Paclitaxel 6mg/Ml Concentrate For Solution For Infusion

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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Paclitaxel 6 mg/ml concentrate for solution for infusion.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Paclitaxel vials contain 30 mg, 100 mg, 150mg or 300 mg paclitaxel as 6 mg/ml solution.

3 PHARMACEUTICAL FORM

Concentrate for solution for infusion.

Paclitaxel concentrate for solution for infusion is a clear, colourless or slightly yellow, viscous solution.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

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

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

Breast carcinoma: Paclitaxel is indicated for the initial treatment of advanced or metastatic breast cancer in combination with trastuzumab, in patients who over-express HER-2 at a 3+ level as determined by immunohistochemistry and for whom an anthracycline is not suitable (see 4.4 and 5.1).

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

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

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

4.2 Posology and method of administration

All patients must be premedicated with corticosteroids, antihistamines, and H₂ antagonists prior to Paclitaxel, e.g.

Drug	Dose	Administration prior to Paclitaxel
dexamethasone	20 mg oral	approximately 12 and 6 hours
diphenhydramine	50 mg IV	30 to 60 min
cimetidine or ranitidine	300 mg IV 50 mg IV	30 to 60 min

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

First-line chemotherapy of ovarian carcinoma: although other dosage regimens are under investigation, a combination regimen of Paclitaxel and cisplatin is recommended. According to duration of infusion, two doses of Paclitaxel are recommended: Paclitaxel 175 mg/m² administered intravenously over 3 hours, followed by cisplatin at a dose of 75 mg/m every three weeks or Paclitaxel 135 mg/m², in a 24-hour infusion, followed by cisplatin 75 mg/m², with a 3 week interval between courses (see 5.1).

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

First-line chemotherapy of breast carcinoma: when used in combination with trastuzumab, the recommended dose of Paclitaxel is 175 mg/m2 administered intravenously over a period of 3 hours, with a 3-week interval between courses (see 5.1). Paclitaxel infusion may be started the day following the first dose of trastuzumab or immediately after the subsequent doses of trastuzumab if the preceding dose of trastuzumab was well tolerated (for detailed trastuzumab posology see the Summary of Product Characteristics of Herceptin®).

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

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

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

Paclitaxel should not be readministered until the neutrophil count is > 1,500/mm³ and the platelet count is > 100,000/mm³. Patients who experience severe neutropenia (neutrophil count < 500/mm3 for > 7 days) or severe peripheral neuropathy should receive a dose reduction of 20% for subsequent courses (see 4.4).

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

4.3 Contraindications

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

Paclitaxel is contraindicated during pregnancy and lactation (see 4.6)

Paclitaxel should not be used in patients with baseline neutrophils < 1,500/mm3.

4.4 Special warnings and precautions for use

Paclitaxel should be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents. Since significant hypersensitivity reactions may occur, appropriate supportive equipment should be available.

Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug administration.

Patients must be pretreated with corticosteroids, antihistamines and H₂ antagonists (see 4.2).

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

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

Bone marrow suppression (primarily neutropenia) is the dose-limiting toxicity. Frequent monitoring of blood counts should be instituted. Patients should not be retreated until neutrophils recover to > 1,500/mm3 and platelets recover to > 100,000/mm3.

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

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

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

When Paclitaxel is used in combination with doxorubucin or trastuzumab for initial treatment of metastatic breast cancer, attention should be placed on the monitoring of cardiac function. When patients are candidates for treatment with Paclitaxel in these combinations, they should undergo baseline cardiac assessment including history, physical examination, ECG, echocardiogram, and/or MUGA scan. Cardiac function should be further monitored during treatment (e.g. every three months). Monitoring may help to identify patients who develop cardiac dysfunction and treating physicians should carefully assess the cumulative dose (mg/m²) of anthracycline administered when making decisions regarding frequency of ventricular function assessment. When testing indicates deterioration in cardiac function, even asymptomatic, treating physicians should carefully assess the clinical benefits of further therapy against the potential for producing cardiac damage, including potentially irreversible damage. Patients who develop asymptomatic cardiac dysfunction may benefit from more frequent monitoring (e.g. every 6-8 weeks). If patients have a continued decrease in left ventricular ejection fraction, but remain asymptomatic, the physician should carefully evaluate the risk-benefit. If further treatment is administered, monitoring of cardiac function should be more frequent (e.g. every 1-2 cycles). For more details see Summary of Product Characteristics of Herceptin or doxorubicin.

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

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

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

Since Paclitaxel contains ethanol (396 mg/ml), consideration should be given to possible CNS and other effects.

Pseudomembranous colitis has been rarely reported including cases in patients who have not been concomitantly treated with antibiotics. This reaction should be considered in the differential diagnosis of cases of severe or persistent diarrhoea occurring during or shortly after treatment with Paclitaxel.

4.5 Interaction with other medicinal products and other forms of interaction

The recommended regimen of Paclitaxel administration for the first-line chemotherapy of ovarian carcinoma is for Paclitaxel to be given before cisplatin.

When Paclitaxel is given before cisplatin, the safety profile of Paclitaxel is consistent with that reported for single-agent use. When Paclitaxel was given after cisplatin, patients showed a more profound myelosuppression and an approximately 20% decrease in Paclitaxel clearance. Patients treated with Paclitaxel and cisplatin may have an increased risk of renal failure as compared to cisplatin alone in gynecological cancers.

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

The metabolism of Paclitaxel is catalysed, in part, by cytochrome P450 isoenzymes CYP2C8 and 3A4 (see 5.2). Clinical studies have demonstrated that

CYP2C8-mediated metabolism of Paclitaxel, to 6a-hydroxypaclitaxel, is the major metabolic pathway in humans. Based on current knowledge, clinically relevant interactions between Paclitaxel and other CYP2C8 substrates are not anticipated. Concurrent administration of ketoconazole, a known potent inhibitor of CYP3A4, does not inhibit the elimination of Paclitaxel in patients; thus, both medicinal products may be administered together without dosage adjustment. Further data on the potential of drug interactions between Paclitaxel and other CYP3A4 substrates/inhibitors are limited. Therefore, caution should be exercised when administering Paclitaxel concomitantly with medicines known to inhibit (e.g. erythromycin, fluoxetine, gemfibrozil) or induce (e.g. rifampicin, carbamazepine, phenytoin, phenobarbital, efavirenz, nevirapine) either CYP2C8 or 3A4.

Paclitaxel clearance is not affected by cimetidine premedication.

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

4.6 Pregnancy and lactation

Paclitaxel has been shown to be embryotoxic and foetotoxic in rabbits, and to decrease fertility in rats.

There is no adequate data from the use of Paclitaxel in pregnant women. Paclitaxel has been shown to be both embryotoxic and foetotoxic in rabbits, and to reduce fertility in rats. As with other cytotoxic medicinal products, Paclitaxel may cause foetal harm when administered to pregnant women. Therefore, Paclitaxel should not be used during pregnancy unless clearly necessary. Women of childbearing potential receiving Paclitaxel should be advised to avoid becoming pregnant, and to inform the treating physician immediately should this occur. Female and male patients of fertile age, and/or their partners should use contraceptions for at least 6 months after treatment with Paclitaxel.

Male patients should seek advice regarding cryoconservation of sperm prior to treatment with Paclitaxel because of the possibility of infertility.

Paclitaxel is contraindicated during lactation (see section 4.3). It is not known whether Paclitaxel is excreted in human milk. Breastfeeding should be discontinued for the duration of therapy.

4.7 Effects on ability to drive and use machines

Paclitaxel has not been demonstrated to interfere with the ability to drive and use machines. However, it should be noted that Paclitaxel does contain alcohol (see 4.4 and 6.1).

4.8 Undesirable effects

Unless otherwise noted, the following discussion refers to the overall safety database of 812 patients with solid tumours treated with single-agent Paclitaxel in clinical studies.

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

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

The most frequent significant undesirable effect was bone marrow suppression. Severe neutropenia (< 500 cells/mm³) occurred in 28% of patients, but was not associated with febrile episodes. Only 1% of patients experienced severe neutropenia for > 7 days. Thrombocytopenia was reported in 11% of patients. Three percent of patients had a platelet count nadir < 50,000/mm³ at least once while on study.

Anaemia was observed in 64% of patients, but was severe (Hb < 5 mmol/l) in only 6% of patients. Incidence and severity of anaemia is related to baseline haemoglobin status.

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

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

Injection site reactions during intravenous administration may lead to localised oedema, pain, erythema, and induration; on occasion, extravasation can result in cellulitis. Skin sloughing and/or peeling has been reported, sometimes related to extravasation. Skin discoloration may also occur. Recurrence of skin reactions at a site of previous extravasation following administration of Paclitaxel at a different site, i.e. “recall”, has been reported rarely. A specific treatment for extravasation reactions is unknown at this time.

In some cases, the onset of the injection site reaction either occurred during a prolonged infusion or was delayed by a week to 10 days.

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

The frequency of adverse reactions listed below is defined using the following convention:very common (> 1/10); common (> 1/100, < 1/10); uncommon (> 1/1,000, < 1/100); rare (> 1/10,000, < 1/1,000); very rare (< 1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

System organ Class	Frequency	Adverse reactions
Infections and infestations	very common uncommon	infection (mainly urinary tract and upper respiratory tract infections), with reported cases of fatal outcome

	rare	septic shock
		sepsis, peritonitis, pneumonia*
Blood and lymphatic	very common	Myelosuppression,
system disorders		neutropenia,anaemia, thrombocytopenia, leucopenia, bleeding
	rare	febrile neutropenia*
	very rare	acute myeloid leukaemia, myelodysplastic syndrome
Immune system disorders	very common	minor hypersensitivity reactions (mainly flushing and rash)
	uncommon	significant hypersensitivity reactions requiring therapy (e.g., hypotension, angioneurotic oedema, respiratory distress. generalised urticaria, chills,
	rare	back pain, chest pain, tachycardia, abdominal pain, pain in extremities,
	very rare	diaphoresis and hypertension)
		anaphylactic reactions*
		anaphylactic shock*
Metabolism and nutrition	very rare	anorexia*
disorders	not known	tumor lysis syndrome*
Psychiatric disorders	very rare	confusional state*
Nervous system disorders	very common	neurotoxicity (mainly: peripheral neuropathy)
	rare	motor neuropathy (with
	very rare	resultant minor distal weakness)*

		grand mal seizures, autonomic neuropathy (resulting in paralytic ileus and orthostatic hypotension), encephalopathy,* convulsions, dizziness, ataxia, headache
Eye disorders	very rare	optic nerve and/or visual disturbances (scintillating scotomata)*, particularly in patients who have received higher doses than
	not known	recommended macular oedema,photopsia, vitreous floaters*
Ear and labyrinth disorders	very rare	hearing loss, ototoxicity, tinnitus, vertigo
Cardiac disorders	common	bradycardia
	uncommon	myocardial infarction, AV block and syncope, cardiomyopathy, asymptomatic ventricular
	rare	tachycardia, tachycardia with
	very rare	bigeminy cardiac failure atrial fibrillation, supraventricular tachycardia
Vascular disorders	very common	hypotension
	uncommon very rare	thrombosis, hypertension, thrombophlebitis shock*
	not known	phlebitis*
Respiratory, thoracic and	rare	respiratory failure*,
mediastinal disorders		pulmonary embolism*, lung

	very rare	fibrosis, interstitial pneumonia, dyspnoea, pleural effusion
		cough*
Gastrointestinal disorders	very common rare	diarrhoea, vomiting, nausea, mucosal inflammation
	very rare	bowel obstruction, bowel perforation, ischaemic colitis, pancreatitis*
		mesenteric thrombosis, pseudomembranous colitis, neutropenic colitis, ascites, oesophaaitis, constipation
Hepatobiliary disorders	very rare	hepatic necrosis, hepatic encephalopathy (both with reported cases of fatal outcome)
Skin and subcutaneous tissue disorders	very common common rare	alopecia transient and mild nail and skin changes
	very rare	pruritus, rash, erythema*
	not known	Stevens-Johnson syndrome, epidermal necrolysis, erythema multiforme, exfoliative dermatitis,urticaria, onycholysis (patients on therapy should wear sun protection on hands and feet)
		scleroderma*
Musculoskeletal and	very common	arthralgia, myalgia

connective tissue disorders	not known	systemic lupus erythematosus*
General disorders and	common	injection site radiations
administration		(including localised
site conditions	rare	oedema, pain, erythema, induration, on occasion extravasation can result in cellulitis, skin fibrosis and skin necrosis)
		pyrexia, dehydration, asthenia, oedema, malaise*
Investigations	Uncommon	severe elevation in bilirubin
	rare	increase in blood creatinine*

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

Combination treatment

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

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

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

When Paclitaxel was administered as a 3-hour infusion in combination with trastuzumab for the first line treatment of patients with metastatic breast cancer, the following events (regardless of relationship to Paclitaxel or trastuzumab) were reported more frequently than with single agent Paclitaxel: heart failure (8% vs 1%), infection (46% vs 27%), chills (42% vs 4%), fever (47% vs 23%), cough (42% vs 22%), rash (39% vs 18%), arthralgia (37% vs 21%), tachycardia (12% vs 4%), diarrhoea (45% vs 30%), hypertonia (11% vs 3%), epistaxis (18% vs 4%), acne (11% vs 3%), herpes simplex (12% vs 3%), accidental injury (13% vs 3%), insomnia (25% vs 13%), rhinitis (22% vs 5%), sinusitis (21% vs 7%), and injection site reaction (7% vs 1%). Some of these frequency differences may be due to the increased number and duration of treatments with Paclitaxel/trastuzumab combination vs single agent Paclitaxel. Severe events were reported at similar rates for Paclitaxel/trastuzumab and single agent Paclitaxel.

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

Radiation pneumonitis has been reported in patients receiving concurrent radiotherapy.

4.9 Overdose

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

Overdoses in paediatric patients may be associated with acute ethanol toxicity.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group / ATC code: cytostatic agent, L01C D01.

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

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

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

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

(p < 0.008).

5.2 Pharmacokinetic properties

Following intravenous administration, paclitaxel exhibits a biphasic decline in plasma concentrations.

The pharmacokinetics of paclitaxel were determined following 3 and 24 hour infusions at doses of 135 and 175 mg/m². Mean terminal half-life estimates ranged from 3.0 to 52.7 hours, and mean, non-compartmentally derived, values for total body clearance ranged from 11.6 to 24.0 l/hr/m2; total body clearance appeared to decrease with higher plasma concentrations of paclitaxel. Mean steady-state volume of distribution ranged from 198 to 688 l/m2, indicating extensive extravascular distribution and/or tissue binding. With the 3-hour infusion, increasing doses result in non-linear pharmacokinetics. For the 30% increase in dose from 135 mg/m2 to 175 mg/m2, the C_max and AUC₀^« values increased 75% and 81%, respectively.

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

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

The disposition of paclitaxel has not been fully elucidated in humans. Mean values for cumulative urinary recovery of unchanged drug have ranged from 1.3 to 12.6% of the dose, indicating extensive non-renal clearance. Hepatic metabolism and biliary clearance may be the principal mechanism for disposition of paclitaxel. Paclitaxel appears to be metabolised primarily by cytochrome P450 enzymes. Following administration of a radiolabelled paclitaxel, an average of 26, 2 and 6% of the radioactivity was excreted in the faeces as 6a-hydroxypaclitaxel, 3’-p-hydroxypaclitaxel, and 6a-3’-p-dihydroxy-paclitaxel, respectively. The formation of these hydroxylated metabolites is catalysed by CYP2C8, -3A4, and both -2C8 and -3A4 respectively. The effect of renal or hepatic dysfunction on the disposition of paclitaxel following a 3-hour infusion has not been investigated formally. Pharmacokinetic parameters obtained from one patient undergoing haemodialysis who received a 3-hour infusion of Paclitaxel 135 mg/m² were within the range of those defined in non-dialysis patients.

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

5.3 Preclinical safety data

The carcinogenic potential of Paclitaxel has not been studied. However, paclitaxel is a potential carcinogenic and genotoxic agent, based upon its pharmacodynamic mechanism of action. Paclitaxel has been shown to be mutagenic in both in vitro and in vivo mammalian test systems.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Macrogolglycerol ricinoleate, ethanol, citric acid.

6.2 Incompatibilities

Macrogolglycerol ricinoleate can result in DEHP [di-(2-ethylhexyl)phthalate] leaching from plasticized polyvinyl chloride (PVC) containers at levels which increase with time and concentration. Consequently, the preparation, storage and administration of diluted Paclitaxel should be carried out using non-PVC-containing equipment.

6.3 Shelf life

Vial: 2 years (if unopened)

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

Diluted solutions: chemical and physical in-use stability of the solution prepared for infusion has been demonstrated for 27 hours at 25°C.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.

6.4 Special precautions for storage

Before and after opening: Do not store above 25°C. Store in original package in order to protect from light.

Diluted solutions: Do not refrigerate or freeze diluted solutions.

6.5 Nature and contents of container

Type I glass vials with bromobutyl rubber stoppers containing 30 mg of paclitaxel in 5 ml solution, 100 mg in 16.7 ml, 150 mg in 25 ml or 300 mg in 50 ml solution. The vials are available individually packaged in a carton.

6.6 Special precautions for disposal

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

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

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

Preparation for IV administration: Prior to infusion, Paclitaxel must be diluted, using aseptic techniques, in 0.9% Sodium Chloride Injection, or 5% Dextrose Injection, or 5% Dextrose and 0.9% Sodium Chloride Injection, or 5% Dextrose in Ringer's Injection, to a final concentration of 0.3 to 1.2 mg/ml.

Chemical and physical in-use stability of the solution prepared for infusion has been demonstrated for 27 hours at 25°C.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage time and conditions prior to use are the responsibility of the user. Diluted solutions should not be refrigerated. After dilution the solution is for single use only.

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

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

To minimise patient exposure to DEHP, which may be leached from plasticized PVC infusion bags, sets, or other medical instruments, diluted Paclitaxel solutions should be stored in non-PVC bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets. Use of filter devices (e.g. IVEX-2®) which incorporate short inlet and/or outlet plasticized PVC tubing has not resulted in significant leaching of DEHP.

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

7 MARKETING AUTHORISATION HOLDER

Teva UK Limited Brampton Road Hampden Park Eastbourne East Sussex BN22 9AG

8 MARKETING AUTHORISATION NUMBER(S)

PL 00289/1260

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

22/11/2004 / 03/07/2009

DATE OF REVISION OF THE TEXT

05/10/2011