Taxespira (previously Docetaxel Hospira UK Limited ) - patient leaflet, side effects, dosage

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Ventricular arrhythmia including ventricular tachycardia (sometimes fatal) has been reported in patients treated with docetaxel in combination regimens including doxorubicin, 5-fluorouracil and/or cyclophosphamide (see section 4.8).

Baseline cardiac assessment is recommended.

Eye disorders

Cystoid macular oedema (CMO) has been reported in patients treated with docetaxel. Patients with impaired vision should undergo a prompt and complete ophthalmologic examination. In case CMO is diagnosed, docetaxel treatment should be discontinued and appropriate treatment initiated (see section 4.8).

Others

Contraceptive measures must be taken by both men and women during treatment and for men at least 6 months after cessation of therapy (see section 4.6).

The concomitant use of docetaxel with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin and voriconazole) should be avoided (see section 4.5).

Additional cautions for use in adjuvant treatment of breast cancer

Complicated neutropenia

For patients who experience complicated neutropenia (prolonged neutropenia, febrile neutropenia or infection), G-CSF and dose reduction should be considered (see section 4.2).

Gastrointestinal reactions

Symptoms such as early abdominal pain and tenderness, fever, diarrhoea, with or without neutropenia, may be early manifestations of serious gastrointestinal toxicity and should be evaluated and treated promptly.

Congestive heart failure (CHF)

Patients should be monitored for symptoms of congestive heart failure during therapy and during the follow up period. In patients treated with the TAC regimen for node positive breast cancer, the risk of CHF has been shown to be higher during the first year after treatment (see sections 4.8 and 5.1).

Leukaemia

In the docetaxel, doxorubicin and cyclophosphamide (TAC) treated patients, the risk of delayed myelodysplasia or myeloid leukaemia requires haematological follow-up.

Patients with 4+ nodes

As the benefit observed in patient with 4+ nodes was not statistically significant on disease-free survival (DFS) and overall survival (OS), the positive benefit/risk ratio for TAC in patients with 4+ nodes was not fully demonstrated at the final analysis (see section 5.1).

Elderly people

There are limited data available in patients >70 years of age on docetaxel use in combi doxorubicin and cyclophosphamide.

Of the 333 patients treated with docetaxel every three weeks in a prostate canc were 65 years of age or greater and 68 patients were older than 75 years. In pa docetaxel every three weeks, the incidence of related nail changes occurr patients who were 65 years of age or greater compared to younger patient fever, diarrhoea, anorexia, and peripheral oedema occurred at rates > 10 % 75 years of age or greater versus less than 65 years.

Among the 300 (221 patients in the phase III part of the study and 79 patients in the phase II part) patients treated with docetaxel in combination with cisplatin and 5-fluorouracil in the gastric cancer study, 74 were 65 years of age or older and 4 patients were 75 years of age or older. The incidence of serious adverse events was higher in older people compared to younger patients. The incidence of the following adverse events (all grades): lethargy, stomatitis, neutropenic infection occurred at rates > 10% higher in patients who were 65 years of age or older compared to younger patients.

Older people treated with TCF should be closely monitored.

50 vol % ethanol anhydrous (alcohol), i.e. up to 395 mg ethanol equivalent to 10 ml of beer or 4 ml of wine.

80mg/4 ml:

This medicinal product contains 50 vol % ethanol anhydrous (alcohol), i.e. up to 1580 mg ethanol anhydrous ml vial. This is equivalent to 40 ml of beer or17 ml of wine.

This medicinal product contains 50 vol % ethanol anhydrous (alcohol), i.e. up to 2370 mg ethanol anhydrous per 6 ml vial. This is equivalent to 60 ml of beer or 25 ml of wine.

140mg/7 ml:

This medicinal product contains 50 vol % ethanol anhydrous (alcohol), i.e. up to 2765 mg ethanol anhydrous per 7 ml vial. This is equivalent to 70 ml of beer or 29 ml of wine.

160mg/8 ml:

This medicinal product contains 50 vol % ethanol anhydrous (alcohol), i.e. up to 3160 mg ethanol anhydrous per 8 ml vial. This is equivalent to 80 ml of beer or 33 ml of wine.

Harmful for those suffering from alcoholism.

To be taken into account in pregnant or breast-feeding women, in children and in high-risk groups such as patients with liver disease, or epilepsy.

Consideration should be given to possible effects on the central nervous system.

• 4.5 Interaction with other medicinal products and other forms of interaction

The amount of alcohol in this medicinal product may alter the effects of other medicinal products.

In vitro studies have shown that the metabolism of docetaxel may be modified by the concomitant administration of compounds which induce, inhibit or are metabolised by (and thus may inhibit the enzyme competitively) cytochrome P450–3A such as ciclosporine, ketoconazole and erythromycin. As a result, caution should be exercised when treating patients with these medicinal products as concomitant therapy since there is a potential for a significant interaction.

In case of combination with CYP3A4 inhibitors, the occurrence of docetaxel adverse reactions may increase, as a result of reduced metabolism. If the concomitant use of a strong CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin and voriconazole) cannot be avoided, a close clinical surveillance is warranted and a dose-adjustment of docetaxel may be suitable during the treatment with the strong CYP3A4 inhibitor (see section 4.4). In a pharmacokinetic study with 7 patients, the co-administration of docetaxel with the strong CYP3A4 inhibitor ketoconazole leads to a significant decrease in docetaxel clearance by 49%.

Docetaxel pharmacokinetics in the presence of prednisone was studied in patients with metastatic prostate cancer. Docetaxel is metabolised by CYP3A4 and prednisone is known to induce CYP3A4. No statistically significant effect of prednisone on the pharmacokinetics of docetaxel was observed.

Docetaxel is highly protein bound (>95%). Although the possible in vivo interaction of docetaxel with concomitantly administered medicinal product has not been investigated formally, in vitro interactions with tightly protein-bound agents such as erythromycin, diphenhydramine, propranolol, propafenone, phenytoin, salicylate, sulfamethoxazole and sodium valproate did not affect protein binding of docetaxel. In addition, dexamethasone did not affect protein binding of docetaxel. Docetaxel did not influence the binding of digitoxin.

The pharmacokinetics of docetaxel, doxorubicin and cyclophosphamide were not influenced by the co-administration. Limited data from a single uncontrolled study were suggestive of an interaction between docetaxel and carboplatin. When combined to docetaxel, the clearance of carboplatin was about 50% higher than values previously reported for carboplatin monotherapy.

• 4.6 Fertility, pregnancy and lactation

Pregnancy

There is no information on the use of docetaxel in pregnant women. Docetaxel has been shown to be both embryotoxic and foetotoxic in rabbits and rats, and to reduce fertility in rats. As with other cytotoxic medicinal products, docetaxel may cause foetal harm when administered to pregnant women. Therefore, docetaxel must not be used during pregnancy unless clearly indicated.

Women of childbearing age receiving docetaxel should be advised to avoid becoming pregnant, and to inform the treating physician immediately should this occur.

Breast-feeding

Docetaxel is a lipophilic substance but it is not known whether it is excreted in human milk.

Consequently, because of the potential for adverse reactions in nursing infants, breast feeding must be discontinued for the duration of docetaxel therapy.

Contraception in males and females

An effective method of contraception should be used during treatment.

Fertility

In non-clinical studies, docetaxel has genotoxic effects and may alter male fertility (see section 5.3). Therefore, men being treated with docetaxel are advised not to father a child during and up to 6 months after treatment and to seek advice on conservation of sperm prior to treatment

• 4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. The amount of alcohol in this medicinal product and the side effects of the product may impair the ability to drive or use machines (see sections 4.4 and 4.8). Therefore, patients should be warned of the potential impact of the amount of alcohol and the side effects of this medicinal product on the ability to drive or use machines, and be advised not to drive or use machines if they experience these side effects during treatment.

• 4.8 Undesirable effects

Summary of the safety profile for all indications

The adverse reactions considered to be possibly or probably related to the administration of docetaxel have been obtained in:

• 1,312 and 121 patients who received 100 mg/m2 and 75 mg/m2 of docetaxel as a single agent

respectively.

• 258 patients who received docetaxel in combination with doxorubicin.
• 406 patients who received docetaxel in combination with cisplatin.
• 92 patients treated with docetaxel in combination with trastuzumab.
• 255 patients who received docetaxel in combination with capecitabine.
• 332 patients who received docetaxel in combination with prednisone or prednisolone (clinically

important treatment related adverse events are presented).

• 1,276 patients (744 and 532 in TAX 316 and GEICAM 9805 respectively) who received

docetaxel in combination with doxorubicin and cyclophosphamide (clinically important treatment related adverse events are presented).

• 300 gastric adenocarcinoma patients (221 patients in the phase III part of the study and

79 patients in the phase II part) who received docetaxel in combination with cisplatin and 5-fluorouracil (clinically important treatment related adverse events are presented).

• 174 and 251 head and neck cancer patients who received docetaxel in combination with

cisplatin and 5-fluorouracil (clinically important treatment related adverse events are presented).

Frequencies are defined as: very common (>1/10), common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from available data

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

The most commonly reported adverse reactions of docetaxel alone are: neutropenia (which was reversible and not cumulative; the median day to nadir was 7 days and the median duration of severe neutropenia (<500 cells/mm3) was 7 days), anaemia, alopecia, nausea, vomiting, stomatitis, diarrhoea and asthenia. The severity of adverse events of docetaxel may be increased when docetaxel is given in combination with other chemotherapeutic agents.

For combination with trastuzumab, adverse events (all grades) reported in >10% are displayed. There was an increased incidence of SAEs (40% vs. 31%) and Grade 4 AEs (34% vs. 23%) in the trastuzumab combination arm compared to docetaxel monotherapy.

For combination with capecitabine, the most frequent treatment-related undesirable effects (>5%) reported in a phase III study in breast cancer patients failing anthracycline treatment are presented (see capecitabine summary of product characteristics).

The following adverse reactions are frequently observed with docetaxel:

Immune system disorders

Hypersensitivity reactions have generally occurred within a few minutes following the start of the infusion of docetaxel and were usually mild to moderate. The most frequently reported symptoms were flushing, rash with or without pruritus, chest tightness, back pain, dyspnoea and fever or chills. Severe reactions were characterised by hypotension and/or bronchospasm or generalized rash/erythema (see section 4.4).

Nervous system disorders

The development of severe peripheral neurotoxicity requires a reduction of dose (see sections 4.2 and 4.4). Mild to moderate neuro-sensory signs are characterised by paraesthesia, dysesthe pain

including burning. Neuro-motor events are mainly characterised by weakness.

Skin and subcutaneous tissue disorders

Reversible cutaneous reactions have been observed and were generally consid moderate. Reactions were characterised by a rash including localised eru

hands (including severe hand and foot syndrome), but also on the a associated with pruritus. Eruptions generally occurred within one Less frequently, severe symptoms such as eruptions followed b interruption or discontinuation of docetaxel treatment were rep nail disorders are characterised by hypo- or hyperpigmentation

General disorders and administration site conditions. ,^

Infusion site reactions were generally mild and consisted of hyper pigmentation, inflammation, redness or dryness of the skin, phlebitis or extravasation and swelling of the vein.

heral oedema and less frequently pleural effusion,. The peripheral oedema usually starts at the lower h a weight gain of 3 kg or more. Fluid retention is

Tabulated list of adverse reactions in breast cancer for Taxespira 100 mg/m2 single agent

MedDRA system organ classes	^erycommon adverse ^reactions	Common adverse reactions	Uncommon adverse reactions
Infections and infestations ♦ A .7^	Infections (G3/4: 5.7%; including sepsis and pneumonia, fatal in 1.7%)	Infection associated with G4 neutropenia (G3/4: 4.6%)
Blood and lymphatic system disorders	Neutropenia (G4: 76.4%); Anaemia (G3/4: 8.9%); Febrile neutropenia	Thrombocytopenia (G4: 0.2%)
Immune system disorders	Hypersensitivity (G3/4: 5.3%)
Metabolism and nutrition disorders	Anorexia
Nervous system disorders	Peripheral sensory neuropathy (G3: 4.1%); Peripheral motor neuropathy (G3/4: 4%); Dysgeusia (severe:

MedDRA system organ classes	Very common adverse reactions	Common adverse reactions	Uncommon adverse reactions
	0.07%)
Cardiac disorders		Arrhythmia (G3/4: 0.7%)	Cardiac failure
Vascular disorders		Hypotension; Hypertension; Haemorrhage
Respiratory, thoracic and mediastinal disorders	Dyspnoea (severe: 2.7%)
Gastrointestinal disorders	Stomatitis (G3/4: 5.3%); Diarrhoea (G3/4: 4%); Nausea (G3/4: 4%); Vomiting (G3/4: 3%)	Constipation (severe: 0.2%); Abdominal pain (severe: 1%); Gastrointestinal haemorrhage (severe: 0.3%)	Oesophagitis (severe: 0.4%) ry Cv
Skin and subcutaneous tissue disorders	Alopecia; Skin reaction (G3/4: 5.9%); Nail disorders (severe: 2.6%)
Musculoskeletal and connective tissue disorders	Myalgia (severe: 1.4%)	Arthralgia <4
General disorders and administration site conditions	Fluid retention (severe: 6.5%); Asthenia (severe: 11.2%); Pain	Infusion site reaction; Non-cardiac chest pain (severe: 0.4%)
Investigations		G3/4 Blood bilirubin increased (<5%); G3/4 Blood alkaline phosphatase increased (<4%); G3/4 AST increased (<3%); G3/4 ALT increased (<2%)

Description of selected adverse reactions in breast cancer for Taxespira 100 mg/m2 single agent

Blood and lymphatic system disorders

Rare: bleeding episodes associated with grade 3/4 thrombocytopenia.

Nervous syste disorders

Reversibility data are available among 35.3% of patients who developed neurotoxicity following docetaxel treatment at 100 mg/m2 as single agent. The events were spontaneously reversible within 3 months.

Skin and subcutaneous tissue disorders

Very rare: one case of alopecia non-reversible at the end of the study. 73% of the cutaneous reactions were reversible within 21 days.

General disorders and administration site conditions

The median cumulative dose to treatment discontinuation was more than 1,000 mg/m2 and the median time to fluid retention reversibility was 16.4 weeks (range 0 to 42 weeks). The onset of moderate and severe retention is delayed (median cumulative dose: 818.9 mg/m2) in patients with premedication compared with patients without premedication (median cumulative dose: 489.7 mg/m2); however, it has been reported in some patients during the early courses of therapy.

Tabulated list of adverse reactions in non-small cell lung cancer for Taxespira 75 mg/m2 single agent

MedDRA system organ classes	Very common adverse reactions	Common adverse reactions
Infections and infestations	Infections (G3/4: 5%)
Blood and lymphatic system disorders	Neutropenia (G4: 54.2%); Anaemia (G3/4: 10.8%); Thrombocytopenia (G4: 1.7%)	Febrile neutropenia
Immune system disorders		Hypersensitivity (no severe)
Metabolism and nutrition disorders	Anorexia
Nervous system disorders	Peripheral sensory neuropathy (G3/4: 0.8%)	Peripheral motor neuropathy (G3/4: 2.5%) v
Cardiac disorders		Arrhythmia (no severe)"^
Vascular disorders		Hypotension
Gastrointestinal disorders	Nausea (G3/4: 3.3%); Stomatitis (G3/4: 1.7%); Vomiting (G3/4: 0.8%); Diarrhoea (G3/4: 1.7%)	Constipation
Skin and subcutaneous tissue disorders	Alopecia; Skin reaction (G3/4: 0.8%)	Nail disorders (severe: 0.8%)
Musculoskeletal and connective tissue disorders		Myalgia
General disorders and administration site conditions	Asthenia (severe: 12.4%); Fluid retention (severe: 0.8%); Pain
Investigations		G3/4 Blood bilirubin increased (<2%)

Tabulated list of adverse reactions in breast cancer for Taxespira 75 mg/m2 in combination with doxorubicin V >

MedDRA system organ classes	Very common adverse reactions	Common adverse reactions	Uncommon adverse reactions
Infections and infestations	Infection (G3/4: 7.8%)
Blood and lymphatic system disorders	Neutropenia (G4: 91.7%); Anaemia \G3/4: 9.4%); Febrile 'neutropenia; Thrombocytopenia (G4: 0.8%)
Immune system* disorders		Hypersensitivity (G3/4: 1.2%)
Metabolism and nutrition disorders		Anorexia
Nervous system disorders	Peripheral sensory neuropathy (G3: 0.4%)	Peripheral motor neuropathy (G3/4: 0.4%)
Cardiac disorders		Cardiac failure; Arrhythmia (no severe)
Vascular disorders			Hypotension
Gastrointestinal disorders	Nausea (G3/4: 5%); Stomatitis (G3/4: 7.8%); Diarrhoea (G3/4: 6.2%); Vomiting (G3/4: 5%);

	Constipation
Skin and subcutaneous tissue disorders	Alopecia; Nail disorders (severe: 0.4%); Skin reaction (no severe)
Musculoskeletal and connective tissue disorders		Myalgia
General disorders and administration site conditions	Asthenia (severe: 8.1%); Fluid retention (severe: 1.2%); Pain	Infusion site reaction
Investigations		G3/4 Blood bilirubin increased (<2.5%); G3/4 Blood alkaline phosphatase increased (<2.5%)	G3/4 AST increased (<1%); (?) G3/4 ALT increased (<i%) <Xr

Tabulated list of adverse reactions in non-small cell lung cancer for Taxespira 75 mg/m2 in combination with cisplatin ./

MedDRA system organ classes	Very common adverse reactions	Common adverse reactions	Uncommon adverse reactions
Infections and infestations	Infection (G3/4: 5.7%)	\OX
Blood and lymphatic system disorders	Neutropenia (G4: 51.5%); < Anaemia (G3/4: u 6.9%); Thrombocytopenia^ (G4: 0.5%)	Febrile neutropenia
Immune system disorders	Hypersensitivity (G3/4:4.^%)
Metabolism and nutrition disorders	Anorexia
Nervous system disorders	Peripheral sensory {neuropathy (G3: 3.7%); Peripheral motor neuropathy (G3/4: 2%)
Cardiac disorders		Arrhythmia (G3/4: 0.7%)	Cardiac failure
Vascular ’disorders		Hypotension (G3/4: 0.7%)
Gastrointestinal disorders	Nausea (G3/4: 9.6%); Vomiting (G3/4: 7.6%); Diarrhoea (G3/4: 6.4%); Stomatitis (G3/4: 2%)	Constipation
Skin and subcutaneous tissue disorders	Alopecia; Nail disorders (severe: 0.7%); Skin reaction (G3/4:

Tabulated list of adverse reactions in breast cancer for Taxespira 100 mg/m2 in combinati trastuzumab

MedDRA system organ classes	Very common adverse reactions	Common adverse reactions
Blood and lymphatic system disorders	Neutropenia (G3/4: 32%); Febrile neutropenia (includes neutropenia associated with fever and antibiotic use) or neutropenic sepsis
Metabolism and nutrition disorders	Anorexia Ch
Psychiatric disorders	Insomnia
Nervous system disorders	Paresthesia; Headache/Dysgeusia; Hypoaesthesia
Eye disorders	Lacrimation increased; ConjunctivitisQ^'^
Cardiac disorders		Cardiac failure
Vascular disorders	Lymphoedema
Respiratory, thoracic and mediastinal disorders	Epistaxis; Pharyngolaryngeal pain; Nasopharyngitis; Dyspnoea; Cough; Rhinorrhoea
Gastrointestinal disorders	Nausea; Diarrhoea; Vomiting; Constipation; Stomatitis; Dyspepsia; Abdominal pain
Skin and subcutaneous^issue disorders	Alopecia; Erythema; Rash; Nail disorders
Musculoskeleta­Landconnective tissue disorders	Myalgia; Arthralgia; Pain in extremity; Bone pain; Back pain
General disorders and administration site conditions	Asthenia; Oedema peripheral; Pyrexia; Fatigue; Mucosal inflammation; Pain; Influenza like illness; Chest pain; Chills	Lethargy
Investigations	Weight increased

Description of selected adverse reactions in breast cancer for Taxespira 100 mg/m2 in combination with trastuzumab

Cardiac disorders

Symptomatic cardiac failure was reported in 2.2% of the patients who received docetaxel plus trastuzumab compared to 0% of patients given docetaxel alone. In the docetaxel plus trastuzumab arm, 64% had received a prior anthracycline as adjuvant therapy compared with 55% in the docetaxel arm alone.

Blood and lymphatic system disorders

Very common: Haematological toxicity was increased in patients receiving trastuzumab and docetaxel, compared with docetaxel alone (32% grade 3/4 neutropenia versus 22%, using NCI-CTC criteria). Note that this is likely to be an underestimate since docetaxel alone at a dose of 100 mg/m2 is known to result in neutropenia in 97% of patients, 76% grade 4, based on nadir blood counts. The incidence of febrile neutropenia/ne­utropenic sepsis was also increased in patients treated with Herceptin plus docetaxel (23% versus 17% for patients treated with docetaxel alone).

Tabulated list of adverse reactions in breast cancer for Taxespira 75 mg/m2 in combination with capecitabine

MedDRA system organ classes	Very common adverse reactions	Common adverse reactions
Infections and infestations		Oral candidiasis (G3/4: <1%)
Blood and lymphatic system disorders	Neutropenia (G3/4: 63%); Anaemia (G3/4: 10%)	Thrombocytope­niO^G3/4: 3%)
Metabolism and nutrition disorders	Anorexia (G3/4: 1%); Decreased appetite	Dehydration (G3/4: 2%)
Nervous system disorders	Dysgeusia (G3/4: <1%); Paraesthesia (G3/4: <1%)	Dizziness; Headache (G3/4: <1%); Neuropathy peripheral
Eye disorders	Lacrimation increased
Respiratory, thoracic and mediastinal disorders	Pharyngolaryngeal pain (G3/4: 2%)	Dyspnoea (G3/4: 1%); Cough (G3/4: <1%); Epistaxis (G3/4: <1%)
Gastrointestinal disorders	Stomatitis (G3/4: 18%)SDiarrhoea (G3/4: 14%); Nausea (G3/4: 6%); Vomiting (G3/4: 4%); Constipation (G3/4: 1%); Abdominal pain (G3/4: 2%); Dyspepsia	Abdominal pain upper; Dry mouth
Skin and subcutaneous tissue disorders	Hand-foot4yndrome (G3/4: 24%); Alopecia (G3/4: 6%); Nail disorders (G3/4: 2%)	Dermatitis; Rash erythematous (G3/4: <1%); Nail discolouration; Onycholysis (G3/4: 1%)
Musculoskeletal and connective^ tissue disorders K	► Myalgia (G3/4: 2%); Arthralgia (G3/4: 1%)	Pain in extremity (G3/4: <1%); Back pain (G3/4: 1%)
General disorders and administration site conditions	Asthenia (G3/4: 3%); Pyrexia (G3/4: 1%); Fatigue/weakness (G3/4: 5%); Oedema peripheral (G3/4: 1%)	Lethargy; Pain
Investigation^^		Weight decreased; G3/4 Blood bilirubin increased (9%)

Tabulated list of adverse reactions in prostate cancer for Taxespira 75 mg/m2 in combination with prednisone or prednisolone

MedDRA system organ classes	Very common adverse reactions	Common adverse reactions
Infections and infestations	Infection (G3/4: 3.3%)
Blood and lymphatic system disorders	Neutropenia (G3/4: 32%); Anaemia (G3/4: 4.9%)	Thrombocytopenia (G3/4: 0.6%); Febrile neutropenia
Immune system disorders		Hypersensitivity (G3/4: 0.6%)
Metabolism and nutrition disorders	Anorexia (G3/4: 0.6%)
Nervous system disorders	Peripheral sensory neuropathy	Peripheral motor neuropathy

	(G3/4: 1.2%); Dysgeusia (G3/4: 0%)	(G3/4: 0%)
Eye disorders		Lacrimation increased (G3/4: 0.6%)
Cardiac disorders		Cardiac left ventricular function decrease (G3/4: 0.3%)
Respiratory, thoracic and mediastinal disorders		Epistaxis (G3/4: 0%); Dyspnoea (G3/4: 0.6%); Cough (G3/4: 0%)
Gastrointestinal disorders	Nausea (G3/4: 2.4%); Diarrhoea (G3/4: 1.2%); Stomatitis/Pha­ryngitis (G3/4: 0.9%); Vomiting (G3/4: 1.2%)
Skin and subcutaneous tissue disorders	Alopecia; Nail disorders (no severe)	Exfoliative rash (G3/4: 0.3%)
Musculoskeletal and connective bone disorders		Arthralgia (G3/4: 0.3%);
General disorders and administration site conditions	Fatigue (G3/4: 3.9%); Fluid retention (severe: 0.6%)	Myalgia^G340.3%) v Ik

Tabulated list of adverse reactions in breast cancer for adjuvant therapy with Taxespira 75 mg/m2 in combination with doxorubicin and cyclophosphamide in patients with node-positive (TAX 316) and node-negative (GEICAM 9805) breast cancer – pooled data

MedDRA System Organ classes	Very common adverse reactions	Common adverse reactions	Uncommon adverse reactions
Infections and infestations	Infection (G3/4: 2.4%); / Neutropenic infection^^? (G3/4: 2.6%) v N	5
Blood and lymphatic system disorders	Anaemia (G3/4: 3%); Neutropenia (G3/4: 59.2%); Thrombocytopenia (G3/4A6%o); Febrile neutropenia (G3/4: NA)
Immune system disorders		Hypersensitivity (G3/4: 0.6%)
Metabolism and * nutrition disorders^^	^Anorexia (G3/4: 1.5%)
Nervous system disorders	Dysgeusia (G3/4: 0.6%); Peripheral sensory neuropathy (G3/4: <0.1%)	Peripheral motor neuropathy (G3/4: 0%)	Syncope (G3/4: 0%); Neurotoxicity (G3/4: 0%); Somnolence (G3/4: 0%)
Eye disorders	Conjunctivitis (G3/4: <0.1%)	Lacrimation increased (G3/4: <0.1%)
Cardiac disorders		Arrhythmia (G3/4: 0.2%)
Vascular disorders	Hot flush (G3/4: 0.5%)	Hypotension (G3/4: 0%); Phlebitis (G3/4: 0%)	Lymphoedema (G3/4: 0%)
Respiratory, thoracic and mediastinal disorders		Cough (G3/4: 0%)
Gastrointestinal disorders	Nausea (G3/4: 5.0%); Stomatitis (G3/4: 6.0%);	Abdominal pain (G3/4: 0.4%)

	Vomiting (G3/4: 4.2%); Diarrhoea (G3/4: 3.4%); Constipation (G3/4: 0.5%)
Skin and subcutaneous tissue disorders	Alopecia (persisting: <3%); Skin disorder (G3/4: 0.6%); Nail disorders (G3/4: 0.4%)
Musculoskeletal and connective tissue disorders	Myalgia (G3/4: 0.7%); Arthralgia (G3/4: 0.2%)
Reproductive system and breast disorders	Amenorrhoea (G3/4: NA)		6.
General disorders and administration site conditions	Asthenia (G3/4: 10.0%); Pyrexia (G3/4: NA); Oedema peripheral (G3/4: 0.2%)		Cv
Investigations		Weight increased (G3/4: 0%); Weight decreased (G3/4: \ 0.2%)

Description of selected adverse reactions for adjuvant therapy with Taxespira 75 mg/m2 in combination with doxorubicin and cyclophosphamide in patients with node-positive (TAX 316) and node-negative (GEICAM 9805) breast cancer ^^2/

Nervous system disorders

In study TAX316, peripheral sensory neuropathy started during the treatment period and persisted into the follow-up period in 84 patients (11.3%) in TAC arm and 15 patients (2 %) in FAC arm. At the end of the follow-up period (median follow-up time of 8 years), peripheral sensory neuropathy was observed to be ongoing in 10 patients (1.3%) in TAC arm, and in 2 patients (0.3%) in FAC arm. In GEICAM 9805 study, peripheral sensory neuropathy that started during the treatment period persisted into the follow-up period in 10 patients (1.9%) in TAC arm and 4 patients (0.8 %) in FAC arm. At the end of the follow-up period (median follow-up time of 10 years and 5 months), peripheral sensory neuropathy was observed to be ongoing in 3 patients (0.6%) in TAC arm, and in 1 patient (0.2%) in FAC arm.

Cardiac disorders

In study TAX316, 26 patients (3.5%) in the TAC arm and 17 patients (2.3%) in the FAC arm experienced congestive heart failure. All except one patient in each arm were diagnosed with CHF more than 30 days after the treatment period. Two patients in the TAC arm and 4 patients in the FAC arm died because of cardiac failure.

In GEICAM 9805 study, 3 patients (0.6 %) in TAC arm and 3 patients (0.6 %) in FAC arm developed congestive heart failure during the follow-up period. At the end of the follow-up period (actual median follow-up time of 10 years and 5 months), no patients had CHF in TAC arm and 1 patient in TAC arm died because of dilated cardiomyopathy and CHF was observed to be ongoing in 1 patient (0.2%) in FAC arm.

Skin and subcutaneous tissue disorders

In study TAX316 alopecia persisting into the follow-up period after the end of chemotherapy was reported in 687 of 744 TAC patients (92.3%) and 645 of 736 FAC patients (87.6%).

At the end of the follow-up period (actual median follow-up time of 8 years), alopecia was observed to be ongoing in 29 TAC patients (3.9%) and 16 FAC patients (2.2%).

In GEICAM 9805 study alopecia that started during the treatment period and persisted into the followup period was observed to be ongoing in 49 patients (9.2 %) in TAC arm and 35 patients (6.7 %) in FAC arm. Alopecia related to study drug started or worsened during the follow-up period in 42 patients (7.9 %) in TAC arm and 30 patients (5.8 %) in FAC arm. At the end of the follow-up period (median follow-up time of 10 years and 5 months), alopecia was observed to be ongoing in 3 patients (0.6%) in TAC arm, and in 1 patient (0.2%) in FAC arm.

Asthenia that started during the treatment period and persisted into the follow-up period was observed to be ongoing in 12 patients (2.3 %) in TAC arm and 4 patients (0.8 %) in FAC arm. At the end of the follow-up period, asthenia was observed to be ongoing in 2 patients (0.4%) in TAC arm, and in 2 patients (0.4%) in FAC arm.

Acute leukaemia /Myelodysplastic syndrome

After 10 years of follow up in study TAX316, acute leukaemia was reported in 3 of 744 TAC patients (0.4%) and in 1 of 736 FAC patients (0.1%). One TAC patient (0.1%) and 1 FAC patient (0.1%) died due to AML during the follow-up period (median follow-up time of 8 years). Myelodysplastic syndrome was reported in 2 of 744 TAC patients (0.3%) and in 1 of 736 FAC patients (0.1%).

After 10 years of follow-up in GEICAM 9805 study, acute leukaemia occurred in 1 of 532 (0.2%)patients in TAC arm. No cases were reported in patients in FAC arm. No patient was diagnosed with myelodysplastic syndrome in either treatment groups.

Neutropenic complications

Table below shows that the incidence of Grade 4 neutropenia, febrile neutropenia and neutropenic infection was decreased in patients who received primary G-CSF prophylaxis after it was made mandatory in the TAC arm – GEICAM study.

Neutropenic complications in patients receiving TAC with or without primary G-CSF prophylaxis (GEICAM 9805)

	Without primary G-CSF prophylaxis (n =111) n (%)	With primary G-CSF prophylaxis (n = 421) < n (%)
Neutropenia (Grade 4)	104 (93.7)	135 (32.1) /
Febrile neutropenia	28 (25.2)	______23 (ve^
Neutropenic infection	14 (12.6)	21 (5.0) ’
Neutropenic infection (Grade 3–4)	2 (1.8)	5 (1.2)

Tabulated list of adverse reactions in gastric adenocarcinoma cancer for Taxespira 75 mg/m2 in combination with cisplatin and 5-fluorouracil

MedDRA system organ classes	Very common adverse reactions f	Common adverse reactions
Infections and infestations	Neutropenic infection; Infection (G3/4: 11.7%)
Blood and lymphatic system disorders	Anaemia (G3/4: 20.9%); Neutropenia (G3/4: 83.2%); Thrombocytopctfi­ajG^M: 8.8%); Febrile neutropenia
Immune system disorders	Hypersensitivity (G3/4: 1.7%)
Metabolism and nutrition disorders	Anorexia (G3/4: 11.7%)
Nervous system disorders	Peripheral sensory neuropathy (G3/4: 8.7%)	Dizziness (G3/4: 2.3%); Peripheral motor neuropathy (G3/4: 1.3%)
Eye disorders		Lacrimation increased (G3/4: 0%)
Ear and labyrinth disorders	/	Hearing impaired (G3/4: 0%)
Cardiac disorders		Arrhythmia (G3/4: 1.0%)
Gastrointestinal disorders	Diarrhoea (G3/4: 19.7%); Nausea (G3/4: 16%); Stomatitis (G3/4: 23.7%); Vomiting (G3/4: 14.3%)	Constipation (G3/4: 1.0%); Gastrointestinal pain (G3/4: 1.0%); Oesophagitis/dys­phagia/odynop­hagia (G3/4: 0.7%)
Skin and subcutaneous tissue disorders	Alopecia (G3/4: 4.0%)	Rash pruritus (G3/4: 0.7%); Nail disorders (G3/4: 0.7%); Skin exfoliation (G3/4: 0%)
General disorders and administration site conditions	Lethargy (G3/4: 19.0%); Fever (G3/4: 2.3%); Fluid retention (severe/life-threatening: 1%)

Description of selected adverse reactions in gastric adenocarcinoma cancer for Taxespira 75 mg/m2 in combination with cisplatin and 5-fluorouracil

Blood and lymphatic system disorders

Febrile neutropenia and neutropenic infection occurred in 17.2% and 13.5% of patients respectively, regardless of G-CSF use. G-CSF was used for secondary prophylaxis in 19.3% of patients (10.7 % of the cycles). Febrile neutropenia and neutropenic infection occurred respectively in 12.1% and 3.4 % of patients when patients received prophylactic G-CSF, in 15.6% and 12.9% of patients without prophylactic G-CSF (see section 4.2).

Tabulated list of adverse reactions in head and neck cancer for Taxespira 75 mg/m2 in combination with cisplatin and 5-fluorouracil

• Induction chemotherapy followed by radiotherapy (TAX 323)

MedDRA system organ classes	Very common adverse reactions	Common adverse reactions	Uncommon adverse reactions
Infections and infestations	Infection (G3/4: 6.3%); Neutropenic infection		&
Neoplasms benign, malignant and unspecified (incl cysts and polyps)		Cancer pain (G3/4: 0.6%)
Blood and lymphatic system disorders	Neutropenia (G3/4: 76.3%); Anaemia (G3/4: 9.2%); Thrombocytopenia (G3/4: 5.2%)	Febrile neutropenia
Immune system disorders		HvpersensitivityXno severe)
Metabolism and nutrition disorders	Anorexia (G3/4: 0.6%)	^¿>
Nervous system disorders	Dysgeusia/Parosmia; Peripheral sensory neuropathy (G3/4: 0.6%)	Dizziness p
Eye disorders		Lacrimation increased; Conjunctivitis
Ear and labyrinth disorders		Hearing impaired
Cardiac disorders	<o TV	Myocardial ischemia (G3/4:1.7%)	Arrhythmia (G3/4: 0.6%)
Vascular disorders		Venous disorder (G3/4: 0.6%)
Gastrointestinal * disorders	Nausea (G3/4: 0.6%); Stomatitis (G3/4: 4.0%); Diarrhoea (G3/4: 2.9%); Vomiting (G3/4: 0.6%)	Constipation; Oesophagitis/dys­phagia/ odynophagia (G3/4: 0.6%); Abdominal pain; Dyspepsia; Gastrointestinal haemorrhage (G3/4: 0.6%)
Skin and subcutaneous tissue disorders	Alopecia (G3/4: 10.9%)	Rash pruritic; Dry skin; Skin exfoliative (G3/4: 0.6%)
Musculoskeletal and connective tissue disorders		Myalgia (G3/4: 0.6%)
General disorders and administration site conditions	Lethargy (G3/4: 3.4%); Pyrexia (G3/4: 0.6%); Fluid retention; Oedema

Weight increased

• Induction chemotherapy followed by chemoradiotherapy (TAX 324)

MedDRA system organ classes	Very common adverse reactions	Common adverse reactions	Uncommon adverse reactions
Infections and infestations	Infection (G3/4: 3.6%)	Neutropenic infection
Neoplasms benign, malignant and unspecified (incl cysts and polyps)		Cancer pain (G3/4: 1.2%)	________X
Blood and lymphatic system disorders	Neutropenia (G3/4: 83.5%); Anaemia (G3/4: 12.4%); Thrombocytopenia (G3/4: 4.0%); Febrile neutropenia		z
Immune system disorders			hypersensitivity
Metabolism and nutrition disorders	Anorexia (G3/4: 12.0%)	0–
Nervous system disorders	Dysgeusia/Parosmia (G3/4: 0.4%); Peripheral sensory neuropathy (G3/4: 1.2%)	Dizziness (Q3^4y 2.0%); Peripheral motor neuropathy (G3/4: 0.4%)
Eye disorders		^Lacrimation increased	Conjunctivitis
Ear and labyrinth disorders	Hearing impaired (G3/4: 1.2%)
Cardiac disorders		Arrhythmia (G3/4: 2.0%)	Ischemia myocardial
Vascular disorders			Venous disorder
Gastrointestinal disorders	Nausea/G3/4ri3.9%); Stomatitis (G3/4: 20.7%); Vomiting (G3/4: 8.4%); Diarrhoea NG3/4: 6.8%); nDesophagitis/dys­phagia/ odynophagia (G3/4: 12.0%); Constipation (G3/4: 0.4%)	Dyspepsia (G3/4: 0.8%); Gastrointestinal pain (G3/4: 1.2%); Gastrointestinal haemorrhage (G3/4: 0.4%)
Skin and subcutaneous tissue -disorders	Alopecia (G3/4: 4.0%); Rash pruritic	Dry skin; Desquamation
Musculoskeletal, connective tissue bone disorders		Myalgia (G3/4: 0.4%)
General disorders and administration site conditions	Lethargy (G3/4: 4.0%); Pyrexia (G3/4: 3.6%); Fluid retention (G3/4: 1.2%); Oedema (G3/4: 1.2%)
Investigations	Weight decreased		Weight increased

Post-marketing experience

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Cases of acute myeloid leukaemia and myelodysplastic syndrome have been reported in association with docetaxel when used in combination with other chemotherapy agents and/or radiotherapy.

Blood and lymphatic system disorders

Bone marrow suppression and other haematologic adverse reactions have been reported. Disseminated intravascular coagulation (DIC), often in association with sepsis or multiorgan failure, has been reported.

Immune system disorders

Some cases of anaphylactic shock, sometimes fatal, have been reported.

Hypersensitivity reactions (frequency not known) have been reported with docetaxel in patients previously experienced hypersensitivity reactions to paclitaxel.

Nervous system disorders

Rare cases of convulsion or transient loss of consciousness have been observed wit administration. These reactions sometimes appear during the infusion of the medici

Eye disorders

Very rare cases of transient visual disturbances (flashes, flashing lights, scotomata) typically occurring during infusion of the medicinal product and in association with hypersensitivity reactions have been reported. These were reversible upon discontinuation of the infusion.es of lacrimation with or without conjunctivitis, as cases of lacrimal duct obstruction resultiin excessive tearing have been rarely reported. Cases of cystoid macular oedema (CMO) hareported in patients treated with docetaxel.

Ear and labyrinth disorders

Rare cases of ototoxicity, hearing impaired and/or hearing loss have been reported.

Cardiac disorders

Rare cases of myocardial infarction have been reported.

Ventricular arrhythmia including ventricular tachycardia (frequency not known), sometimes fatal, has been reported in patients treated with docetaxel in combination regimens including doxorubicin, 5–

Vascular disorders

Venous thromboembolic events have rarely been reported.

d mediastinal disorders

ress syndrome and cases of interstitial pneumonia/pne­umonitis, interstitial lung fibrosis and respiratory failure sometimes fatal have rarely been reported. Rare n pneumonitis have been reported in patients receiving concomitant radiotherapy.

Gastrointestinal disorders

Rare cases of enterocolitis, including colitis, ischemic colitis, and neutropenic enterocolitis, have been reported with a potential fatal outcome (frequency not known).

Rare occurrences of dehydration have been reported as a consequence of gastrointestinal events including enterocolitis and gastrointestinal perforation.

Rare cases of ileus and intestinal obstruction have been reported.

Hepatobiliary disorders

Very rare cases of hepatitis, sometimes fatal primarily in patients with pre-existing liver disorders, have been reported.

Skin and subcutaneous tissue disorders

Very rare cases of cutaneous lupus erythematosus and bullous eruptions such as erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, have been reported with docetaxel. In some cases concomitant factors may have contributed to the development of these effects. Sclerodermal-like changes usually preceded by peripheral lymphoedema have been reported with docetaxel. Cases of permanent alopecia (frequency not known) have been reported.

Renal and urinary disorders

Renal insufficiency and renal failure have been reported. In about 20% of these cases there were no risk factors for acute renal failure such as concomitant nephrotoxic medicinal products and gastro-intestinal disorders.

Pharmacotherapeutic group: antineoplastic agents, taxanes, ATC Code: L01CD02

Mechanism of action

Docetaxel is an antineoplastic agent which acts by promoting the assembly of tubulin into stable microtubules and inhibits their disassembly which leads to a marked decrease of free tubulin. The binding of docetaxel to microtubules does not alter the number of protofilaments.

Docetaxel has been shown in vitro to disrupt the microtubular network in cells which is essential for vital mitotic and interphase cellular functions.

Pharmacodynamic effects

Docetaxel was found to be cytotoxic in vitro against various murine and human tumour cell lines and against freshly excised human tumour cells in clonogenic assays. Docetaxel achieves high intracellular concentrations with a long cell residence time. In addition, docetaxel was found to be active on some but not all cell lines over expressing the p-glycoprotein which is encoded by the multidrug resistance gene. In vivo , docetaxel is schedule independent and has a broad spectrum of experimental antitumour activity against advanced murine and human grafted tumours.

Clinical efficacy and safety

Breast cancer

Taxespira in combination with doxorubicin and cyclophosphamide: adjuvant therapy

Patients with operable node-positive breast cancer (TAX 316)

Data from a multicenter open label randomized study support the use of docetaxel for the adjuvant treatment of patients with operable node-positive breast cancer and KPS >80%, between 18 and 70 years of age. After stratification according to the number of positive lymph nodes (1–3, 4+), 1,491 patients were randomized to receive either docetaxel 75 mg/m2 administered 1-hour after doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 (TAC arm), or doxorubicin 50 mg/m2 followed by fluorouracil 500 mg/m2 and cyclosphosphamide 500 mg/m2 (FAC arm). Both regimens were administered once every 3 weeks for 6 cycles. Docetaxel was administered as a 1-hour infusion, all other medicinal products were given as intravenous bolus on day one. G-CSF was administered as secondary prophylaxis to patients who experienced complicated neutropenia (febrile neutropenia, prolonged neutropenia, or infection). Patients on the TAC arm received antibiotic prophylaxis with ciprofloxacin 500 mg orally twice daily for 10 days starting on day 5 of each cycle, or equivalent. In both arms, after the last cycle of chemotherapy, patients with positive estrogen and/or progesterone receptors received tamoxifen 20 mg daily for up to 5 years. Adjuvant radiation therapy was prescribed according to guidelines in place at participating institutions and was given to 69 % of patients who received TAC and 72% of patients who received FAC. Two interim analyses and one final analysis were performed. The first interim analysis was planned 3 years after the date when half of study enrollment was done. The second interim analysis was done after 400 DFS events had been recorded overall, which led to a median follow-up of 55 months. The final analysis was performed when all patients had reached their 10-year follow-up visit (unless they had a DFS event or were lost to follow-up before). Disease-free survival (DFS) was the primary efficacy endpoint and OS was the secondary efficacy endpoint.

A final analysis was performed with an actual median follow up of 96 months. Significantly longer disease-free survival for the TAC arm compared to the FAC arm was demonstrated. Incidence of relapses at 10 years was reduced in patients receiving TAC compared to those who received FAC (39% versus 45%, respectively) i.e. an absolute risk reduction by 6% (p = 0.0043). OS at 10 years was also significantly increased with TAC compared to FAC (76% versus 69%, respectively) i.e. an absolute reduction of the risk of death by 7% (p = 0.002). As the benefit observed in patients with 4 + nodes was not statistically significant on DFS and OS, the positive benefit/risk ratio for TAC in patients with 4 + nodes was not fully demonstrated at the final analysis.

Overall, the study results demonstrate a positive benefit risk ratio for TAC compared to FAC.

TAC-treated patient subsets according to prospectively defined major prognostic factors were analysed:

		Disease free survival			Overall survival
Patient subset	Number of patients	Hazard ratio*	95% CI	P =	Hazard ratio*	95% CI	P =
No of positive

nodes Overall	745	0.80	0.68–0.93	0.0043	0.74	0.61–0.90	0.0020
1–3	467	0.72	0.58–0.91	0.0047	0.62	0.46–0.82	0.0008
4+	278	0.87	0.70–1.09	0.2290	0.87	0.67–1.12	0.2746

a hazard ratio of less than 1 indicates that TAC is associated with a longer disease-free survival and OS compared to FAC

Patients with operable node-negative breast cancer eligible to receive chemotherapy (GEICAM 9805)

At the median follow-up time of 77 months, significantly longer disease-free survival for the TAC arm compared to the FAC arm wonstrated. TAC-treated patients had a 32% reduction in the risk of relapse compared to those tr with FAC (hazard ratio = 0.68, 95% CI (0.49–0.93), p = 0.01).At the

median follow up timeyears and 5 months, TAC-treated patients had a 16.5% reduction in the risk of relapse compthose treated with FAC (hazard ratio = 0.84, 95% CI (0.65–1.08), p=0.1646). DFS d favour of TAC.

At the median follow-up time of 77 months, OS was longer in the TAC arm with TAC-treated patients having a 24% reduction in the risk of death compared to FAC (hazard ratio = 0.76, 95% CI (0.46–1.26, p = 0.29). However, the distribution of OS was not significantly different between the 2 groups.

At the median follow up time of 10 years and 5 months, TAC-treated patients had a 9% reduction in the risk of death compared to FAC-treated patients (hazard ratio = 0.91, 95% CI (0.63–1.32)).

The survival rate was 93.7% in the TAC arm and 91.4 % in the FAC arm, at the 8-year follow-up timepoint, and 91.3 % in the TAC arm and 89 % in the FAC arm, at the 10-year follow-up timepoint.

The positive benefit risk ratio for TAC compared to FAC remained unchanged.

TAC-treated patient subsets according to prospectively defined major prognostic factors were analysed in the primary analysis (at the median follow-up time of 77 months) (see table below):

Subset analyses-adjuvant therapy in patients with node-negative breast cancer study (intent-to-treat analysis)

Patient subset	Number of patients in TAC group	Disease free survival
		Hazard ratio	95% CI
Overall	539	0.68	0.49–0.93
Age category 1 <50 years >50 years	260 279	0.67 0.67	0.43–1.05 0.43–1.05
Age category 2 <35 years >35 years	42 497	0.31 0.73	0.11–0.89 0.52–1.01
Hormonal receptor status Negative Positive	195 344	0.7 0.62	0.45–1.1 çy 0.4–0.971
Tumour size <2 cm >2 cm	285 254	0.69 0.68	0.43–1.1 /■045–1.04
Histological grade			Vv'
Gradel (includes grade not assessed) Grade 2 Grade 3	64 216 259	0.79 0.77 0.59 <	0.24–2.6 0.46–1.3 0.39–0.9
Menopausal status Pre-Menopausal Post-Menopausal	285 254	■<4r 0.72	0.40–1 0.47–1.12

a hazard ratio (TAC/FAC) of less than 1 indicates that TAC is associated with a longer disease free survival compared to FAC.

Exploratory subgroup analyses for disease-free survival for patients who meet the 2009 St. Gallen chemotherapy criteria – (ITT population) were performed and presented here below:

	TAC X	FAC	Hazard ratio (TAC/FAC)
Subgroups	(n=539>^J	(n=521)	(95% CI)	p-value
Meeting relative indication for chemotherapy a
No ♦	r%>8/214 f\Y(8.4%)	26/227 (11.5%)	0.796 (0.434 – 1.459)	0.4593
Yes	48/325 (14.8%)	69/294 (23.5%)	0.606 (0.42 – 0.877)	0.0072

TAC = docetaxel, doxorubicin and cyclophosphamide -fluorouracil, doxorubicin and cyclophosphamide fidence interval; ER = estrogen receptor gesterone receptor

ER/PR-negative or Grade 3 or tumour size >5 cm

The estimated hazard ratio was using Cox proportional hazard model with treatment group as the factor.

Taxespira as single agent

Two randomised phase III comparative studies, involving a total of 326 alkylating or 392 anthracycline failure metastatic breast cancer patients, have been performed with docetaxel at the recommended dose and regimen of 100 mg/m2 every 3 weeks.

In alkylating-failure patients, docetaxel was compared to doxorubicin (75 mg/m2 every 3 weeks). Without affecting OS time (docetaxel 15 months vs. doxorubicin 14 months, p = 0.38) or time to progression (docetaxel 27 weeks vs. doxorubicin 23 weeks, p = 0.54), docetaxel increased response rate (52% vs. 37%, p = 0.01) and shortened time to response (12 weeks vs. 23 weeks, p = 0.007). Three docetaxel patients (2%) discontinued the treatment due to fluid retention, whereas 15 doxorubicin patients (9%) discontinued due to cardiac toxicity (three cases of fatal congestive heart failure).

In anthracycline-failure patients, docetaxel was compared to the combination of mitomycin C and vinblastine (12 mg/m2 every 6 weeks and 6 mg/m2 every 3 weeks). Docetaxel increased response rate (33% vs. 12%, p <0.0001), prolonged time to progression (19 weeks vs. 11 weeks, p = 0.0004) and prolonged OS (11 months vs. 9 months, p = 0.01).

During these two phase III studies, the safety profile of docetaxel was consistent with the sa profile observed in phase II studies (see section 4.8).

An open-label, multicenter, randomized phase III study was conducted to compare docetaxel monotherapy and paclitaxel in the treatment of advanced breast cancer in patients whose previous therapy should have included an anthracycline. A total of 449 patients were rized to receive either docetaxel monotherapy 100 mg/m2 as a 1 hour infusion or paclitax /m2 as a 3 hour

infusion. Both regimens were administered every 3 weeks.

Without affecting the primary endpoint, overall response rate ( prolonged median time to progression (24.6 weeks vs 15.6 wee (15.3 months vs 12.7 months; p = 0.03).

More grade 3/4 adverse events were observed for doce paclitaxel (23.0%).

Taxespira in combination with doxorubicin One large randomized phase III study, invo disease, has been performed with doxorubic (AT arm) versus doxorubicin (60 mg/m2) in combination with cyclophosphamide (600 mg/m2) (AC arm). Both regimens were administered on day 1 every 3 weeks.

Time to progression (TTP) was significantly longer in the AT arm versus AC arm, p = 0.0138. The median TTP was7.3 weeks (95% CI: 33.4 – 42.1) in AT arm and 31.9 weeks (95% CI: 27.4 – 36.0) in A Overall respo The ORR was AC arm

arm showed a higher incidence of severe neutropenia (90% versus 68.6%), febrile

33.3% versus 10%), infection (8% versus 2.4%), diarrhoea (7.5% versus 1.4%), asthenia ersus 2.4%), and pain (2.8% versus 0%) than AC arm. On the other hand, AC arm showed a higher incidence of severe anaemia (15.8% versus 8.5%) than AT arm, and, in addition, a higher incidence of severe cardiac toxicity: congestive heart failure (3.8% versus 2.8%), absolute LVEF decrease >20% (13.1% versus 6.1%), absolute LVEF decrease >30% (6.2% versus 1.1%). Toxic deaths occurred in 1 patient in the AT arm (congestive heart failure) and in 4 patients in the AC arm (1 due to septic shock and 3 due to congestive heart failure).

In both arms, quality of life measured by the EORTC questionnaire was comparable and stable during treatment and follow-up.

Taxespira in combination with trastuzumab

Docetaxel in combination with trastuzumab was studied for the treatment of patients with metastatic breast cancer whose tumours overexpress HER2, and who previously had not received chemotherapy for metastatic disease. One hundred eighty six patients were randomized to receive docetaxel (100 mg/m2) with or without trastuzumab; 60% of patients received prior anthracycline-based adjuvant chemotherapy. Docetaxel plus trastuzumab was efficacious in patients whether or not they had received prior adjuvant anthracyclines. The main test method used to determine HER2 positivity in this pivotal study was immunohistoche­mistry (IHC). A minority of patients were tested using fluorescence in-situ hybridization (FISH). In this study, 87% of patients had disease that was IHC 3+, and 95% of patients entered had disease that was IHC 3+ and/or FISH positive. Efficacy results are summarized in the following table:

Parameter	Docetaxel plus trastuzumab1 n = 92	Docetaxel1 n = 94
Response rate (95% CI)	61% (50–71)	34% K (25–45)
Median duration of response (months) (95% CI)	11.4 (9.2–15.0)	5.^ (4.4–6.2)
Median TTP (months) (95% CI)	10.6 (7.6–12.9)	(5.0–6.5)
Median survival (months) (95% CI)	30.52 (26.8-ne)	<^22.12 _vY(17.6–28 9) _________

TTP = time to progression; “ne” indicates that it could not be estimated or it was not yet reached. 1Full analysis set (intent-to-treat) 2 Estimated median survival

Taxespira in combination with capecitabine

Data from one multicenter, randomised, controlled phase III clinical study support the use of docetaxel in combination with capecitabine for treatment of patients with locally advanced or metastatic breast cancer after failure of cytotoxic chemotherapy, including an anthracycline. In this study, 255 patients were randomised to treatment with docetaxel (75 mg/m2 as a 1 hour intravenous infusion every 3 weeks) and capecitabine (1250 mg/m2 twice daily for 2 weeks followed by 1-week rest period). 256 patients were randomised to treatment with docetaxel alone (100 mg/m2 as a 1 hour intravenous infusion every 3 weeks). Survival was superior in the docetaxel + capecitabine combination arm (p = 0.0126). Median survival was 442 days (docetaxel + capecitabine) vs. 352 days (docetaxel alone). The overall objective response rates in the all-randomised population (investigator assessment) were 41.6% (docetaxel + capecitabine) vs. 29.7% (docetaxel alone); p = 0.0058. Time to progressive disease was superior in the docetaxel + capecitabine combination arm (p <0.0001). The median time to progression was 186 days (docetaxel + capecitabine) vs. 128 days (docetaxel alone).

Non-small cell lung cancer

Patients previously treated with chemotherapy with or without radiotherapy

In a phase III study, in previously treated patients, time to progression (12.3 weeks versus 7 weeks) and OS were significantly longer for docetaxel at 75 mg/m2 compared to Best Supportive Care. The 1-year survival rate was also significantly longer in docetaxel (40%) versus BSC (16%).

There was less use of morphinic analgesic (p <0.01), non-morphinic analgesics (p <0.01), other disease-related medicinal products (p = 0.06) and radiotherapy (p <0.01) in patients treated with docetaxel at 75 mg/m2 compared to those with BSC.

The overall response rate was 6.8% in the evaluable patients, and the median duration of response was 26.1 weeks.

Taxespira in combination with platinum agents in chemotherapy-naïve patients

In a phase III study, 1218 patients with unresectable stage IIIB or IV NSCLC, with KPS of 70% or greater, and who did not receive previous chemotherapy for this condition, were randomised to either docetaxel (T) 75 mg/m2 as a 1 hour infusion immediately followed by cisplatin (Cis) 75 mg/m2 over 30–60 minutes every 3 weeks (TCis), docetaxel 75 mg/m2 as a 1 hour infusion in combination with carboplatin (AUC 6 mg/ml.min) over 30–60 minutes every 3 weeks, or vinorelbine (V) 25 mg/m2 administered over 6–10 minutes on days 1, 8, 15, 22 followed by cisplatin 100 mg/m2 administered on day 1 of cycles repeated every 4 weeks (VCis).

Survival data, median time to progression and response rates for two arms of the study are illustrated in the following table:

	TCis n = 408	VCis n = 404	Statistical analysis
OS (Primary end-point): Median survival (months) 1-year Survival (%) 2-year Survival (%)	11.3 46 21	10.1 41 14	Hazard Ratio: 1.122 [97.2% CI: 0.937; 1.342] Treatment difference: 5.4% [95% CI: –1.1; l2£Pj Treatment differenc e26 2% [95% CI: 0.2; 12.3]
Median time to progression (weeks):	22.0	23.0	Hazard Ratio: 1.032 [95%jCr\0*876; 1.216]
Overall response rate (%):	31.6	24.5	Treatment difference: 7.1% [95% CI: 0.7; 13.5]

: Corrected for multiple comparisons and adjusted for stratification factors (stage of disease and region of treatment), based on evaluable patient population.

Secondary end-points included change of pain, global rating of quality of life by EuroQoL-5D, Lung Cancer Symptom Scale, and changes in Karnosfky performance status. Results on these end-points were supportive of the primary end-points results.

For docetaxel/car­boplatin combination, neither equivalent nor non-inferior efficacy could be proven compared to the reference treatment combination VCis.

Prostate cancer

The safety and efficacy of docetaxel in combination with prednisone or prednisolone in patients with hormone refractory metastatic prostate cancer were evaluated in a randomized multicenter phase III study. A total of 1006 patients with KPS >60 were randomized to the following treatment groups:

• Docetaxel 75 mg/m2 every 3 weeks for 10 cycles.
• Docetaxel 30 mg/m2 administered weekly for the first 5 weeks in a 6 week cycle for 5 cycles.
• Mitoxantrone 12 mg/m2 every 3 weeks for 10 cycles.

All 3 regimens were administered in combination with prednisone or prednisolone 5 mg twice daily, continuously.

Patients who received docetaxel every three weeks demonstrated significantly longer OS compared to those treated with mitoxantrone. The increase in survival seen in the docetaxel weekly arm was not statistically significant compared to the mitoxantrone control arm. Efficacy endpoints for the docetaxel arms versus the control arm are summarized in the following table:

Endpoint	Docetaxel every 3 weeks	Docetaxel every week	Mitoxantrone every 3 weeks
Number of patients	335	334	337
Median survival (months)	18.9	17.4	16.5
95% CI	(17.0–21.2)	(15.7–19.0)	(14.4–18.6)
Hazard ratio	0.761	0.912	—
95% CI	(0.619–0.936)	(0.747–1.113)	—
p-value1	0.0094	0.3624	—
Number of patients	291	282	300
PSA** response rate (%)	45.4	47.9	31.7

95% CI p-value*	(39.5–51.3) 0.0005	(41.9–53.9) <0.0001	(26.4–37.3) —
Number of patients	153	154	157
Pain response rate (%)	34.6	31.2	21.7
95% CI	(27.1–42.7)	(24.0–39.1)	(15.5–28.9)
p-value*	0.0107	0.0798	—
Number of patients	141	134	137
Tumour response rate (%)	12.1	8.2	6.6
95% CI	(7.2–18.6)	(4.2–14.2)	(3.0–12.1)
p-value*	0.1112	0.5853	—

'Stratified log rank test

*Threshold for statistical significance = 0.0175

PSA: Prostate-Specific Antigen

Given the fact that docetaxel every week presented a slightly better safety profile than docetaxel every 3 weeks, it is possible that certain patients may benefit from docetaxel every week.

No statistical differences were observed between treatment groups for Global Quality of Life.

Gastric adenocarcinoma

A multicenter, open-label, randomized study was conducted to evaluate the safety and efficacy of docetaxel for the treatment of patients with metastatic gastric adenocarcinoma, including adenocarcinoma of the gastroesophageal junction, who had not received prior chemotherapy for metastatic disease. A total of 445 patients with KPS >70 were treated with either docetaxel (T) (75 mg/m2 on day 1) in combination with cisplatin © (75 mg/m2 on day 1) and 5-fluorouracil (F) (750 mg/m2 per day for 5 days) or cisplatin (100 mg/m2 on day 1) and 5-fluorouracil (1000 mg/m2 per day for 5 days). The length of a treatment cycle was 3 weeks for the TCF arm and 4 weeks for the CF arm. The median number of cycles administered per patient was 6 (with a range of 1–16) for the TCF arm compared to 4 (with a range of 1–12) for the CF arm. Time to progression (TTP) was the primary endpoint. The risk reduction of progression was 32.1% and was associated with a significantly longer TTP (p = 0.0004) in favour of the TCF arm. OS was also significantly longer (p = 0.0201) in favour of the TCF arm with a risk reduction of mortality of 22.7%. Efficacy results are summarized in the following table:

Efficacy of docetaxel in the treatment of patients with gastric adenocarcinoma

Endpoint <	TCF n = 221	CF n = 224
__ Median TTP (months) (95% CI) * Hazard ratio (95% CI) Xy' p-value£jXi/	5.6 (4.86–5.91)	3.7 (3.45–4.47)
	(1.1 0	1.473 19–1.825).0004
Median survival (months) (95% CI) 2-year estimate (%) Hazard ratio (95% CI) *p-value	9.2 (8.38–10.58) 18.4	8.6 (7.16–9.46) 8.8
	(1.0' 0	1.293 11–1.606).0201
Overall response rate (CR+PR) (%) p-value	36.7	25.4
	0.0106
Progressive disease as best overall response (%)	16.7	25.9

*Unstratified logrank test

Subgroup analyses across age, gender and race consistently favoured the TCF arm compared to the CF arm.

A survival update analysis conducted with a median follow-up time of 41.6 months no longer showed a statistically significant difference although always in favour of the TCF regimen and showed that the benefit of TCF over CF is clearly observed between 18 and 30 months of follow up.

Overall, quality of life (QoL) and clinical benefit results consistently indicated improvement in favour of the TCF arm. Patients treated with TCF had a longer time to 5% definitive deterioration of global health status on the QLQ-C30 questionnaire (p = 0.0121) and a longer time to definitive worsening of Karnofsky performance status (p = 0.0088) compared to patients treated with CF.

Head and neck cancer

• Induction chemotherapy followed by radiotherapy (TAX323)

The safety and efficacy of docetaxel in the induction treatment of patients with squamous cell carcinoma of the head and neck (SCCHN) was evaluated in a phase III, multicenter, open-label, randomized study (TAX323). In this study, 358 patients with inoperable locally advanced SCCHN, and WHO performance status 0 or 1, were randomized to one of two treatment arms. Patients on the docetaxel arm received docetaxel (T) 75 mg/m2 followed by cisplatin (P) 75 mg/m2 followed by 5-fluorouracil (F) 750 mg/m2 per day as a continuous infusion for 5 days. This regimen was administered every three weeks for 4 cycles in case at least a minor response (>25% reduction in bidimensionally measured tumour size) was observed after 2 cycles. At the end of chemotherapy, with a minimal interval of 4 weeks and a maximal interval of 7 weeks, patients whose disease did not progress received radiotherapy (RT) according to institutional guidelines for 7 weeks (TPF/RT). Patients on the comparator arm received cisplatin (P) 100 mg/m2 followed by 5-fluorouracil (F) 1,000 mg/m2 per day for 5 days. This regimen was administered every three weeks for 4 cycles in case at least a minor response (>25% reduction in bidimensionally measured tumour size) was observed after 2 cycles. At the end of chemotherapy, with a minimal interval of 4 weeks and a maximal interval of 7 weeks, patients whose disease did not progress received radiotherapy (RT) according to institutional guidelines for 7 weeks (PF/RT). Locoregional therapy with radiation was delivered either with a conventional fraction (1.8 Gy – 2.0 Gy once a day, 5 days per week for a total dose of 66 to 70 Gy), or accelerated/hy­perfractionated regimens of radiation therapy (twice a day, with a minimum interfraction interval of 6 hours, 5 days per week). A total of 70 Gy was recommended for accelerated regimens and 74 Gy for hyperfractionated schemes. Surgical resection was allowed following chemotherapy, before or after radiotherapy. Patients on the TPF arm received antibiotic prophylaxis with ciprofloxacin 500 mg orally twice daily for 10 days starting on day 5 of each cycle, or equivalent. The primary endpoint in this study, progression-free survival (PFS), was significantly longer in the TPF arm compared to the PF arm, p = 0.0042 (median PFS: 11.4 vs. 8.3 months respectively) with an overall median follow up time of 33.7 months. Median OS was also significantly longer in favour of the TPF arm compared to the PF arm (median OS: 18.6 vs. 14.5 months respectively) with a 28% risk reduction of mortality, p = 0.0128. Efficacy results are presented in the table below:

Efficacy of docetaxel in the induction treatment of patients with inoperable locally advanced SCCHN (Intent-to-Treat Analysis)

Endpoint	Docetaxel + Cis + 5-FU n = 177	Cis + 5-FU n = 181
Median progression free survival (months)	11.4	8.3
(95% CI)	(10.1–14.0)	(7.4–9.1)
Adjusted hazard ratio	0.70
(95% CI)	(0.55–0.89)
*p-value	0.0042
Median survival (months)	18.6	14.5
(95% CI)	(15.7–24.0)	(11.6–18.7)
Hazard ratio	0.72
(95% CI)	(0.56–0.93)
p-value	0.0128
Best overall response to chemotherapy (%)	67.8	53.6

(95% CI) p-value	(60.4–74.6)	(46.0–61.0)
	0.006
Best overall response to study treatment [chemotherapy +/- radiotherapy] (%) (95% CI) p-value	72.3 (65.1–78.8)	58.6 (51.0–65.8)
	0.006
Median duration of response to chemotherapy ± radiotherapy (months) (95% CI) Hazard ratio (95% CI) p-value	n = 128 15.7 (13.4–24.6)	n = 106 11.7 (10.2–17.4)
	0.72 (0.52–0.99) 0.0457

A hazard ratio of less than 1 favours docetaxel + cisplatin + 5-FU

*Cox model (adjustment for Primary tumour site, T and N clinical stages and PSWHO)

Logrank test

Chi-square test

Quality of life parameters

Patients treated with TPF experienced significantly less deterioration of their G compared to those treated with PF (p = 0.01, using the EORTC QLQ-C30 scale

Clinical benefit parameters

The performance status scale, for head and neck (PSS-HN) subscales designed to measure understandability of speech, ability to eat in public, and normaet, was significantly in favour of TPF as compared to PF.

Median time to first deterioration of WHO performance s compared to PF. Pain intensity score improved during t pain management.

• Induction chemotherapy followed by chemoradiotherapy (TAX324)

The safety and efficacy of docetaxel in the induction treatment of patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) was evaluated in a randomized, multicenter open-label, phase III study (TAX324). In this study, 501 patients, with locally advanced SCCHN, and a WHO performance status of 0 or 1, were randomized to one of two arms. The study population comprised patients with technically unresectable disease, patients with low probability of surgical cure and patients aiming at organ preservation. The efficacy and safety evaluation solely addressed survival endpoints and the success of organ preservation was not formally addressed. Patients on the docetaxel arm received docetaxel (T) 75 mg/m2 by intravenous infusion on day 1 followed by cisplatin (P) 100 mg/im administered as a 30-minute to three-hour intravenous infUsion, followed by the continuous intravenous infusion of 5-fluorouracil (F) 1,000 mg/m2/day from day 1 to day 4. The cycles

weeks for 3 cycles. All patients who did not have progressive disease were to iotherapy (CRT) as per protocol (TPF/CRT). Patients on the comparator arm in (P) 100 mg/m2 as a 30-minute to three-hour intravenous infusion on day 1 followed uous intravenous infusion of 5-fluorouracil (F) 1,000 mg/m2/day from day 1 to day 5. The re repeated every 3 weeks for 3 cycles. All patients who did not have progressive disease receive CRT as per protocol (PF/CRT).

Patients in both treatment arms were to receive 7 weeks of CRT following induction chemotherapy with a minimum interval of 3 weeks and no later than 8 weeks after start of the last cycle (day 22 to day 56 of last cycle). During radiotherapy, carboplatin (AUC 1.5) was given weekly as a one-hour intravenous infusion for a maximum of 7 doses. Radiation was delivered with megavoltage equipment using once daily fractionation (2 Gy per day, 5 days per week for 7 weeks, for a total dose of 70–72 Gy). Surgery on the primary site of disease and/or neck could be considered at anytime following completion of CRT. All patients on the docetaxel-containing arm of the study received prophylactic antibiotics. The primary efficacy endpoint in this study, OS was significantly longer (log-rank test, p = 0.0058) with the docetaxel-containing regimen compared to PF (median OS: 70.6 versus 30.1 months respectively), with a 30% risk reduction in mortality compared to PF (hazard ratio (HR) = 0.70, 95% confidence interval (CI) = 0.54–0.90) with an overall median follow up time of 41.9 months. The secondary endpoint, PFS, demonstrated a 29% risk reduction of progression or death and a 22 month improvement in median PFS (35.5 months for TPF and 13.1 for PF). This was also statistically significant with an HR of 0.71; 95% CI 0.56–0.90; log-rank test p = 0.004. Efficacy results are presented in the table below:

Efficacy of docetaxel in the induction treatment of patients with locally advanced SCCHN (Intent-to-Treat Analysis)

Endpoint	Docetaxel + Cis + 5-FU n = 255	Cis + 5-FU n = 246 *
Median OS (months) (95% CI) Hazard ratio: (95% CI) *p-value	70.6 (49.0-NA)	30.1 (x (20.9–51/)>Z’
	0.70 (0.54–0.90) 0.0058 ~
Median PFS (months) (95% CI) Hazard ratio: (95% CI) p-value	35.5 (19.3-NA)	CJ13.1 kN*xT0.6 – 20.2)
	0.7^^ (0.56–0.90) 0.004
Best overall response (CR + PR) to chemotherapy (%) (95% CI) p-value	71.8 (65.8–772)-/	64.2 (57.9–70.2)
	0.070
Best overall response (CR + PR) to study treatment [chemotherapy +/- chemoradiotherapy] (%) (95%CI) p-value	\076.5 >70.8–81.5)	71.5 (65.5–77.1)
	Q 0.209

A hazard ratio of less than 1 favours docetaxel + cisplatin + fluorouracil

*un-adjusted log-rank test

• un-adjusted log-rank test, not adjusted for multiple comparisons

• Chi square test, not adjusted for multiple comparisons

NA-not applicable

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Taxespira in all subsets of the paediatric population in breast cancer, non-small cell lung cancer, prostate cancer, gastric carcinoma and head and neck cancer, not including type II and III less differentiated nasopharyngeal carcinoma (see section 4.2 for information on paediatric use).

• 5.2 Pharmacoki­netic properties

Absorption

The pharmacokinetics of docetaxel have been evaluated in cancer patients after administration of 20–115 mg/m2 in phase I studies. The kinetic profile of docetaxel is dose independent and consistent with a three-compartment pharmacokinetic model with half lives for the a, P and y phases of 4 min, 36 min and 11.1 h, respectively. The late phase is due, in part, to a relatively slow efflux of docetaxel from the peripheral compartment.

Distribution

Following the administration of a 100 mg/m2 dose given as a one-hour infusion a mean peak plasma

level of 3.7 pg/ml was obtained with a corresponding AUC of 4.6 h.pg/ml. Mean values for total body clearance and steady-state volume of distribution were 21 l/h/m2 and 113 l, respectively. Inter individual variation in total body clearance was approximately 50%. Docetaxel is more than 95% bound to plasma proteins. ♦

Elimination

A study of 14C-docetaxel has been conducted in three cancer patients. Docetax both the urine and faeces following cytochrome P450-mediated oxidative meta ester group, within seven days, the urinary and faecal excretion accounted for the administered radioactivity, respectively. About 80% of the radioactivity rec

excreted during the first 48 hours as one major inactive metabolite and 3 minor inactive metabolites and very low amounts of unchanged medicinal product.

Special populations

Age and gender

A population pharmacokinetic analysis has been pe Pharmacokinetic parameters estimated by the m studies. The pharmacokinetics of docetaxel wer

h clinical chemistry data suggestive of mild to moderate liver es the ULN associated with alkaline phosphatase > 2.5 times

y 27% on average (see section 4.2).

ified in patients with mild to moderate fluid retention and there are severe fluid retention.

combination, docetaxel does not influence the clearance of doxorubicin and the plasma levels of doxorubicinol (a doxorubicin metabolite). The pharmacokinetics of docetaxel, doxorubicin and cyclophosphamide were not influenced by their co-administration.

Capecitabine

Phase I study evaluating the effect of capecitabine on the pharmacokinetics of docetaxel and vice versa showed no effect by capecitabine on the pharmacokinetics of docetaxel (Cmax and AUC) and no effect by docetaxel on the pharmacokinetics of a relevant capecitabine metabolite 5'-DFUR.

Cisplatin

Clearance of docetaxel in combination therapy with cisplatin was similar to that observed following monotherapy. The pharmacokinetic profile of cisplatin administered shortly after docetaxel infusion is similar to that observed with cisplatin alone.

Cisplatin and 5-fluorouracil

The combined administration of docetaxel, cisplatin and 5-fluorouracil in 12 patients with solid tumours had no influence on the pharmacokinetics of each individual medicinal product.

Prednisone and dexamethasone

The effect of prednisone on the pharmacokinetics of docetaxel administered with standard dexamethasone premedication has been studied in 42 patients.

Prednisone

No effect of prednisone on the pharmacokinetics of docetaxel was observed.

• 5.3 Preclinical safety data

  
  

The carcinogenic potential of docetaxel has not been studied.

Docetaxel has been shown to be mutagenic in the in vitro micronucleus and chromoso

test in CHO-K1 cells and in the in vivo micronucleus test in the mouse. However, it diinduce mutagenicity in the Ames test or the CHO/HGPRT gene mutation assay. These results are consistent with the pharmacological activity of docetaxel.

Undesirable effects on the testis observed in rodent toxicity studies sugg male fertility.

• 6. PHARMACEUTICAL PARTICULARS

  6.1 List of excipients

  
  

Polysorbate 80

Ethanol (anhydrous)

Citric acid monohydrate

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

the vial

or single use and should be used immediately after opening. If not used immediately, age times and conditions are the responsibility of the user.

Once added to the infusion bag

From a microbiological point of view, reconstitution/di­lution must take place in controlled and aseptic conditions and the medicinal product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user.

Once added as recommended into the infusion bag, the docetaxel infusion solution, if stored below 25°C, is stable for 6 hours. It should be used within 6 hours (including the one hour infusion intravenous administration).

In addition, physical and chemical in-use stability of the infusion solution prepared with sodium chloride 9 mg/ml (0.9%) or 5% glucose infused solution in non-PVC bags or with 5% glucose in glass bottles has been demonstrated for up to 48 hours when stored between 2°C to 8°C and for up to 6 hours when stored below 25°C.

Docetaxel infusion solution is supersaturated, therefore may crystallize over time. If crystals appear, the solution must no longer be used and shall be discarded.

• 6.4 Special precautions for storage

Do not store above 25°C.

Store in the original package in order to protect from light.

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

• 6.5 Nature and contents of container

  Clear glass (type I) vial with a chlorobutyl rubber stopper and an aluminium sea

  
  

20mg/1 ml contains 1 ml of concentrate.

80mg/4 ml contains 4 ml of concentrate 120mg/6 ml contains 6 ml of concentrate.

140mg/7 ml contains 7 ml of concentrate.

160mg/8 ml contains 8 ml of concentrate.

Each box contains 1 vial.

Not all pack sizes may be marketed.

• 6.6 Special precautions for disposal and other handling

Taxespira is an antineoplastic agent and, as with other potentially toxic compounds, caution should be exercised when handling it and preparing Taxespira solutions. The use of gloves is recommended.

or infusion solution should come into contact with skin, wash immediately oap and water. If Taxespira concentrate should come into contact with mucous mmediately and thoroughly with water.

Preparation for the intravenous administration

Preparation of the infusion solution

DO NOT use other docetaxel medicinal products consisting of 2 vials (concentrate and solvent) with this medicinal product (Taxespira 20 mg/1 ml concentrate for solution for infusion, which contains only 1 vial).

DO NOT use other docetaxel medicinal products consisting of 2 vials (concentrate and solvent) with this medicinal product (Taxespira 80 mg/4 ml concentrate for solution for infusion, which contains only 1 vial).

DO NOT use other docetaxel medicinal products consisting of 2 vials (concentrate and solvent) with this medicinal product (Taxespira 120 mg/6 ml concentrate for solution for infusion, which contains only 1 vial).

Honey Lane, Hurley, Maidenhead, SL6 6RJ,

United Kingdom

• 8. MARKETING AUTHORISATION NUMBER(S)

EU/1/15/1017/001

EU/1/15/1017/002

EU/1/15/1017/003

EU/1/15/1017/004

EU/1/15/1017/005

• 9. DATE OF FIRST AUTHORISATION/RE­NEWAL OF THE AUTHORISATION

28 August 2015

• A. MANUFACTURERS RESPONSI

  ANNEX II

  BATCH RELEASE

  
  

• B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

NS AND REQUIREMENTS OF THE MARKETING

TRICTIONS WITH REGARD TO THE SAFE OF THE MEDICINAL PRODUCT

Name and address of the manufacturers responsible for batch release

Hospira UK Limited

Horizon,

Honey Lane,

Hurley,

Maidenhead,

SL6 6RJ,

United Kingdom

Hospira Enterprises B.V. Randstad 22–11

NL-1316 BN Almere The Netherlands

The printed package leaflet of the medicinal product must state the name and addre manufacturer responsible for the release of the concerned batch.

• B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product Characteristics, section 4.2).

• C. OTHER CONDITIONS AND REQUIREMENTS OF AUTHORISATION

• Periodic safety update reports

ety update reports for this medicinal product are set ist) provided for under Article 107c(7) of Directive lished on the European medicines web-portal.

NS WITH REGARD TO THE SAFE AND EFFECTIVE UCT

The MAH shall perform the required pharmacovigilance activities and interventions detailed in the esented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent

P.

P should be submitted:

equest of the European Medicines Agency;

• Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached.

1. NAME OF THE MEDICINAL PRODUCT

Taxespira 20 mg/1 ml concentrate for solution for infusion. Docetaxel

Cytotoxic

• 8. EXPIRY DATE

Exp:

• 9. SPECIAL STORAGE CONDITIONS

Do not store above 25°C.

Store in the original package in order to protect from light.

Hospira UK Limited

Hurley,

SL6 6RJ, United Kingdom

• 12. MARKETING AUTHORISATION NUMBERÇ

EU/1/15/1017/001 20 mg/1 ml vial x 1 vial

• 13. BATCH NUMBER

Lot: __

• 14. GENERAL CLASSIFICATION FOR SUPPLY

• 15. INSTRUCTIONS ON USE

• 16. INFORMATION IN BRAILLE

Justification for not including Braille accepted

• 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included.

  18. UNIQUE IDENTIFIER – HUMAN READABLE DATA

  
  

  PC:

  SN:

  NN:

  
  
  
  

1. NAME OF THE MEDICINAL PRODUCT

Taxespira 80 mg/4 ml concentrate for solution for infusion. Docetaxel

Concentrate for solution for infusion

1 vial

• 5. METHOD AND ROUTE(S) OF ADMINISTRATION

–

For intravenous use

Ready to add to infusion solution.

Read the package leaflet before use

• 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT

OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

• 7. OTHER SPECIAL WARNING(S), IF NECESSARY

Cytotoxic

• 8. EXPIRY DATE

Exp:

including Braille accepted

NIQUE IDENTIFIER –2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA

PC:

SN:

NN:

including Braille accepted

NIQUE IDENTIFIER –2D BARCODE 2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA

PC:

SN:

NN:

Outer Carton

1. NAME OF THE MEDICINAL PRODUCT

Taxespira 140 mg/7 ml concentrate for solution for infusion. Docetaxel

Excipients: polysorbate 80, ethanol anhydrous (see leaflet for further information), citric acid monohydrate.

4. PHARMACEUTICAL FORM AND CONTENTS

Concentrate for solution for infusion.

Ready to add to infusion solution.

Read the package leaflet before use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT

OF THE SIGHT AND REACH OF CHILDREN _____________­____________

Keep out of the sight and reach of children.

THER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

Exp:

including Braille accepted

NIQUE IDENTIFIER –2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA

PC:

SN:

NN:

• 1. NAME OF THE MEDICINAL PRODUCT

Taxespira 160 mg/8 ml concentrate for solution for infusion. Docetaxel

• 2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each 1 ml of concentrate contains 20 mg docetaxel (as trihydrate)

• 3. LIST OF EXCIPIENTS

  
  

Excipients: polysorbate 80, ethanol anhydrous (see leaflet for further information), citric acid monohydrate.

• 4. PHARMACEUTICAL FORM AND CONTENTS /CC2

Concentrate for solution for infusion

1 vial

8. EXPIRY DATE

Exp:

including Braille accepted

NIQUE IDENTIFIER –2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA

PC:

SN:

NN:

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

Taxespira 20 mg/1 ml concentrate for solution for infusion.

Docetaxel

IV

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

• 4. BATCH NUMBER

Lot:

• 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

80 mg/4 ml

(20mg/ml)

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

Taxespira 140 mg/7 ml concentrate for solution for infusion.

Docetaxel

IV

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

Taxespira 160 mg/8 ml concentrate for solution for infusion.

Docetaxel

IV

Package leaflet: Information for the patient

Taxespira 20 mg/1 ml concentrate for solution for infusion Taxespira 80 mg/4 ml concentrate for solution for infusion Taxespira 120 mg/6 ml concentrate for solution for infusion Taxespira 140 mg/7 ml concentrate for solution for infusion Taxespira 160 mg/8 ml concentrate for solution for infusion

Docetaxel

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

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

If you have any further questions, ask your doctor, hospital pharmacist or nurse If you get any side effects talk to your doctor, hospital pharmacist or nurse. Thi possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

• 1. What Taxespira is and what it is used for

• 2. What you need to know before you use Taxespira

• 3. How to use Taxespira

• 4. Possible side effects

• 5. How to store Taxespira

• 6. Contents of the pack and other information

1. What Taxespira is and what it is used for

The name of this medicine is Taxespira. Its common name is docetaxel. Docetaxel is a substance derived from the needles of yew trees. Docetaxel belongs to the group of anti-cancer medicines called taxoids.

Taxespira has been prescribed by your doctor for the treatment of breast cancer, special forms of lung cancer (non-small cell lung cancer), prostate cancer, gastric cancer or head and neck cancer:

of advanced breast cancer, Taxespira could be administered either alone or in doxorubicin, or trastuzumab, or capecitabine.

of early breast cancer with or without lymph node involvement, Taxespira ered in combination with doxorubicin and cyclophosphamide.

eatment of lung cancer, Taxespira could be administered either alone or in ion with cisplatin.

eatment of prostate cancer, Taxespira is administered in combination with prednisone dnisolone.

r the treatment of metastatic gastric cancer, Taxespira is administered in combination with cisplatin and 5-fluorouracil.

• For the treatment of head and neck cancer, Taxespira is administered in combination with

cisplatin and 5-fluorouracil.

2. What you need to know before you use TaxespiraYou must not be given Taxespira if you are allergic (hypersensitive) to docetaxel or any of the other ingredients of Taxespira

(listed in section 6).

• if the number of your white blood cells is too low.
• if you have a severe liver disease.

Warnings and precautions

Before each treatment with Taxespira, you will have blood tests to check that you have enough blood cells and sufficient liver function to receive Taxespira. In case of white blood cells disturbances, you may experience associated fever or infections.

Tell your doctor, hospital pharmacist, or nurse immediately if you have abdominal pain or tenderness, diarrhoea, rectal haemorrhage, blood in stool or fever. These symptoms may be the first signs of a serious gastrointestinal toxicity, which could be fatal. Your doctor should address them immediately.

Tell your doctor, hospital pharmacist or nurse if you have vision problems. In case of vision problems, in particular blurred vision, you should immediately have your eyes and vision examined.

Tell your doctor, hospital pharmacist or nurse if you have heart problems.

Tell your doctor, hospital pharmacist or nurse if you have experienced an allergic reaction to previous paclitaxel therapy.

If you develop acute or worsening problems with your lungs (fever, shortness of breath or cough), please tell your doctor, hospital pharmacist or nurse immediately. Your doctor may stop your treatment immediately.

You will be asked to take premedication consisting of an oral corticosteroid such as dexamethasone, one day prior to Taxespira administration and to continue for one or two days after it in order to minimise certain undesirable effects which may occur after the infusion of Taxespira in particular allergic reactions and fluid retention (swelling of the hands, feet, legs or weight gain).

During treatment, you may be given other medicines to maintain the number of your blood cells.

Taxespira contains alcohol. Discuss with your doctor if you suffer from alcohol dependency, epilepsy, or liver impairment. See also section “Taxespira contains ethanol (alcohol)” below.

Other medicines and Taxespira

Please tell your doctor or hospital pharmacist if you are taking or have recently taken any other medicine, including medicines obtained without a prescription. This is because Taxespira or the other medicine may not work as well as expected and you may be more likely to get a side effect.

The amount of alcohol in this medicinal product may alter the effects of other medicines.

P h tf d- df tit

Pregnancy, breast-feeding and fertility

Ask your doctor for advice before being given any medicine.

Taxespira must NOT be administered if you are pregnant unless clearly indicated by your doctor.

You must not become pregnant during treatment with this medicine and must use an effective method of contraception during therapy, because Taxespira may be harmful for the unborn baby. If pregnancy occurs during your treatment, you must immediately inform your doctor.

You must not breast-feed while you are treated with Taxespira.

If you are a man being treated with Taxespira you are advised not to father a child during and up to 6 months after treatment and to seek advice on conservation of sperm prior to treatment because Docetaxel may alter male fertility.

Driving and using machines

The amount of alcohol in this medicinal product may impair your ability to drive or use machines. You may experience side effects of this medicine that may impair your ability to drive, use tools or operate machines (see section 4 Possible side effects). If this happens, do not drive or use any tools or machines before discussing with your doctor, nurse or hospital pharmacist.

Taxespira contains ethanol (alcohol) 20mg/1ml:

This medicine contains 50 vol % ethanol anhydrous (alcohol), i.e. up to 395 mg ethanol anhydrous per 1 ml, equivalent to 10 ml of beer or 4 ml wine.

80mg/4 ml:

This medicine contains 50 vol % ethanol anhydrous (alcohol), i.e. up to 1580 mg eth per 4 ml vial, equivalent to 40 ml of beer or 17 ml wine.

120mg/6 ml:

This medicine contains 50 vol % ethanol anhydrous (alcohol), i.e. up to 237 per 6 ml vial, equivalent to 60 ml of beer or 25 ml wine.

140mg/7 ml:

This medicine contains 50 vol % ethanol anhydrous (alcohol), i.e. up to 2765 mg ethanol anhydrous per 7 ml vial, equivalent to 70 ml of beer or 29 ml wine.

160mg/8 ml:

This medicine contains 50 vol % ethanol anhydrous (alcohol), i.e. up to 3160 mg ethanol anhydrous per 8 ml vial, equivalent to 80 ml of beer or 33 ml wine.

The amount of alcohol in this medicinal product may have effects on the central nervous system (the part of the nervous system that includes the brain and spinal cord).

Harmful for those suffering from alc

To be taken into account in pregnant or breast-feeding women, children and high-risk groups such as patients with liver disease, or epilepsy.

e administered to you by a healthcare professional.

The dose will depend on your weight and your general condition. Your doctor will calculate your body surface area in square meters (m2) and will determine the dose you should receive.

Method and route of administration

Taxespira will be given by infusion into one of your veins (intravenous use). The infusion will last approximately one hour during which you will be in the hospital.

Frequency of administration

You should usually receive your infusion once every 3 weeks.

Your doctor may change the dose and frequency of dosing depending on your blood tests, your general condition and your response to Taxespira. In particular, please inform your doctor in case of diarrhoea, sores in the mouth, feeling of numbness or pins and needles, fever and give her/him the results of your blood tests. Such information will allow her/him to decide whether a dose reduction is needed. If you have any further questions on the use of this medicine, ask your doctor, or hospital pharmacist.

4. Possible side effects

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

Your doctor will discuss these with you and will explain the potential risks and benefits of y treatment.

The most commonly reported adverse reactions of Taxespira alone are: decrease in blood cells or white blood cells, alopecia (hair loss), nausea, vomiting, sores in and tiredness.

The severity of adverse events of Taxespira may be increased when Taxespira is given in combination with other chemotherapeutic agents.

The hospital staff will monitor your condition closely during treatment. Tell them immediately if you notice any of these effects.

Between infusions of Taira the following may occur, and the frequency may vary with the combinations of medicines that are received: t in fighting infection) and platelets (important in blood clotting) : if this happens you must tell your doctor immediately lergic reactions as described above

oss of appetite (anorexia)

insomnia

feeling of numbness or pins and needles

pain in the joints or muscles

headache

alteration in sense of taste

inflammation of the eye or increased tearing of the eyes

swelling caused by faulty lymphatic drainage

shortness of breath

nasal drainage; inflammation of the throat and nose; cough

• bleeding from the nose
• sores in the mouth
• stomach upsets including nausea, vomiting and diarrhoea, constipation
• abdominal pain
• indigestion
• hair loss: in most cases normal hair growth should return. In some cases (frequency not known)

permanent hair loss has been observed

• redness and swelling of the palms of your hands or soles of your feet which may cause your

skin to peel (this may also occur on the arms, face, or body)

• change in the colour of your nails, which may detach
• muscle aches and pains; back pain or bone pain
• change or absence of menstrual periods
• swelling of the hands, feet, legs
• tiredness or flu-like symptoms
• weight gain or loss.

Common (may affect up to 1 in 10 people):

• oral candidiasis (thrush)
• dehydration
• dizziness
• hearing impaired
• decrease in blood pressure; irregular or rapid heart beat
• heart failure
• oesophagitis (inflammation of the gullet)
• dry mouth
• difficulty or painful swallowing
• haemorrhage (bleeding)
• raised liver enzymes (hence the need for regular blood tests).

Uncommon (may affect up to 1 in 100 people):

• fainting
• at the injection site, skin reactions, phlebitis (inflammation of the vein) or swelling
• blood clots.
• inflammation of the colon, small intestine, which could be fatal (frequency not known);

intestinal perforation.

Frequency not known (cannot be estimated from available data):

• interstitial lung disease (inflammation of the lungs causing coughing and difficulty breathing.

Inflammation of the lungs can also develop when docetaxel therapy is used with radiotherapy)

• pneumonia (infection of the lungs)
• pulmonary fibrosis (scarring and thickening in the lungs with shortness of breath)
• blurred vision due to swelling of the retina within the eye (cystoid macular oedema)
• decrease of the sodium, potassium, magnesium, and/or calcium in your blood (electrolyte

balance disorders).

• ventricular arrhythmia or ventricular tachycardia (manifested as irregular and/or rapid heartbeat,

severe shortness of breath, dizziness, and/or fainting). Some of these symptoms can be serious. If this happens, you must tell your doctor immediately.

• injection site reactions at the site of a previous reaction.

Reporting of side effects

If you get any side effects talk to your doctor, hospital pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.

5. How to store Taxespira

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the outer carton and on the label of the vial after EXP. The expiry date refers to the last day of that month.

Do not store above 25°C.

Store in the original package in order to protect from light.

Use the vial immediately after its opening. If not used immediately, in-use storage tim conditions are the responsibility of the user.

From a microbiological point of view, reconstitution/di­lution must take place i conditions.

Use immediately the medicine once added into the infusion bag. If not used immediately, in-use storage times and conditions are the responsibility of the user and would normally not be longer than 6 hours below 25°C including the one hour infusion.

Physical and chemical in-use stability of the infusion solut demonstrated in non-PVC bags up to 48 hours when st

Docetaxel infusion solution is supersaturated, therefore may crystallize over time. If crystals appear, the solution must no longer be used and shall be discarded.

Do not throw away any medicines via wastewater. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack

What Taxespira contai

docetaxel (as trihydrate). Each ml of solution contains 20 mg of docetaxel (as 20mg/1

One vial of 1 ml of concentrate contains 20 mg docetaxel.

80mg/4 ml

One vial of 4 ml concentrate contains 80 mg docetaxel.

120mg/6 ml

One vial of 6 ml concentrate contains 120 mg docetaxel.

140mg/7 ml

One vial of7 ml concentrate contains 140 mg docetaxel.

160mg/8 ml

One vial of8 ml concentrate contains 160 mg docetaxel.

– The other ingredients are polysorbate 80, ethanol anhydrous (see section 2) and citric acid monohydrate.

What Taxespira looks like and contents of the pack

Taxespira concentrate for solution for infusion is a pale yellow to brownish-yellow solution provided in glass vials.

Vials containing 20 mg/1 ml, 80 mg/4 ml, 120 mg/6 ml, 140 mg/7 ml and 160 mg/8 ml are available in packs containing a single vial.

Not all pack sizes are marketed.

Marketing Authorisation Holder and Manufacturer

Hospira UK Limited Horizon, Honey Lane, Hurley, Maidenhead, SL6 6RJ, United Kingdom

For any information about this medicine, please contact the Authorisation Holder:

BE / LU

Pfizer SA/NV

Tél/Tel: +32 2 554 62 11

BG / EL / MT / RO / UK

Hospira UK Limited

Tel: + 44 (0) 1628 515500

CZ

Pfizer, spol. s r.o.

Tel: +420–283–004–111

NL

Pfizer bv

Tel: +31 (0)10 406 43 01

DE

Pfizer Pharma PFE GmbH

Tel: + 49 (0)800 8535555

Recommendations for the safe handling

Docetaxel is an antineoplastic agent and, as with other potentially toxic compounds, caution should be exercised when handling it and preparing its solutions. The use of gloves is recommended.

If Taxespira concentrate or infusion solution should come into contact with skin, wash immediately and thoroughly with soap and water. If it should come into contact with mucous membranes, wash immediately and thoroughly with water.

Preparation of the intravenous administration

Preparation of the infusion solution

DO NOT use other docetaxel medicinal products consisting of 2 vials (concentrate and solvent) with this medicinal product (Taxespira 20 mg/1 ml concentrate for solution for infusion, which contains only 1 vial).

DO NOT use other docetaxel medicinal products consisting of 2 vials (concentrate and solvent) with this medicinal product (Taxespira 80 mg/4 ml concentrate for solution for infusion, which contains only 1 vial).

DO NOT use other docetaxel medicinal products consisting of 2 vials (concentrate and solvent) with this medicinal product (Taxespira 120 mg/6 ml concentrate for solution for infusion, which contains only 1 vial).

DO NOT use other docetaxel medicinal products consisting of 2 vials (concentrate and with this medicinal product (Taxespira 140 mg/7 ml concentrate for solution for infusion, which contains only 1 vial).

DO NOT use other docetaxel medicinal products consisting of 2 vials (conc with this medicinal product (Taxespira 160 mg/8 ml concentrate for solution for infusion, which contains only 1 vial).

Taxespira concentrate for solution for infusion requires NO prior dilution with a solvent and is ready to add to the infusion solution.

Each vial is for single use and should be used immediately after opening. If not used immediately, in-use storage times and conditions are the responsibility of the user. More than one vial of Taxespira concentrate for solution for infusion may be necessary to obtain the required dose for the patient. For example, a dose of 140 mg docetaxel would require 7 ml Taxespira 20 mg/1 ml concentrate for solution for infusion.

In Taxespira 20 mg/1 ml, 80 mg/4 ml, 120 mg/6 ml, 140 mg/7 ml and 160 mg/8 ml vials the concentration of docetaxel is 20 mg/ml.

Inject the required dose (in mg) via a single injection (one shot) into a 250 ml non-PVC infusion bag containing either 5% glucose solution or sodium chloride 9 mg/ml (0.9%) solution for infusion or with 5% glucose solution in a glass bottle. If a dose greater than 190 mg of docetaxel is required, use a larger volume of the infusion vehicle so that a concentration of 0.74 mg/ml docetaxel is not exceeded.

Mix the infusion bag or bottle manually using a rocking motion.

From a microbiological point of view, reconstitution /dilution must take place in controlled and aseptic conditions and the infusion solution should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user.

Once added as recommended into the infusion bag, the docetaxel infusion solution, if stored below 25°C, is stable for 6 hours. It should be used within 6 hours (including the one hour infusion intravenous administration).

In addition, physical and chemical in-use stability of the infusion solution prepared as recommended in non-PVC bags or bottles has been demonstrated up to 48 hours when stored between 2°C to 8°C, and for up to 6 hours when stored below 25°C.

Docetaxel infusion solution is supersaturated, therefore may crystallize over time. If crystals appear, the solution must no longer be used and shall be discarded.

• As with all parenteral products, infusion solution should be visually inspected prior to use,

solutions containing a precipitate should be discarded.

Disposal

All materials that have been utilised for dilution and administration should be disposed of according to standard procedures. Do not throw away any medicines via wastewater. These measures will help protect the environment.

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