Hospira UK Ltd

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 (> 1cm) after initial laparotoamy, in combination with cisplatin.


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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. 

 

Paclitaxel is contraindicated during pregnancy and 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.


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4.4        Special warnings and special precautions for use

 

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

 

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

 

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

 

Significant hypersensitivity reactions,:  aAs 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 paclitaxel.  Macrogolglycerol ricinoleate (polyoxyl castor oil), an excipient in this medicinal product, can cause these reactions.

 

Bone marrow suppression,:  (Pprimarily neutropenia,) is the dose-limiting toxicity.  Frequent monitoring of blood counts should be instituted.  Patients should not be retreated until the neutrophil count is ³1.5 x 10⁹/l (³1 x 10⁹/l for KS patients) and the platelets recover to ³100 x 10⁹/l (³75 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:  hHave been reported rarely.  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 this combination, 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).

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).  Paclitaxel is not recommended in patients with severely impaired hepatic function.

 

Since paclitaxel contains ethanol (396 mg/ml), consideration should be given to possible central nervous system and other effects.  The amount of alcohol in this medicinal product may alter the effects of other medicines.

 

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:  Hhas 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 female and male patients of reproductive age must take contraceptive measures for themselves and/or their sexual partners during and for at least 6 months after therapy (see section 4.6).  Male patients are advised to seek advice on conservation of sperm 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%.

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4.6       Pregnancy and lactation

 

There are no adequate data from the use of paclitaxel in pregnant women.  Studies in animals have shown reproductive toxicity (see section 5.3) and paclitaxel is suspected to cause serious birth defects when administered during pregnancy.

 

As with other cytotoxic drugs, paclitaxel may cause fetal harm, and is therefore contraindicated during pregnancy.

 

Women should be advised to avoid becoming pregnant during therapy with paclitaxel, and to inform the treating physician immediately should this occur (see section 4.4).

Based on human experience, paclitaxel, is suspected to cause congenital malformations when administered during pregnancy. 

 

Studies in animals have shown reproductive toxicity (see section 5.3). 

 

Paclitaxel Hospira 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. 

 

Women of childbearing potential have to use effective contraception during and up to 6 months after treatment.

 

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


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4.8         Undesirable effects

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.

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Psychiatric disorders:

Very rare*:  Confusional state

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Cardiac disorders:

Common:  Bradycardia   Uncommon:  Cardiomyopathy, asymptomatic ventricular tachycardia, tachycardia with bigeminy, atrio-ventricular block and syncope, myocardial infarction Very rare*:  Atrial fibrillation, supraventricular tachycardia

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6.            PHARMACEUTICAL PARTICULARS

 

6.1        List of excipients

 

Macrogolglycerol ricinoleate (polyoxyl castor oil)

Ethanol, anhydrous 49.7% v/v

Citric acid, anhydrous

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

 DATE CHANGE

24 February 2005 / 18 April 2011

10.            DATE OF REVISION OF THE TEXT:

 

 

 DATE CHANGE

July 2010April 2011