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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Paclitaxel 6 mg/ml Concentrate for Solution for Infusion

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml of concentrate for solution for infusion contains 6 mg of paclitaxel.

A vial of 5 ml contains 30 mg of paclitaxel.

A vial of 16.7 ml contains 100 mg of paclitaxel.

A vial of 25 ml contains 150 mg of paclitaxel.

A vial of 50 ml contains 300 mg of paclitaxel.

A vial of 100 ml contains 600 mg of paclitaxel.

Excipients:

Polyoxyl Castor oil (Macrogolglycerol ricinoleate) 527.0 mg/ml Ethanol (391 mg/ml) For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Concentrate for solution for infusion

Paclitaxel 6 mg/ml, concentrate for solution for infusion is a clear colourless to slightly yellow solution with a pH in range of 3.0 - 5.5 and an osmolarity of > 4000 mOsm/l.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Ovarian carcinoma: in the first-line chemotherapy of ovarian cancer, paclitaxel is indicated for the treatment of patients with advanced carcinoma of the ovary or with residual disease (> 1 cm) after initial laparotomy, in combination with (cisplatin or carboplatin)

In the second-line chemotherapy of ovarian cancer, paclitaxel is indicated for the treatment of metastatic carcinoma of the ovary after failure of standard, platinum containing therapy.

Breast carcinoma: In the adjuvant setting, Paclitaxel is indicated for the treatment of patients with node-positive breast carcinoma following anthracycline and cyclophosphamide (AC) therapy. Adjuvant treatment with Paclitaxel should be regarded as an alternative to extended AC therapy.

Paclitaxel is indicated for the initial treatment of locally advanced or metastatic breast cancer either in combination with an anthracycline in patients for whom anthracycline therapy is suitable, or in combination with trastuzumab, in patients who over-express HER-2 (human epidermal growth factor receptor 2) at a 3+ level as determined by immunohistochemistry and for whom an anthracycline is not suitable (see section 4.4 and 5.1).

As a single agent, Paclitaxel is indicated for the treatment of metastatic carcinoma of the breast in patients who have failed, or are not candidates for standard, anthracycline containing therapy.

Advanced non-small cell lung carcinoma: Paclitaxel, in combination with cisplatin, is indicated for the treatment of non-small cell lung carcinoma (NSCLC) in patients who are not candidates for potentially curative surgery and/or radiation therapy.

AIDS-related Kaposi’s sarcoma: Paclitaxel is indicated for the treatment of patients with advanced AIDS-related Kaposi’s sarcoma (KS) who have failed prior liposomal anthracycline therapy.

Limited efficacy data supports this indication, a summary of the relevant studies is shown in section 5.1.

4.2 Posology and method of administration

Paclitaxel should only be administered under the supervision of a qualified oncologist in units specialised in the administration of cytotoxic agents (see section 6.6).

All patients must be premedicated with corticosteroids, antihistamines, and H2 antagonists prior to Paclitaxel 6 mg/ml, concentrate for solution for infusion, e.g.

Medicinal product	Dose	Administration prior to Paclitaxel
dexamethasone	20 mg oral* or IV	For oral administration: approximately 12 and 6 hours or for

		IV administration: 30 to 60 min
diphenhydramine**	50 mg IV	30 to 60 min
cimetidine or ranitidine	300 mg IV 50 mg IV	30 to 60 min

*8-20 mg in KS patients

** or an equivalent antihistamine e.g. chlorpheniramine

For instructions on dilution of the product before administration, see section 6.6.

Paclitaxel should be administered intravenously through an in-line filter with a microporous membrane ^ 0.22 pm (see section 6.6).

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 75 mg/m every three weeks or paclitaxel 135 mg/m², in a 24-hour infusion, followed by cisplatin 75 mg/m², with a 3 week interval between courses (see section 5.1).

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 (see section 4.5 and 5.1). When used in combination with trastuzumab, the recommended dose of paclitaxel is 175 mg/m2 administered intravenously over a period of 3 hours, with a 3-week interval between courses (see section 5.1). 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 over a period of 3 hours, with a 3-week interval between courses.

The treatment of advanced non-small-cell lung carcinoma (NSCLC): the

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

The treatment of AIDS-related KS: the recommended dose of paclitaxel is 100 mg/m² administered as a 3-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/mm³ (> 75,000/mm3 for KS patients). Patients who experience severe neutropenia (neutrophil count < 500/mm3 for a week or longer) or severe peripheral neuropathy should receive a dose reduction of 20% for subsequent courses (25% for KS patients) (see section 4.4).

Patients with hepatic impaired: Inadequate data are available to recommend dosage alterations in patients with mild to moderate hepatic impairments (see section 4.4 and 5.2). Patients with severe hepatic impairment should not be treated with paclitaxel.

Paediatric use: Paclitaxel is not recommended for use in children below 18 years due to lack of data on safety and efficacy

4.3 Contraindications

Paclitaxel is contraindicated in patients with severe hypersensitivity to paclitaxel or to any excipient, especially polyoxyethylated castor oil (see section 4.4).

Paclitaxel is contraindicated during lactation (see section 4.6), and should not be used in patients with baseline neutrophils < 1,500/mm3 (< 1,000/mm3 for KS patients).

In KS, Paclitaxel is also contraindicated in patients with concurrent, serious, uncontrolled infections.

4.4 Special warnings and precautions for use

Paclitaxel should be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents. Since significant hypersensitivity reactions may occur, appropriate supportive equipment should be available. Patients must be pretreated with corticosteroids, antihistamines and H₂ antagonists (see section 4.2).

Paclitaxel should be given before cisplatin when used in combination (see section 4.5).

Significant hypersensitivity reactions characterised by dyspnoea and hypotension requiring treatment, angioedema and generalised urticaria have occurred in < 1% of patients receiving paclitaxel after adequate premedication. These reactions are probably histamine-mediated. In the case of severe hypersensitivity reactions, paclitaxel infusion should be discontinued immediately, symptomatic therapy should be initiated and the patient should not be rechallenged with the medicinal product.

Bone marrow suppression (primarily neutropenia) is the dose-limiting toxicity. Frequent monitoring of blood counts should be instituted. Patients should not be retreated until neutrophils recover to ^ 1,500/mm³ 1,000/mm³

for KS patients) and platelets recover to ^ 100,000/mm³ 75,000/mm³ for

KS patients). In the KS clinical study, the majority of patients were receiving granulocyte colony stimulating factor (G-CSF).

Patients with hepatic impairment may be at increased risk of toxicity, particularly Grade 3-4 myelosuppression. There is no evidence that the toxicity of paclitaxel is increased when given as a 3-hour infusion to patients with mildly abnormal liver function. When paclitaxel is given as a longer infusion, increased myelosuppression may be seen in patients with moderate to severe hepatic impairment. Patients should be monitored closely for the development of profound myelosuppression (see section 4.2). Inadequate data are available to recommend dosage alterations in patients with mild to moderate hepatic impairments (see section 5.2).

No data are available for patients with severe baseline cholestasis. Patients with severe hepatic impairment must not be treated with paclitaxel.

Severe cardiac conduction abnormalities have been reported rarely with single agent paclitaxel. If patients develop significant conduction abnormalities during paclitaxel administration, appropriate therapy should be administered and continuous cardiac monitoring should be performed during subsequent therapy with paclitaxel. Hypotension, hypertension, and bradycardia have been observed during paclitaxel administration; patients are usually asymptomatic and generally do not require treatment. Frequent vital sign monitoring, particularly during the first hour of paclitaxel infusion, is recommended. Severe cardiovascular events were observed more frequently in patients with NSCLC than breast or ovarian carcinoma. A single case of heart failure related to paclitaxel was seen in the AIDS-KS clinical study.

When paclitaxel is used in combination with doxorubucin or trastuzumab for initial treatment of metastatic breast cancer, attention should be placed on the monitoring of cardiac function. 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 three 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). For more details see Summary of Product Characteristics of Herceptin^® or doxorubicin.

Although the occurrence of peripheral neuropathy is frequent, the development of severe symptoms is rare. In severe cases, a dose reduction of 20% (25% for KS patients) for all subsequent courses of paclitaxel is recommended. In NSCLC patients and in ovarian cancer patients treated in the first-line setting, the administration of paclitaxel as a three hour infusion in combination with cisplatin, resulted in a greater incidence of severe neurotoxicity than both single agent paclitaxel and cyclophosphamide followed by cisplatin.

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.

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

Since paclitaxel concentrate for solution for infusion contains ethanol (391 mg/ml), consideration should be given to possible CNS and other effects.

Paclitaxel concentrate for solution for infusion contains Polyoxyl Castor oil, which may cause severe allergic reactions.

Pseudomembranous colitis has been rarely reported including cases 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.

In KS patients, severe mucositis is rare. If severe reactions occur, the paclitaxel dose should be reduced by 25%

Paclitaxel has shown to be teratogenic, embryotoxic and mutagenic in many experimental systems.

Therefore sexually active fertile female and male patients should use effective methods of contraception during treatment and up to six months after treatment for men and women (see section 4.6). Hormonal contraception is contraindicated in hormone receptor positive tumors.

4.5 Interaction with other medicinal products and other forms of interaction

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. When paclitaxel was given after cisplatin, patients showed a more profound myelosuppression and an approximately 20% decrease in paclitaxel clearance. Patients treated with paclitaxel and cisplatin may have an increased risk of renal failure as compared to cisplatin alone in gynecological cancers.

Since the elimination of doxorubicin and its active metabolites can be reduced when paclitaxel and doxorubicin are given closer in time, paclitaxel for initial treatment of metastatic breast cancer should be administered 24 hours after doxorubicin (see section 5.2).

The metabolism of paclitaxel is catalysed, in part, by cytochrome P450 isoenzymes CYP2C8 and CYP3A4 (see section 5.2). Clinical studies have demonstrated that CYP2C8-mediated metabolism of paclitaxel, to 6a-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 other CYP3A4 substrates/inhibitors are limited. Therefore, caution should be exercised when administering paclitaxel concomitantly with medicines known to inhibit (e.g. erythromycin, fluoxetine, gemfibrozil) or induce (e.g. rifampicin, carbamazepine, phenytoin, phenobarbital, efavirenz, nevirapine) either CYP2C8 or CYP3A4.

Paclitaxel clearance is not affected by cimetidine premedication.

Studies in KS patients, who were taking multiple concomitant medicinal product, suggest that the systemic clearance of paclitaxel was significantly lower in the presence of nelfinavir and ritonavir, but not with indinavir. Insufficient information is available on interactions with other protease inhibitors. Consequently, paclitaxel should be administered with caution in patients receiving protease inhibitors as concomitant therapy.

4.6 Pregnancy and lactation

Pregnancy:

There are very limited data on the use of paclitaxel in human pregnancy. Paclitaxel is suspected to cause serious birth defects when administered during pregnancy. Paclitaxel has been shown to be both embryotoxic and foetotoxic in rabbits, and to reduce fertility 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. Also Paclitaxel should not be used in women of childbearing potential not using effective contraception, unless the clinical condition of the mother requires treatment with paclitaxel.

Women of childbearing potential should use effective contraception during and up to 6 month after receiving treatment with Paclitaxel.

Male patients treated with paclitaxel are advised not to father a child during and up to six months after treatment.

Lactation

Paclitaxel is contraindicated during lactation (see section 4.3). It is not known whether paclitaxel excreted in human breast milk. Studies in animals have shown transfer of paclitaxel into milk (see section 5.3). Breastfeeding should be discontinued for the duration of therapy.

Fertility

Paclitaxel induced infertility in male rats (see section 5.3). The relevance for humans is unknown. Male patients should seek advice regarding cryoconservation of sperm prior to treatment with paclitaxel because of the possibility of irreversible infertility.

4.7 Effects on ability to drive and use machines

Paclitaxel has not been demonstrated to interfere with this ability. However, it should be noted that the formulation contains alcohol (see section 4.4 and 6.1).

The ability to drive or to use machines may be decreased due to alcohol content of this medicinal product.

4.8 Undesirable effects

Unless otherwise noted, the following discussion refers to the overall safety database of 812 patients with solid tumours treated with single-agent paclitaxel in clinical studies. As the KS population is very specific, a special chapter based on a clinical study with 107 patients, is presented at the end of this section.

The frequency and severity of adverse reactions, unless otherwise mentioned, are generally similar between patients receiving paclitaxel for the treatment of ovarian carcinoma, breast carcinoma, or NSCLC. None of the observed toxicities were clearly influenced by age.

A significant hypersensitivity reaction with possible fatal outcome (defined as hypotension requiring therapy, angioedema, respiratory distress requiring bronchodilator therapy, or generalised urticaria) occurred in two (< 1%) patients. Thirty-four percent of patients (17% of all courses) experienced minor hypersensitivity reactions. These minor reactions, mainly flushing and rash, did not require therapeutic intervention nor did they prevent continuation of paclitaxel therapy.

The most frequent significant adverse reactions was bone marrow suppression. Severe neutropenia (< 500 cells/mm³) occurred in 28% of patients, but was not associated with febrile episodes. Only 1% of patients experienced severe neutropenia for £7 days.

Thrombocytopenia was reported in 11% of patients. Three percent of patients had a platelet count nadir < 50,000/mm3 at least once while on study. Anaemia was observed in 64% of patients, but was severe (Hb < 5 mmol/l) in only 6% of patients. Incidence and severity of anaemia is related to baseline haemoglobin status.

Neurotoxicity, mainly peripheral neuropathy, appeared to be more frequent and severe with a 175 mg/m² 3-hour infusion (85% neurotoxicity, 15% severe) than with a 135 mg/m 24-hour infusion (25% peripheral neuropathy, 3% severe) when paclitaxel was combined with cisplatin. In NSCLC patients and in ovarian cancer patients treated with paclitaxel over 3 hours followed by cisplatin, there is an apparent increase in the incidence of severe neurotoxicity. Peripheral neuropathy can occur following the first course and can worsen with increasing exposure to paclitaxel. Peripheral neuropathy was the cause of paclitaxel discontinuation in a few cases. Sensory symptoms have usually improved or resolved within several months of paclitaxel discontinuation. Preexisting neuropathies resulting from prior therapies are not a contraindication for paclitaxel therapy.

Arthralgia or myalgia affected 60% of patients and was severe in 13% of patients.

Injection site reactions during intravenous administration may lead to localised oedema, pain, erythema, and induration; on occasion, extravasation can result in cellulitis. Skin sloughing and/or peeling has been reported, sometimes related to extravasation. Skin discoloration may also occur. 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. A specific treatment for extravasation reactions is unknown at this time.

The table below lists adverse reactions associated with the administration of single agent paclitaxel administered as a three hour infusion in the metastatic setting (812 patients treated in clinical studies) and as reported in the postmarketing surveillance* of paclitaxel.

The frequency of adverse reactions listed below is defined using the following convention:

very common 1/10); common 1/100, < 1/10); uncommon 1/1,000, < 1/100); rare 1/10,000, < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data)

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

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
Blood and the lymphatic system disorders:	Very common: myelosuppression, neutropenia, anaemia, thrombocytopenia, leucopenia, bleeding Rare: febrile neutropenia Very rare: acute myeloid leukaemia, myelodysplastic syndrome
Immune system disorders:	Very common: minor hypersensitivity reactions (mainly flushing and rash) Uncommon: significant hypersensitivity reactions requiring therapy (e.g., hypotension, angioneurotic oedema, respiratory distress, generalised urticaria, chills, back pain, chest pain, tachycardia, abdominal pain, pain in extremities, diaphoresis and hypertension) Rare: anaphylactic reactions Very rare: anaphylactic shock
Metabolism and nutrition disorders:	Very rare*: anorexia
Psychiatric disorders:	Very rare*: confusional state

Nervous system disorders:	Very common: neurotoxicity (mainly: peripheral neuropathy) Rare: motor neuropathy (with resultant minor distal weakness) 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 (scintillating scotomata), particularly in patients who have received higher doses than recommended
Ear and labyrinth disorders:	Very rare*: hearing loss, ototoxicity, tinnitus, vertigo
Cardiac disorders:	Common: bradycardia Uncommon: myocardial infarction, AV block and syncope, cardiomyopathy, asymptomatic ventricular tachycardia, tachycardia with bigeminy Very rare*: atrial fibrillation, supraventricular tachycardia
Vascular disorders:	Very common: hypotension Uncommon: thrombosis, hypertension, thrombophlebitis Very rare*: shock
Respiratory, thoracic and mediastinal disorders:	Rare: respiratory failure, pulmonary embolism, lung fibrosis, interstitial pneumonia, dyspnoea, pleural effusion Very rare: cough
Gastrointestinal disorders:	Very common: diarrhoea, vomiting, nausea, mucosal inflammation Rare: bowel obstruction, bowel perforation, ischaemic colitis, pancreatitis Very rare: mesenteric thrombosis, pseudomembranous colitis, neutropenic colitis, ascites, oesophagitis, constipation
Hepatobiliary disorders:	Very rare*: hepatic necrosis, hepatic encephalopathy (both with reported cases of fatal outcome)
Skin and subcutaneous tissue disorders:	Very common: alopecia Common: transient and mild nail and skin changes Rare*: pruritus, rash, erythema

	Very rare*: Stevens-Johnson syndrome, epidermal necrolysis, erythema multiforme, exfoliative dermatitis, urticaria, onycholysis (patients on therapy should wear sun protection on hands and feet)
Musculoskeletal and connective tissue disorders:	Very common: arthralgia, myalgia
General disorders and administration site conditions:	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
Investigations:	Common: severe elevation in AST (SGOT), severe elevation in alkaline phosphatase Uncommon: severe elevation in bilirubin Rare*: increase in blood creatinine

Breast cancer patients who received paclitaxel in the adjuvant setting following AC experienced more neurosensory toxicity, hypersensitivity reactions, arthralgia/myalgia, anaemia, infection, fever, nausea/vomiting and diarrhoea than patients who received AC alone. However, the frequency of these events was consistent with the use of single agent paclitaxel, as reported above.

Combination treatment

The following discussion refers to two major trials for the first-line chemotherapy of ovarian carcinoma (paclitaxel + cisplatin: over 1050 patients); two phase III trials in the first line treatment of metastatic breast cancer: one investigating the combination with doxorubicin (paclitaxel + doxorubicin: 267 patients), another one investigating the combination with trastuzumab (planned subgroup analysis paclitaxel + trastuzumab: 188 patients) and two phase III trials for the treatment of advanced NSCLC (paclitaxel + cisplatin: over 360 patients) (see section 5.1).

When administered as a three hour infusion for the first-line chemotherapy of ovarian cancer, neurotoxicity, arthralgia/myalgia, and hypersensitivity were reported as more frequent and severe by patients treated with paclitaxel followed by cisplatin than patients treated with cyclophosphamide followed by cisplatin. Myelosuppression appeared to be less frequent and severe with paclitaxel as a three hour infusion followed by cisplatin compared with cyclophosphamide followed by cisplatin.

For the first line chemotherapy of metastatic breast cancer, neutropenia, anaemia, peripheral neuropathy, arthralgia/myalgia, asthenia, fever, and diarrhoea were reported more frequently and with greater severity when paclitaxel (220 mg/m²) was administered as a 3-hour infusion 24 hours following doxorubicin (50 mg/m2) when compared to standard FAC therapy (5-FU 500 mg/m2, doxorubicin 50 mg/m2, cyclophosphamide 500 mg/m2). Nausea and vomiting appeared to be less frequent and severe with the paclitaxel (220 mg/m2) / doxorubicin (50 mg/m2) regimen as compared to the standard FAC regimen. The use of corticosteroids may have contributed to the lower frequency and severity of nausea and vomiting in the paclitaxel/doxorubicin arm.

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 (8% vs. 1%), infection (46% vs. 27%), chills (42% vs. 4%), fever (47% vs. 23%), cough (42% vs. 22%), rash (39% vs. 18%), arthralgia (37% vs. 21%), tachycardia (12% vs. 4%), diarrhoea (45% vs. 30%), hypertonia (11% vs. 3%), epistaxis (18% vs. 4%), acne (11% vs. 3%), herpes simplex (12% vs. 3%), accidental injury (13% vs. 3%), insomnia (25% vs. 13%), rhinitis (22% vs. 5%), sinusitis (21% vs. 7%), and injection site reaction (7% vs. 1%).

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.

When doxorubicin was administered in combination with paclitaxel in metastatic breast cancer, cardiac contraction abnormalities 20% reduction of left ventricular ejection fraction) were observed in 15% of patients vs. 10% with standard FAC regimen. Congestive heart failure was observed in < 1% in both paclitaxel/doxorubicin and standard FAC arms. Administration of trastuzumab in combination with paclitaxel in patients previously treated with anthracyclines resulted in an increased frequency and severity of cardiac dysfunction in comparison with patients treated with paclitaxel single agent (nYHA Class I/II 10% vs. 0%; NYHA Class III/IV 2% vs. 1%) and rarely has been associated with death (see trastuzumab Summary of Product Characteristics). In all but these rare cases, patients responded to appropriate medical treatment.

Radiation pneumonitis has been reported in patients receiving concurrent radiotherapy.

AIDS-related Kaposi's sarcoma

Except for haematologic and hepatic undesirable effects (see below), the frequency and severity of undesirable effects are generally similar between KS patients and patients treated with paclitaxel monotherapy for other solid tumours, based on a clinical study including 107 patients.

Blood and the lymphatic system disorders : bone marrow suppression was the major dose-limiting toxicity. Neutropenia is the most important haematological toxicity. During the first course of treatment, severe neutropenia (< 500 cells/mm ) occurred in 20% of patients. During the entire treatment period, severe neutropenia was observed in 39% of patients. Neutropenia was present for > 7 days in 41% and for 30-35 days in 8% of patients. It resolved within 35 days in all patients who were followed. The incidence of Grade 4 neutropenia lasting ^ 7 days was 22%.

Neutropenic fever related to paclitaxel was reported in 14% of patients and in 1.3% of treatment cycles. There were 3 septic episodes (2.8%) during paclitaxel administration related to the medicinal product that proved fatal.

Thrombocytopenia was observed in 50% of patients, and was severe (< 50,000 cells/mm³) in 9%. Only 14% experienced a drop in their platelet count < 75,000 cells/mm , at least once while on treatment. Bleeding episodes related to paclitaxel were reported in < 3% of patients, but the haemorrhagic episodes were localised.

Anaemia (Hb < 11 g/dL) was observed in 61% of patients and was severe (Hb < 8 g/dL) in 10%. Red cell transfusions were required in 21% of patients.

Hepato-biliary disorders : Among patients (> 50% on protease inhibitors) with normal baseline liver function, 28%, 43% and 44% had elevations in bilirubin, alkaline phosphatase and AST (SGOT), respectively. For each of these parameters, the increases were severe in 1% of cases.

4.9 Overdose

There is no known antidote for paclitaxel overdose. In case of overdose, the patient should be closely monitored. Treatment should be directed at the primary anticipated toxicities, which consist of bone marrow suppression, peripheral neurotoxicity and mucositis.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: antineoplastic agents (taxanes), ATC code: L01C D01.

Paclitaxel is a antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers and stabilises microtubules by preventing depolymerization. This stability results in the inhibition of the normal dynamic reorganisation of the microtubule network that is essential for vital interphase and mitotic cellular functions. In addition, paclitaxel induces abnormal arrays or bundles of microtubules throughout the cell cycle and multiple asters of microtubules during mitosis.

Ovarian carcinoma

In the first-line chemotherapy of ovarian carcinoma, the safety and efficacy of paclitaxel were evaluated in two major, randomised, controlled (vs. cyclophosphamide 750 mg/m / cisplatin 75 mg/m ) trials. In the Intergroup trial (BMS CA139-209), over 650 patients with stage II_b-c, III or IV primary ovarian cancer received a maximum of 9 treatment courses of paclitaxel (175 mg/m² over 3 hr) followed by cisplatin (75 mg/m²) or control. The second major trial (GOG-111/BMS CA139-022) evaluated a maximum of 6 courses of either paclitaxel (135 mg/m² over 24 hrs) followed by cisplatin (75 mg/m²) or control in over 400 patients with stage III/IV primary ovarian cancer, with a > 1 cm residual disease after staging laparotomy, or with distant metastases. While the two different paclitaxel posologies were not compared with each other directly, in both trials patients treated with paclitaxel in combination with cisplatin had a significantly higher response rate, longer time to progression, and longer survival time when compared with standard therapy. Increased neurotoxicity, arthralgia/myalgia but reduced myelosuppression were observed in advanced ovarian cancer patients administered 3-hour infusion paclitaxel/cisplatin as compared to patients who received cyclophosphamide/cisplatin.

Breast carcinoma

In the adjuvant treatment of breast carcinoma, 3121 patients with node positive breast carcinoma were treated with adjuvant paclitaxel therapy or no chemotherapy following four courses of doxorubicin and cyclophosphamide (CALGB 9344, BMS CA 139-223). Median follow-up was 69 months. Overall, paclitaxel patients had a significant reduction of 18% in the risk of disease recurrence relative to patients receiving AC alone (p = 0.0014), and a significant reduction of 19% in the risk of death (p = 0.0044) relative to patients receiving AC alone. Retrospective analyses show benefit in all patient subsets. In patients with hormone receptor negative/ unknown tumours, reduction in risk of disease recurrence was 28% (95%CI: 0.59-0.86). In the patient subgroup with hormone receptor positive tumours, the risk reduction of disease recurrence was 9% (95%CI: 0.78-1.07).

However, the design of the study did not investigate the effect of extended AC therapy beyond 4 cycles. It cannot be excluded on the basis of this study alone that the observed effects could be partly due to the difference in duration of chemotherapy between the two arms (AC 4 cycles; AC + paclitaxel 8 cycles). Therefore, adjuvant treatment with paclitaxel should be regarded as an alternative to extended AC therapy.

In a second large clinical study in adjuvant node positive breast cancer with a similar design, 3060 patients were randomized to receive or not four courses of paclitaxel at a higher dose of 225 mg/m2 following four courses of AC (NSABP B-28, BMS CA139-270). At a median follow-up of 64 months, paclitaxel patients had a significant reduction of 17% in the risk of disease recurrence relative to patients who received AC alone (p = 0.006) ; paclitaxel treatment was associated with a reduction in the risk of death of 7% (95%CI: 0.78-1.12). All subset analyses favored the paclitaxel arm. In this study patients with hormone receptor positive tumour had a reduction in the risk of disease recurrence of 23% (95%CI: 0.6-0.92); in the patient subgroup with hormone receptor negative tumour the risk reduction of disease recurrence was 10% (95%CI: 0.7-1.11).

• In the first-line treatment of metastatic breast cancer, the efficacy and safety of paclitaxel were evaluated in two pivotal, phase III, randomised, controlled open-label trials. In the first study (BMS CA139-278), the combination of bolus doxorubicin (50 mg/m²) followed after 24 hours by paclitaxel (220 mg/m2 by 3-hour infusion) (AT), was compared versus standard FAC regimen (5-FU 500 mg/m2, doxorubicin 50 mg/m2, cyclophosphamide 500 mg/m2), both administered every three weeks for eight courses. In this randomised study, 267 patients with metastatic breast cancer, who had either received no prior chemotherapy or only non-anthracycline chemotherapy in the adjuvant setting, were enrolled. Results showed a significant difference in time to progression for patients receiving AT compared to those receiving FAC (8.2 vs. 6.2 months; p= 0.029). The median survival was in favour of paclitaxel/doxorubicin vs. FAC (23.0 vs. 18.3 months; p= 0.004). In the AT and FAC treatment arm 44% and 48% respectively received follow-up chemotherapy which included taxanes in 7% and 50% respectively. The overall response rate was also significantly higher in the AT arm compared to the FAC arm (68% vs. 55%). Complete responses were seen in 19% of the paclitaxel/doxorubicin arm patients vs. 8% of the FAC arm patients. All efficacy results have been subsequently confirmed by a blinded independent review.

• In the second pivotal study, the efficacy and safety of the paclitaxel and Herceptin®combination was evaluated in a planned subgroup analysis (metastatic breast cancer patients who formerly received adjuvant anthracyclines) of the study HO648g. The efficacy of Herceptin® in combination with paclitaxel in patients who did not receive prior adjuvant anthracyclines has not been proven. The combination of trastuzumab (4 mg/kg loading dose then 2 mg/kg weekly) and paclitaxel (175 mg/m2) 3-hour infusion, every three weeks was compared to single-agent paclitaxel (175 mg/m2) 3-hour infusion, every three weeks in 188 patients with metastatic breast cancer overexpressing HER2 (2+ or 3+ as measured by immunohistochemistry), who had previously been treated with anthracyclines. Paclitaxel was administered every three weeks for at least six courses while trastuzumab was given weekly until disease progression. The study showed a significant benefit for the paclitaxel/trastuzumab combination in terms of time to progression (6.9 vs. 3.0 months), response rate (41% vs. 17%), and duration of response (10.5 vs. 4.5 months) when compared to paclitaxel alone. The most significant toxicity observed with the paclitaxel/trastuzumab combination was cardiac dysfunction (see section 4.8)

Advanced non-small cell lung carcinoma

In the treatment of advanced NSCLC, paclitaxel 175 mg/m² followed by cisplatin 80 mg/m2 has been evaluated in two phase III trials (367 patients on paclitaxel containing regimens). Both were randomised trials, one compared to treatment with cisplatin 100 mg/m2, the other used teniposide 100 mg/m2 followed by cisplatin 80 mg/m2 as comparator (367 patients on comparator). Results in each trial were similar. For the primary outcome of mortality, there was no significant difference between the paclitaxel containing regimen and the comparator (median survival times 8.1 and 9.5 months on paclitaxel containing regimens, 8.6 and 9.9 months on comparators). Similarly, for progression-free survival there was no significant difference between treatments. There was a significant benefit in terms of clinical response rate. Quality of life results are suggestive of a benefit on paclitaxel containing regimens in terms of appetite loss and provide clear evidence of the inferiority of paclitaxel containing regimens in terms of peripheral neuropathy (p < 0.008).

AIDS-related Kaposi’s sarcoma

In the treatment of AIDS-related KS, the efficacy and safety of paclitaxel were investigated in a non-comparative study in patients with advanced KS, previously treated with systemic chemotherapy. The primary end-point was best tumour response. Of the 107 patients, 63 were considered resistant to liposomal anthracyclines. This subgroup is considered to constitute the core efficacy population. The overall success rate (complete/partial response) after 15 cycles of treatment was 57% (CI 44 - 70%) in liposomal anthracycline-resistant patients. Over 50% of the responses were apparent after the first 3 cycles. In liposomal anthracycline-resistant patients, the response rates were comparable for patients who had never received a protease inhibitor (55.6%) and those who received one at least 2 months prior to treatment with paclitaxel (60.9%). The median time to progression in the core population was 468 days (95% CI 257-NE). Median survival could not be computed, but the lower 95% bound was 617 days in core patients.

5.2 Pharmacokinetic properties

Following intravenous administration, paclitaxel exhibits a biphasic decline in plasma concentrations. The pharmacokinetics of paclitaxel were determined following 3 and 24 hour infusions at doses of 135 and 175 mg/m2. Mean terminal half-life estimates ranged from 3.0 to 52.7 hours, and mean, non-compartmentally derived, values for total body clearance ranged from 11.6 to 24.0 l/hr/m2; total body clearance appeared to decrease with higher plasma concentrations of paclitaxel. Mean steady-state volume of distribution ranged from 198 to 688 l/m2, indicating extensive extravascular distribution and/or tissue binding. With the 3-hour infusion, increasing doses result in non-linear pharmacokinetics. For the 30% increase in dose from 135 mg/m2 to 175 mg/m², the C_maxand AUC-j-covalues increased 75% and 81%, respectively.

Following an intravenous dose of 100 mg/ m² given as a 3-hour infusion to 19 KS patients, the mean C_max was 1,530 ng/ml (range 761 - 2,860 ng/ml) and the mean AUC 5,619 ng.hr/ml (range 2,609 - 9,428 ng.hr/ml). Clearance was 20.6 l/h/ m2 (range 11-38) and the volume of distribution was 291 l/ m2 (range 121638). The terminal elimination half-life averaged 23.7 hours (range 12 - 33).

Intrapatient variability in systemic paclitaxel exposure was minimal. There was no evidence for accumulation of paclitaxel with multiple treatment courses.

In vitro studies of binding to human serum proteins indicate that 89-98% of medicinal product is bound. The presence of cimetidine, ranitidine, dexamethasone or diphenhydramine did not affect protein binding of paclitaxel.

The disposition of paclitaxel has not been fully elucidated in humans. Mean values for cumulative urinary recovery of unchanged drug have ranged from

1.3 to 12.6% of the dose, indicating extensive non-renal clearance. Hepatic metabolism and biliary clearance may be the principal mechanism for disposition of paclitaxel. Paclitaxel appears to be metabolised primarily by cytochrome P450 enzymes. Following administration of a radiolabelled paclitaxel, an average of 26, 2 and 6% of the radioactivity was excreted in the faeces as 6a-hydroxypaclitaxel, 3'-p-hydroxypaclitaxel, and 6a-3'-p-

dihydroxy-paclitaxel, respectively. The formation of these hydroxylated metabolites is catalysed by CYP2C8, CYP3A4, and both CYP2C8 and CYP3A4 respectively. The effect of renal or hepatic dysfunction on the disposition of paclitaxel following a 3-hour infusion has not been investigated formally. Pharmacokinetic parameters obtained from one patient undergoing haemodialysis who received a 3-hour infusion of paclitaxel 135 mg/m2 were within the range of those defined in non-dialysis patients.

In clinical trials where paclitaxel and doxorubicin were administered concomitantly, the distribution and elimination of doxorubicin and its metabolites were prolonged. Total plasma exposure to doxorubicin was 30% higher when paclitaxel immediately followed doxorubicin than when there was a 24-hour interval between medicinal product.

For use of paclitaxel in combination with other therapies, please consult the Summary of Product Characteristics of cisplatin, doxorubicin or trastuzumab for information on the use of these medicinal products.

5.3 Preclinical safety data

The carcinogenic potential of paclitaxel has not been studied. However, based on the published literature, paclitaxel is a potential carcinogenic and genotoxic agent at clinical doses, based upon its pharmacodynamic mechanism of action.

Paclitaxel has been shown to be mutagenic in both in vitro and in vivo mammalian test systems.

Paclitaxel has also been shown to be both embryotoxic and foetotoxic in rabbits, and to reduce fertility in rats.

Adverse effect on male reproductive organs was seen doses low doses, impairment of male and female fertility were seen at toxic doses. Embryo-fetal toxicity as indicated by intrauterine mortality, increased resorptions and increased foetal deaths was seen at maternally toxic doses in rats and rabbits. In rabbits teratogenic effects were seen at doses below maternal toxicity. Limited excretion of paclitaxel was seen in milk of lactating rats. Paclitaxel was not mutagenic but did cause chromosome aberrations in vitro and in vivo. The carcinogenic potential of paclitaxel has not been studied Delayed neurotoxic effects were seen histopathologically after repeated dosing with no/limited evidence of recovery.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Anhydrous ethanol

Polyoxyl castor oil (Macrogolglycerol ricinoleate)

6.2 Incompatibilities

Polyoxyethylated castor oil can result in DEHP (di-(2-ethylhexyl)phthalate) leaching from plasticised polyvinyl chloride (PVC) containers, at levels, which increase with time and concentration. Consequently, the preparation, storage and administration of diluted paclitaxel should be carried out using non-PVC-containing equipment.

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3 Shelf life

Unopened vial:

24 months

After opening before dilution

Chemical and physical in-use stability has been demonstrated for 28 days at 25°C following multiple needle entries and product withdrawal. From a microbiological point of view, once opened the product may be stored for a maximum of 28 days at 25°C. Other in-use storage times and conditions are the responsibility of the user.

After dilution

Chemical and physical in-use stability of the solution prepared for infusion has been demonstrated at 5°C and at 25°C for 7 days when diluted in 5% Dextrose solution, and for 14 days when diluted in 0.9% Sodium Chloride Injection. 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 and would normally not be longer than 24 hours at 2 to 8°C, unless dilution has taken place in controlled and validated aseptic conditions.

6.4 Special precautions for storage

Do not store above 25°C.

Keep the vial in the outer carton in order to protect from light.

Freezing does not adversely affect the unopened vials.

For storage conditions of the diluted medicinal product, see section 6.3

6.5 Nature and contents of container

Type I glass vials (closed with Omniflex Plus rubber stopper) containing 30 mg, 100 mg, 150mg, 300 mg and 600mg of paclitaxel in 5 ml, 16.7 ml, 25ml,50 ml and 100ml of solution respectively.

The vials are packed separately in a carton.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

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 redissolves 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. Following multiple needle entries and product withdrawals, the 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. The Chemo-Dispensing Pin device or similar devices with spikes should not be used since they can cause the vial stopper to collapse, resulting in loss of sterile integrity.

Preparation for IV administration: prior to infusion, Paclitaxel concentrate for solution for infusion 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.

After dilution the solution is for single use only.

Upon preparation, solutions may show haziness, which is attributed to the formulation vehicle, and is not removed by filtration. Paclitaxel 6 mg/ml concentrate for solution for infusion should be administered through an in-line filter with a microporous membrane ^ 0.22 pm. No significant losses in potency have been noted following simulated delivery of the solution through IV tubing containing an in-line filter.

There have been rare reports of precipitation during paclitaxel infusions, usually towards the end of a 24 hour 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.

To minimise patient exposure to DEHP which may be leached from plasticised 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. Use of filter devices (e.g. IVEX-2) which incorporate short inlet and/or outlet plasticised PVC tubing has not resulted in significant leaching of DEHP.

Disposal: Any unused product or waste material should be disposed of in accordance with local requirements.

Protection instructions for preparation of Paclitaxel solution for infusion

1. Protective chamber should be used and protective gloves as well as protective gown should be worn. If there is no protective chamber available mouth cover and goggles should be used.

2. Pregnant women or women who may become pregnant, should not handle this product.

3. Opened containers, like injection vials and infusion bottles and used canules, syringes, catheters, tubes, and residuals of cytostatics should be considered as hazardous waste and undergo disposal according to local guidelines for the handling of HAZARDOUS WASTE.

4. Follow the instructions below in case of spillage: - protective clothing should be worn - broken glass should be collected and placed in the container for HAZARDOUS WASTE - contaminated surfaces should be flushed properly with copious amounts of cold water - the flushed surfaces should then be wiped thoroughly and the materials used for wiping should be disposed as HAZARDOUS WASTE

5. In the event of contact of Paclitaxel Concentrate for Solution for Infusion with the skin, the area should be rinsed with plenty of running water and then washed with soap and water. In case of contact with mucous membranes, wash the contacted area thoroughly with water. If you have any discomfort, contact a doctor.

6. In case of contact of Paclitaxel Concentrate for Solution for Infusion with eyes, wash them thoroughly with plenty of cold water. Contact an ophthalmologist immediately.

7 MARKETING AUTHORISATION HOLDER

Accord Healthcare Limited, Sage House, 319, Pinner Road, North Harrow,

Middlesex, HA1 4HF,

United Kingdom

MARKETING AUTHORISATION NUMBER(S)

PL 20075/0128

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

15/04/2010

10 DATE OF REVISION OF THE TEXT

25/04/2015