4.1. Therapeutic indications

Ovarian cancer:

In first line chemotherapy of ovarian cancer, paclitaxel is indicated for the treatment of patients with advanced disease or a residual disease (> 1 cm) after initial laparotomy, in combination with cisplatin.

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

Breast cancer:

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

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

As a single agent, treatment of metastatic carcinoma of the breast in patients who have failed to respond adequately to standard treatment with anthracyclines or in whom anthracycline therapy has not been appropriate.

Advanced non-small cell lung cancer (NSCLC):

Paclitaxel, in combination with cisplatin, is indicated for the treatment of non-small cell lung cancer in patients who are not candidates for potentially curative surgical intervention and/or radiation therapy.

AIDS-related Kaposi's sarcoma (KS):

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

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

4.2. Posology and method of administration

Posology

Pre-medication: All patients must be given pre-medication consisting of corticosteroids, antihistamines and H2-receptor antagonists prior to paclitaxel administration, in order to prevent severe hypersensitivity reactions. Such pre-medication may consist of:

Table 1: Pre-medication Schedule

Pre-medication

Dose

Administration Prior to Paclitaxel

Dexamethasone

20 mg oral* or IV**

Oral: Approx. 12 and 6 hours

IV: 30 – 60 min

Diphenhydramine ***

50 mg IV

30 to 60 min

Cimetidine or

Ranitidine

300 mg IV

50 mg IV

30 to 60 min

* 8-20 mg for KS patients

** intravenous

*** or an equivalent antihistamine, e.g. chlorphenamine 10 mg IV, administered 30 to 60 minutes prior to paclitaxel

Paclitaxel should be administered using an in-line filter with a microporous membrane of ≤0.22 microns.

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

First-line treatment of ovarian cancer: Although alternative medication regimens for paclitaxel are under investigation at present, a combination therapy of paclitaxel and cisplatin is recommended.

Depending on the duration of infusion, two different dosages are recommended for paclitaxel treatment: 175 mg/m2 of paclitaxel is administered as an intravenous infusion over a period of three hours followed thereafter by 75 mg/m2 of cisplatin and the therapy is repeated at 3-week intervals, or 135 mg/m2 of paclitaxel is administered as an intravenous infusion over a period of 24 hours followed thereafter by 75 mg/m2 of cisplatin and the therapy is repeated at 3-week intervals (see section 5.1).

Second-line treatment of ovarian cancer: The recommended dose of paclitaxel is 175 mg/m2 administered over 3 hours, with a 3-week interval between courses.

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

First-line chemotherapy of breast carcinoma: When used in combination with doxorubicin (50 mg/m2), paclitaxel should be administered 24 hours after doxorubicin. The recommended dose of paclitaxel is 220 mg/m2 administered intravenously over a period of 3 hours, with a 3-week interval between courses (see sections 4.5 and 5.1).

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

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.

Advanced non-small cell lung cancer: The recommended dose of paclitaxel is 175 mg/m2 administered over 3 hours followed by 80 mg/m2 of cisplatin, with a 3-week interval between courses.

Treatment of AIDS-related KS: The recommended dose of paclitaxel is 100 mg/m2 administered as a 3 hour intravenous infusion every two weeks.

Dose adjustment: Subsequent doses of paclitaxel should be administered according to individual patient tolerance. Paclitaxel should not be re-administered until the neutrophil count is ≥ 1.5 x 109/L (≥ 1 x 109/L for KS patients) and the platelet count is ≥ 100 x 109/L (≥ 75 x 109/L for KS patients).

Patients who experience severe neutropenia (neutrophil count < 0.5 x 109/L for a minimum of 7 days) or severe peripheral neuropathy, should receive a dose reduction of 20% for subsequent courses (25% for KS patients) (see section 4.4).

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

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

Method of administration

Precautions to be taken before handling or administering the medicinal product

The concentrate for solution for infusion must be diluted before use (see section 6.6) and should only be administered intravenously.

4.3. Contraindications

Paclitaxel is contraindicated in patients with severe hypersensitivity reactions to paclitaxel, macrogolglycerol ricinoleate (polyoxyl castor oil) (see section 4.4) or to any of the excipients listed in section 6.1.

Paclitaxel is contraindicated during lactation (see section 4.6).

Paclitaxel should not be used in patients with baseline neutrophils < 1.5 x 109/L (<1 x 109/L for KS patients) or platelets < 100 x 109/L (< 75 x 109/L for KS patients).

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

Patients with severe hepatic impairment must not be treated with paclitaxel.

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 section 4.2).

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

Significant hypersensitivity reactions, as characterised by dyspnoea and hypotension requiring treatment, angioedema, and generalised urticaria have occurred in < 1% of patients receiving paclitaxel after adequate premedication. Fatal hypersensitivity reactions have occurred in patients despite 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 paclitaxel. Macrogolglycerol ricinoleate (polyoxyl castor oil), an excipient in this medicinal product, can cause these reactions.

Bone marrow suppression, primarily neutropenia, is the dose-limiting toxicity. Neutrophil nadirs occurred at a median of 11 days. Frequent monitoring of blood counts should be instituted. Patients should not be retreated until the neutrophil count is ≥ 1.5 x 109/L (≥ 1 x 109/L for KS patients) and the platelets recover to ≥ 100 x 109/L (≥ 75 x 109/L for KS patients). In the KS clinical study, the majority of patients were receiving granulocyte colony stimulating factor (G-CSF).

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 signs monitoring, particularly during the first hour of paclitaxel infusion, is recommended. Severe cardiovascular events were observed more frequently in patients with non-small cell lung cancer than in those with breast or ovarian carcinoma. A single case of heart failure related to paclitaxel was seen in the AIDS-KS clinical study.

When paclitaxel is used in combination with doxorubicin 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, electrocardiogram (ECG), echocardiogram, and/or multigated acquisition (MUGA) scan. Cardiac function should be further monitored during treatment (e.g. every three months). Monitoring may help to identify patients who develop cardiac dysfunction and treating physicians should carefully assess the cumulative dose (mg/m2) of anthracycline administered when making decisions regarding frequency of ventricular function assessment. When testing indicates deterioration in cardiac function, even asymptomatic, treating physicians should carefully assess the clinical benefits of further therapy against the potential for producing cardiac damage, including potentially irreversible damage. If further treatment is administered, monitoring of cardiac function should be more frequent (e.g. every 1-2 cycles). For more details see Summary of Product Characteristics of trastuzumab or doxorubicin.

Peripheral neuropathy: The occurrence of peripheral neuropathy is frequent; the development of severe symptoms is rare. In severe cases, a dose reduction of 20% (25% for KS patients) is recommended for all subsequent courses of paclitaxel. In non-small cell lung cancer patients the administration of paclitaxel in combination with cisplatin resulted in a greater incidence of severe neurotoxicity than administration of single agent paclitaxel. In first-line ovarian cancer patients, administration of paclitaxel as a 3-hour infusion combined with cisplatin resulted in a greater incidence of severe neurotoxicity than administration of a combination of cyclophosphamide and cisplatin.

Impaired hepatic function: Patients with hepatic impairment may be at increased risk of toxicity, particularly grade III-IV 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. No data are available for patients with severe baseline cholestasis. 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). Patients with severe hepatic impairment must not be treated with paclitaxel.

Excipient information: This medicinal product contains 393 mg of alcohol (ethanol) in each mL (49.7% v/v). The amount per dose of this medicine is equivalent to 650 mL beer or 260 mL wine. A dose of 220 mg/m2 of this medicine administered to an adult weighing 70 kg would result in exposure to 370 mg/kg of ethanol which may cause a rise in blood alcohol concentration (BAC) of about 62 mg/100 mL. For comparison, for an adult drinking a glass of wine or 500 mL of beer, the BAC is likely to be about 50 mg/100 mL. This may be harmful to patients suffering from alcoholism. It should also be taken into account when considering using this medicine in children and high-risk groups such as those with liver disease or epilepsy. The amount of ethanol in this medicinal product may alter the effects of other medicines. Co-administration with medicines containing e.g., propylene glycol or ethanol may lead to accumulation of ethanol and induce adverse effects, in patients with low or immature metabolic capacity. The effects of ethanol may be reduced because this medicinal product is normally administered over a period of 3 hours.

Intra-arterial: Special care should be taken to avoid intra-arterial administration of paclitaxel. In animal studies investigating local tolerance, severe tissue reactions occurred following intra-arterial administration.

Pseudomembranous colitis has also been reported, rarely, including cases in patients who have not received concurrent antibiotic treatment. This reaction should be considered in the differential diagnosis of severe or persistent cases of diarrhoea occurring during or shortly after treatment with paclitaxel.

A combination of pulmonary radiotherapy and paclitaxel treatment (irrespective of the order of the treatments) may promote the development of interstitial pneumonitis.

Paclitaxel has been shown to be a teratogen, embryotoxic and a mutagen in several experimental systems. Therefore both female and male patients of reproductive age must use effective contraception during and for a recommended period after treatment with paclitaxel (see section 4.6). Both male and female patients are advised to seek guidance on fertility preservation prior to treatment because of the possibility of irreversible infertility due to therapy with paclitaxel.

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

There have been reports of reduced visual acuity due to cystoid macular oedema (CME) during treatment with paclitaxel as well as with other taxanes. Patients with visual impairment during paclitaxel treatment should seek a prompt and complete ophthalmologic examination. Discontinue paclitaxel treatment if a CME diagnosis is confirmed. Clinicians should consider whether the benefits of restarting paclitaxel treatment after CME resolution are expected to exceed the risks of further therapy.

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

Paclitaxel clearance is not affected by cimetidine premedication.

Cisplatin: Paclitaxel is recommended to be administered before cisplatin. When given before cisplatin, the safety profile of paclitaxel is consistent with that reported for single agent use. Administration of paclitaxel after cisplatin treatment leads to greater myelosuppression and about a 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.

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

Sequence effects characterised by more profound neutropenic and stomatitis episodes have been observed with combination use of paclitaxel and doxorubicin when paclitaxel was administered before doxorubicin and using longer than recommended infusion times (paclitaxel administered over 24 hours; doxorubicin over 48 hours).

Active substances metabolised in the liver:

The metabolism of paclitaxel is catalysed, in part, by cytochrome P450 isoenzymes CYP2C8 and CYP3A4. Therefore, in the absence of a PK drug-drug interaction study, caution should be exercised when administering paclitaxel concomitantly with medicines known to inhibit either CYP2C8 or CYP3A4 (e.g. ketoconazole and other imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, deferasirox, trimethoprim, clopidogrel, cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir) because toxicity of paclitaxel may be increased due to higher paclitaxel exposure. Administering paclitaxel concomitantly with medicines known to induce either CYP2C8 or CYP3A4 (e.g. rifampicin, carbamazepine, phenytoin, efavirenz, nevirapine, St John's wort) is not recommended because efficacy may be compromised because of lower paclitaxel exposures.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential/Contraception in males and females

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

Due to the potential for genotoxicity, female patients of reproductive potential are advised to use effective contraception during treatment and for at least 7 months following the last dose of paclitaxel.

Due to the potential for genotoxicity, male patients with female partners of reproductive potential are advised to use effective contraception during treatment and for at least 4 months following the last dose of paclitaxel.

Pregnancy

Paclitaxel has been shown to be both embryotoxic and foetotoxic in rabbits (see also section 5.3).

There is no adequate data from the use of paclitaxel in pregnant women, however as with other cytotoxic medicinal products, paclitaxel may cause foetal harm when administered to pregnant women.

Paclitaxel 6 mg/mL Concentrate for Solution for Infusion should not be used during pregnancy unless the clinical condition of the woman requires treatment with paclitaxel.

The ethanol content of this medicinal product should be taken into account for pregnant women.

Breast-feeding

Based on published case reports from three women, paclitaxel has been detected in breastmilk after administration. Because of the potential for serious adverse reactions due to paclitaxel in nursing infants, the mother should be advised not to breastfeed while on paclitaxel therapy and for 2 weeks following the last dose of treatment (see section 4.3).

The ethanol content of this medicinal product should be taken into account in women who are breast-feeding.

Fertility

Paclitaxel has been shown to reduce fertility in rats (see also section 5.3).

Male patients should seek advice regarding cryoconservation of sperm prior to treatment with paclitaxel because of the possibility of infertility. It is also recommended to discuss fertility preservation with female patients prior to treatment.

4.7. Effects on ability to drive and use machines

The amount of ethanol in this medicinal product may impair the ability to drive or use machines (see section 4.4).

4.8. Undesirable effects

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

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

The most frequent significant undesirable effect was bone marrow suppression. Severe neutropenia (< 0.5 x 109/L) 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 x 109/L at least once while on study. Anaemia was observed in 64% of patients, but was severe (Hb < 8.1 g/dL) 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/m2 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. Further, it has been demonstrated that peripheral neuropathies can persist beyond 6 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.

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

Cystoid macular oedema (CME): There have been reports of reduced visual acuity due to CME during treatment with paclitaxel as well as with other taxanes. Patients with visual impairment during paclitaxel treatment should seek a prompt and complete ophthalmologic examination.

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.

Disseminated intravascular coagulation (DIC), often in association with sepsis or multi-organ failure, has been reported.

Alopecia: Alopecia was observed in 87% of patients and was abrupt in onset. Pronounced hair loss of ≥ 50% is expected for the majority of patients who experience alopecia.

The table below lists undesirable effects regardless of severity 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 post-marketing surveillance of paclitaxel.

The frequency of undesirable effects listed below is defined using the following convention:

Very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10000, < 1/1000); very rare (< 1/10000).

Infections and infestations:

Very common: Infection (mainly urinary tract and upper respiratory tract infections), with reported cases of fatal outcome

Uncommon: Septic shock

Rare*: Pneumonia, peritonitis, sepsis

Very rare*: Pseudomembranous colitis

Blood and lymphatic system disorders:

Very common: Myelosuppression, neutropenia, anaemia, thrombocytopenia, leucopenia, bleeding

Rare*: Febrile neutropenia

Very rare*: Acute myeloid leukaemia, myelodysplastic syndrome

Not known: Disseminated intravascular coagulation (DIC)

Immune system disorders:

Very common: Minor hypersensitivity reactions (mainly flushing and rash)

Uncommon: Significant hypersensitivity reactions requiring therapy (e.g., hypotension, angioneurotic oedema, respiratory distress, generalised urticaria, chills, back pain, chest pain, tachycardia, abdominal pain, pain in extremity, diaphoresis, and hypertension)

Rare*: Anaphylactic reactions

Very rare*: Anaphylactic shock

Not known*: Bronchospasm

Metabolism and nutrition disorders:

Rare*: Dehydration

Very rare*: Anorexia

Not known*: Tumour lysis syndrome

Psychiatric disorders:

Very rare*: Confusional state

Nervous system disorders:

Very common: Neurotoxicity (mainly: peripheral neuropathy**)

Rare*: Motor neuropathy (with resultant minor distal weakness)

Very rare*: Autonomic neuropathy (resulting in paralytic ileus and orthostatic hypotension), grand mal seizures, convulsions, encephalopathy, dizziness, headache, ataxia

Eye disorders:

Very rare*: Optic nerve and/or visual disturbances (scintillating scotomata), particularly in patients who have received higher doses than recommended

Not known*: Macular oedema, photopsia, vitreous floaters

Ear and labyrinth disorders:

Very rare*: Ototoxicity, hearing loss, tinnitus, vertigo

Cardiac disorders:

Common: Bradycardia

Uncommon: Cardiomyopathy, asymptomatic ventricular tachycardia, tachycardia with bigeminy, atrio-ventricular block and syncope, myocardial infarction

Rare: Cardiac failure

Very rare*: Atrial fibrillation, supraventricular tachycardia

Vascular disorders:

Very common: Hypotension

Uncommon: Hypertension, thrombosis, thrombophlebitis

Very rare*: Shock

Not known*: Phlebitis

Respiratory, thoracic and mediastinal disorders:

Rare*: Dyspnoea, pleural effusion, interstitial pneumonia, lung fibrosis, pulmonary embolism, respiratory failure

Very rare*: Cough

Gastrointestinal disorders:

Very common: Nausea, vomiting, diarrhoea

Rare*: Bowel obstruction, bowel perforation, ischaemic colitis, pancreatitis

Very rare*: Mesenteric thrombosis, neutropenic colitis, oesophagitis, constipation, ascites

Hepato-biliary disorders:

Very rare*: Hepatic necrosis, hepatic encephalopathy (both with reported cases of fatal outcome)

Skin and subcutaneous tissue disorders:

Very common: Alopecia

Common: Transient and mild nail and skin changes

Rare*: Pruritus, rash, erythema

Very rare*: Stevens-Johnson syndrome, epidermal necrolysis, erythema multiforme, exfoliative dermatitis, urticaria, onycholysis (patients on therapy should wear sun protection on hands and feet)

Not known*: Palmar-plantar erythrodysesthesia syndrome

Musculoskeletal and connective tissue disorders:

Very common: Arthralgia, myalgia

Not known*: Systemic lupus erythematosus, scleroderma

General disorders and administration site conditions:

Very common: Mucosal inflammation

Common: Injection site reactions (including localised oedema, pain, erythema, induration, on occasion extravasation can result in cellulitis, skin fibrosis and skin necrosis)

Rare*: Asthenia, pyrexia, oedema, malaise

Investigations:

Common: Severe elevation in aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase (SGOT)), severe elevation in alkaline phosphatase

Uncommon: Severe elevation in bilirubin

Rare*: Increase in blood creatinine

*Adverse reactions from post-marketing experience which may be attributed to paclitaxel regardless of the treatment regimen.

**Can persist beyond 6 months of paclitaxel discontinuation as reported in the post-marketing surveillance of paclitaxel.

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), and another 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.

When used in combination with doxorubicin, paclitaxel should be administered 24 hours after doxorubicin. 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 (New York Heart Association (NYHA) Class I/II 10% vs. 0%; NYHA Class III/IV 2% vs. 1%) and rarely has been associated with death (see trastuzumab Summary of Product Characteristics). In all but these rare cases, patients responded to appropriate medical treatment.

Radiation pneumonitis has been reported in patients receiving concurrent radiotherapy.

AIDS-related Kaposi's sarcoma

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

Blood and the lymphatic system disorders: Bone marrow suppression was the major dose-limiting toxicity. Neutropenia is the most important haematological toxicity. During the first course of treatment, severe neutropenia (< 0.5 x 109/L) occurred in 20% of patients. During the entire treatment period, severe neutropenia was observed in 39% of patients. Neutropenia was present for > 7 days in 41% and for 30-35 days in 8% of patients. It resolved within 35 days in all patients who were followed. The incidence of Grade 4 neutropenia lasting ≥ 7 days was 22%.

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

Thrombocytopenia was observed in 50% of patients, and was severe (< 50 x 109/L) in 9%. Only 14% experienced a drop in their platelet count < 75 x 109/L, at least once while on treatment. Bleeding episodes related to paclitaxel were reported in < 3% of patients, but the haemorrhagic episodes were localised.

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

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

There is no known antidote for paclitaxel overdose.

In case of overdose, the patient should be closely monitored. Treatment should be directed at the primary anticipated toxicities, which consist of bone marrow suppression, peripheral neurotoxicity and mucositis.

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