.

Pregnancy, breast-feeding and fertility

Ifyou are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

Pregnancy

Paclitaxel must not be given during pregnancy. This medicine may cause birth defects, therefore, you must not become pregnant during treatment with Paclitaxel and must use an effective method of contraception whilst you are receiving treatment and for six months after treatment with Paclitaxel is completed. Ifpregnancy occurs during treatment, or within the six months after treatment has finished, inform your doctor immediately.

Breast-feeding

Paclitaxel should not be used when you are breast-feeding. You should stop breastfeeding while you are being treated with Paclitaxel. Do not restart breast-feeding until your doctor tells you it is safe to do so.

Fertility

This medicine may cause sterility, which could be permanent. Male patients should seek advice regarding cryoconservation of sperm prior to treatment.

Both females and males of fertile age, and/or their partners should use contraception for at least 6 months after treatment with Paclitaxel.

Driving and using machines

There is no reason why you cannot continue driving between courses of Paclitaxel but you should remember that this medicine contains some alcohol and it may be unwise to drive immediately after a course of treatment. As in all cases, you should not drive ifyou feel dizzy or lightheaded.

Paclitxel contains ethanol and macrogolglycerol ricinoleate

This medicine contains 40 % by volume of ethanol. This medicine must not be taken by children, pregnantwomen and people suffering from liver disease, epilepsy, alcoholism and brain injury.

This medicine contains macrogolglycerol ricinoleate, which can cause severe allergic (hypersensitivity) reactions.

3. HOWTOUSEPACLITAXEL

4. POSSIBLESIDEEFFECTS

2. WHATYOUNEEDTOKNOW BEFORE YOU USE PACLITAXEL

Do not use Paclitaxel if you:

•    Are hypersensitive (allergic) to paclitaxel, or similar medicines or any of the other ingredients of this medicine. One of the ingredients, macrogolglycerol ricinoleate can cause severe allergic reactions

•    Are pregnant or breastfeeding

•    Have low levels of white blood cells called neutrophils. Yourdoctor should check the results ofyour last blood test to ensure that you can receive your course oftreatment

•    Have Kaposi's sarcoma. This product should not be used if you have a serious uncontrolled infection.

Warnings and precautions

Before you start treatment and during treatment, you will have regular blood tests to check whether it is safe for you to continue with your treatment. Tell your doctor if:

•    You have heart disease or liver problems

•    You develop severe, prolonged or bloodstained diarrhoea during or after treatment. This may be an indication of severe bowel inflammation (pseudomembranous colitis)

•    You have had nerve problems in your hands or feet, such as numbness, tingling or burning (peripheral neuropathy)

•    You have blood problems, such as changes in the numberofcells

•    You previously had radiation treatment (radiotherapy) to yourchest, as subsequent treatment with Paclitaxel may cause severe lung inflammation (interstitial pneumonitis)

•    You are taking any other medicines that could interact with paclitaxel (See Other medicines and Paclitaxel).

Other medicines and Paclitaxel

Tell your doctor or pharmacist ifyou are taking, have recently taken or might take any other medicines.

•    When used in combination, Paclitaxel should be given before cisplatin

•    Paclitaxel should be given 24 hours after doxorubicin

•    Special care should be observed if you are taking medicines which influence the metabolism of paclitaxel. These include:

Your doctor will decide how much Paclitaxel you will be given. It is given under the supervision of a doctor, who can give you more information.

Paclitaxel is given into a vein from an intravenous drip. The dose you receive will be based on your body surface area and the result of blood tests carried out before treatment.

For ovarian and lung cancer the usual dose is 175 mg/m², body surface area, given over 3 hours, followed by the cisplatin.

For breast cancer the usual dose is 220 mg/m², body surface area, given over 3 hours administered 24 hours after doxorubicin or 175 mg/m², body surface area, given over 3 hours, administered after trastuzumab. The timing of Paclitaxel administration after trastuzumab will depend on how you react to this medicine.

For breast cancer adjuvant therapy the usual dose is 175 mg/m², body surface area, given over 3 hours, administered after anthracycline and cyclophosphamide.

For AIDS-related Kaposi's sarcoma the

usual dose is 100 mg/m² given over3hours.

Will I need to receive any other medicine?

You will be asked to take a steroid tablet 12 hours and 6 hours before receiving Paclitaxel, oryou may be given one steroid injection approximately 30-60 minutes before receiving Paclitaxel. You will also be given two injections of different types of antihistamine approximately 30-60 minutes before you receive Paclitaxel.

How often will I receive Paclitaxel?

Paclitaxel is usually given every 3 weeks. This mayvary, depending on the results of regular blood tests.

Paclitaxel should not be given to children and adolescents under 18years old.

Ifyou are given too much Paclitaxel

Your dose will be carefully calculated by the doctors so overdose is unlikely. However, if too much is given this is likely to make the usual side effects worse, particularly blood disorders, numbness/tingling of the arms, hands, legs or feet, and stomach upsets including vomiting and diarrhoea.

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PLEASE DETACH BEFORE HANDING ABOVE SECTION TO THE PATIENT

INFORMATION FOR HEALTHCARE PROFESSIONALS

Paclitaxel 6mg/ml concentrate for solution for infusion

Below is a summary of information to assist in the administration of Paclitaxel.

Please refer to SPC for complete prescribing information.

Handling:

As with all antineoplastic agents, caution should be exercised when handling Paclitaxel. Dilution should be carried out under aseptic conditions by trained personnel in a designated area. Adequate protective gloves should be worn. Precautions should be taken to avoid contact with the skin and mucous membranes. In the event of contact with the skin, the area should be washed with soap and water. Following topical exposure, tingling, burning and redness have been observed. In the event of contact with the mucous membranes, these should be flushed thoroughly with water. Upon inhalation, dyspnoea, chest pain, burning throat and nausea have been reported.

If unopened vials are refrigerated, a precipitate may form that redisolves with little or no agitation upon reaching room temperature. Product quality is not affected. If the solution remains cloudy or if an insoluble precipitate is noted, the vial should be discarded.

Preparation:

•    Prior to infusion, Paclitaxel must be diluted using aseptic techniques in 0.9% Sodium Chloride Injection, or 5% Dextrose Injection, or 5% Dextrose and 0.9% Sodium Chloride Injection, or 5% Dextrose in Ringer's Injection, to a final concentration of 0.3 to 1.2 mg/ml. Chemical and physical stability has been demonstrated for 27 hours at 25°C. From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.

•

product withdrawals, Paclitaxel multidose vials maintain microbial, chemical and physical stability for up to 28 days at 25°C. Other in-use storage times and conditions are the responsibility of the

user. Diluted solutions should not be refrigerated.

•

similar devices with spikes should not be used since they can cause the vial stopper to collapse, resulting in loss of sterile integrity.

•

haziness, which is attributed to the formulation vehicle, and is not removed by filtration. Paclitaxel should be administered through an in-line filter with a microporous membrane < 0.22pi m. No significant losses in potency have been noted following simulated delivery of the solution through IV tubing containing an in-line filter.

•

precipitation during infusions, usually towards the end of a 24 hours infusion period. Although the cause of this precipitation has not been elucidated, it is probably linked to the supersaturation of the diluted solution. To reduce the precipitation risk, Paclitaxel should be used as soon as possible after dilution, and excessive agitation, vibration or shaking should be avoided. The infusion sets should be flushed thoroughly before use. During infusion, the appearance of the solution should be regularly inspected and the infusion should be stopped if precipitation is present.

•

which may be leached from plasticized PVC infusion bags, sets, or other medical instruments, diluted Paclitaxel solutions should be stored in non-PVC bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets.

Administerthe infusion

All patients must be premedicated with

corticosteroids, antihistamines and H₂

antagonists prior to administration of

Paclitaxel, e.g.

Like all medicines, this medicine can cause side effects, although not everyone gets them.

Allergic reactions may occur rarely, with symptoms such as rash, itching, swelling of the face, wheeziness, shortness of breath, tightness in the chest, fever, low blood pressure and feeling dizzy particularly when standing up. If any of these occur tell your doctor immediately.

If any of the following happens, tell your doctor immediately:

•    Any abnormal bruising, bleeding, or signs of infections such as a sore throat and high temperature.

•    Severe allergic reaction - you may experience a sudden itchy rash (hives), swelling of the hands, feet, ankles, face, lips, mouth or throat (which may cause difficulty in swallowing or breathing), and you may feel you are going to faint.

•    Breathlessness and dry cough due to damage to the lungs (interstitial pneumonia)

•    Reaction at the injection site, e.g. local swelling, pain, redness.

•    Severe skin reactions such as erythema multiforme (circular, irregular red patches), Stevens-Johnson syndrome (severe skin rash with flushing, fever, blisters and ulcers) or toxic epidermal necrolysis (severe rash involving reddening, peeling and swelling of the skin that resembles severe burns), may also be signs of an allergic reaction.

Very common (affects more than 1 out of 10 people):

•    An effect on the bone marrow, which can cause decreased numbers of some blood cells. This may cause anaemia. It can also lead to infections, mainly urinary tract and upper respiratory tract infections with reported cases of fatal outcome.

•    Decreased number of blood platelets and bleeding.

•    Milder allergic (hypersensitivity) reactions, such as flushing and rash.

•    Nerve problems affecting the hands and/orfeet (peripheral neuropathy), which can cause tingling feelings in the skin, numbness and/orpain.

•    Low blood pressure.

•    Feelingsick(nausea),beingsick (vomiting) and diarrhoea.

•    Hairloss.

•    Muscleorjointpain.

•    Inflammation of areas such as the lining of the mouth.

Common (affects more than 1 out of 100 people);

•    Slowheartbeat(pulse).

•    Mild changes in nails and skin which soon disappear.

•    Painful swelling and inflammation where the injection is given which may cause tissue hardening (occasionally cellulitis, thickening and scarring of the skin (skin fibrosis), death of skin cells (skin necrosis)).

•    Changes in blood tests that check how the liver is working.

Uncommon (affects less than 1 out of100 people):

•    A state of shock resulting from blood poisoning

•    Serious allergic (hypersensitivity) reactions with e.g. decreased or increased blood pressure, swelling of the face, difficulty in breathing, skin rash, chills, back pain, chest pain, fast heart beat, abdominal pain, pain in arms and legs, sweating.

•    Serious heart problems like heart muscle degeneration (cardiomyopathy), serious changes in your heart's rhythm even with fainting. Heart attack.

•    Increased blood pressure.

•    Blood clot (thrombosis), inflammation of a vein in connection with blood clots.

•    Yellowing of the skin (jaundice).

Rare (affects less than 1 out of 1,000 people):

•    Pneumonia

•    Heartfailure

•    Reduced number of a type of white blood cell with fever (febrile neutropenia)

•    Serious allergic (anaphylactic) reaction.

•    Effects on the nerves, which can cause muscle weakness in the arms and legs.

•    Difficulty in breathing, fluid on the lungs, inflammation of the lungs and other lung problems (lung fibrosis, pulmonary embolism), markedly impaired pulmonaryfunction (respiratoryfailure).

•    Itching, rash and reddened skin.

•    Weakness, high temperature (fever), dehydration, oedema, swelling of body tissue due to accumulation offluid, feeling ill.

•    Blood poisoning.

•    Blockage of the intestines, penetration of the wall of the small intestine or large bowel, inflammation of the lining of the abdomen (peritoneum), inflammation of the intestine caused by inadequate blood supply, inflammation of the pancreas.

•    Increased level of the substance creatinine in the blood

Very rare (occurs with less than 1 out of 10,000 ofthe users):

•    Acute leukaemia (a type of blood cancer), myelodysplastic syndrome (a diverse collection of blood cell disorders).

•    Life threatening allergic reaction (anaphylactic shock).

•    Loss of appetite, shock due to decreased blood pressure, cough.

•    Effects on the nervous system which can cause paralysis of the intestines (gut) and a decrease in blood pressure when standing up or sitting up from a lying down position, fits (epileptic seizures), cramps, confusion, dizziness, alteration in brain function orstructure, headache,

•    Loss of the ability to co-ordinate muscular movement.

•    Problems with eyesight and visual disturbances, usually in patients given larger doses.

•    Reduction or loss of hearing, ringing in the ears (tinnitus), vertigo.

•    Abnormal heart rhythm (atrial fibrillation, supraventricular tachycardia).

•    A blood clot in the mesenteric artery, pseudomembranous colitis (an infection of the colon caused by specific bacteria), inflammation ofthe oesophagus, constipation. Collection of fluid in the abdomen (belly).

•    Severe inflammation of the large bowel presenting with fever, watery or bloody diarrhoea, and crampy abdominal pain (neutropenic colitis).

•    Death of liver cells (necrosis of the liver), confusion and other effects (hepatic encephalopathy) caused by changes in the way the liverworks (both with reported cases of fatal outcome).

•    Hives (urticaria), scaling and shedding ofthe skin usually accompanied by redness

•    Disintegration of nails. Hands and feet should be protected against sunshine during the treatment time.

Not known (frequency cannot be estimated from the available data):

•    Tumour lysis syndrome (complications which are caused by the break-down products of dying cancer cells) this may cause for example muscle weakness due to increased levels of potassium in your blood, acute kidney failure due to increased levels of phosphate in your blood, seizures and movement disorders due to lower levels of calcium in your blood.

•    Eye complications (macular oedema, flashes of light, seeing spots)

•    Vein inflammation

•    Hard skin (scleroderma)

•    System lupus erythematosus mainly characterized by recurrent red patches on the skin usually accompanied by episodes of inflammation of joints, tendons and other connective tissues and organs.

Reporting of side effects

Ifyou get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard By reporting side effects you can help provide more information on the safety of this medicine.

5. HOWTOSTOREPACLITAXEL

This medicine will be prepared and administrated by a Healthcare Professional. Do not store above 25°C.

Store in the original package to protect from light.

Do not use this medicine after the expiry date printed on the vial or carton. The expiry date refers to the last day of that month.

This medicine will be disposed of in the hospital according to local guidelines.

Forfurther information refer to the SPC for this medicine.

Keep out ofthe sight and reach of children

6. CONTENTS OF THE PACK AND OTHER INFORMATION

What Paclitaxel 6mg/ml concentrate for solution for infusion contains:

Paclitaxel: 6mg perlml ofconcentratefor solution for infusion.

A vial of5ml contains 30mg of paclitaxel.

A vial of 16.7ml contains 100mg of paclitaxel.

The other ingredients are: Ethanol (385 mg/ml), macrogolglycerol ricinoleate, citric acid (anhydrous).

What Paclitaxel looks like and contents of the pack:

Paclitaxel 6 mg/ml of concentrate for solution for infusion is a clear, colourless to slightly yellow viscous solution available in glass vials.

Pack sizes:

1x5ml vial (30mg/5ml)

1x 16.7ml vial (100mg/16.7ml)

Marketing Authorisation Holder

Ennogen Pharma Limited

Unit G4, Riverside Industrial Estate,

RiversideWay, Dartford, DA1 5BS, UK.

Manufacturer of the product:

Actavis Italy S.p.A.,

Nerviano Plant, Viale PasteurlO 20014 Nerviano (Milan) Italy

This leaflet was last amended in June 2015.

*8-20 mg for KS patients

** or an equivalent antihistamine e.g. chlorpheniramine

PACLITAXEL should be administered through an in-line filter with a microporous membrane < 0.22 p m.

Dose:

The recommended doses for the intravenous infusion of Paclitaxel are as follows:

First-line chemotherapy of ovarian carcinoma: Although other dosage regimens are under investigation, a combination regimen of Paclitaxel and cisplatin is recommended. According to duration of infusion, two doses of Paclitaxel are recommended: Paclitaxel 175 mg/m² administered intravenously over 3 hours, followed by cisplatin at a dose of 75mg/m² every three weeks, or Paclitaxel 135 mg/m² in a 24-hour infustion followed by cisplatin 75mg/m², with a 3-week interval between courses.

Second-line chemotherapy of ovarian carcinoma: the recommended dose of Paclitaxel is 175 mg/m² administered over a period of 3 hours, with a 3 week interval between courses.

Adjuvant chemotherapy in breast carcinoma: the recommended dose of Paclitaxel is 175 mg/m² administered over a period of 3 hours every 3 weeks for four courses, following AC therapy.

First-line chemotherapy of breast carcinoma: When used in combination with doxorubicin (50 mg/m²), Paclitaxel should be administered 24 hours after doxorubicin. The recommended dose of Paclitaxel is 220 mg/m² administered intravenously over a period of 3 hours, with a 3-week interval between courses. When used in combination with trastuzumab, the recommended dose of Paclitaxel is 175 mg/m² administered intravenously overaperiod of3hours, with a 3-week interval between courses. 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 (for detailed trastuzumab posology see the Summary of Product Characteristics of Herceptin ®).

Second-line chemotherapy of breast carcinoma: the recommended dose of Paclitaxel is 175 mg/m² administered overa period of 3 hours, with a 3-week interval between courses.

Treatment of advanced NSCLC: the

recommended dose of Paclitaxel is 175 mg/m² administered over a period of 3 hours, followed by cisplatin 80 mg/m² administered over a period of 3 hours, followed by cisplatin 80mg/m², with a 3 week interval between courses.

Treatment of AIDS-related Kaposi's sarcoma (KS): the recommended dose of Paclitaxel is 100mg/m² administered asa3 hour intravenous infusion every two weeks.

Subsequent doses of Paclitaxel should be administered according to individual patient tolerance.

Paclitaxel should not be readministered until the neutrophil count is > 1,500/mm³ (>1,000/mm³ for KS patients) and the platelet count is > 100,000/mm (> 75,000/mm³ for KS patients). Patients who experience severe neutropenia (neutrophil count < 500/mm³ for > 7 days) or severe peripheral neuropathy should receive a dose reduction of20% forsubsequent courses (25% for KS patients),

Patients with hepatic impairment:

Inadequate data are available to recommend dosage alteration in patients with mild to moderate hepatic impairments. Patients with severe hepatic impairment should not be treated with Paclitaxel.

Paediatric use:

Paclitaxel is not recommended for use in children below 18years due to lack ofdata on safety and efficacy.

Disposal: All items used for preparation, administration or otherwise coming into contact with Paclitaxel should undergo disposal according to local guidelines for the handling ofcytotoxic compounds.