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General: Paclitaxel should be administered under the supervision of a physician experienced in the use of chemotherapeutic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available.
Paclitaxel should be given before a platinum compound when it is given in combination with a platinum compound.
Premedication: In order to minimise the possibility of hypersensitivity reactions due to histamine release, patients should be premedicated before every treatment cycle of paclitaxel. Premedication should include corticosteroids (e.g. dexamethasone), antihistamines (e.g. diphenhydramine or promethazine) and an H2-receptor antagonist (e.g. cimetidine or ranitidine) (see Dosage & Administration). The characteristic symptoms of hypersensitivity reactions are dyspnoea and hypotension both requiring treatment, angioedema and widespread urticaria. Anzatax Injection Concentrate must not be used in patients who have exhibited hypersensitivity reactions to paclitaxel.
Neutropenia (see Adverse Reactions): As the dose limiting toxicity of paclitaxel is dose related bone marrow suppression (primarily neutropenia), paclitaxel should not be administered to patients with a pre-treatment neutrophil count of less than 1.5 x 109 cells/L (1,500 cells/mm3) or platelet count of less than 100 x 109 cells/L. Blood counts should be frequently monitored during treatment with paclitaxel. Further cycles of paclitaxel should not be administered until the patient's neutrophil count is greater than 1.5 x 109 cells/L (1,500 cells/mm3) and the platelet count is greater than 100 x 109 cells/L (100,000 cells/mm3).
If there is severe neutropenia during a course of paclitaxel (i.e. neutrophil count less than 0.5 x 109 cells/L [500 cells/mm3], the dose of paclitaxel in subsequent cycles should be reduced by 20%. Previous radiation therapy may induce more severe myelosuppression. There is little information available from such patients at doses above 135 mg/m2.
Cardiovascular toxicity: Hypotension, hypertension and bradycardia have been observed during paclitaxel administration, but generally do not require treatment. Frequent monitoring of vital signs, particular during the first hours of paclitaxel infusion is recommended [see also Adverse Reactions].
Electrocardiographic monitoring is recommended for patients with serious conduction abnormalities and should be commenced for patients who develop abnormal cardiovascular symptoms or signs during monitoring of vital signs.
Severe cardiac conduction abnormalities have been reported rarely during paclitaxel therapy. If patients develop significant conduction abnormalities during paclitaxel administration, appropriate therapy should be administered and continuous electrocardiographic monitoring should be commenced and performed during subsequent therapy with paclitaxel [see also Adverse Reactions]. Severe cardiovascular events were observed more frequently in patients with NSCLC than breast or ovarian cancer.
When paclitaxel is used in combination with trastuzumab or doxorubicin for treatment of metastatic breast cancer, monitoring of cardiac function is recommended. 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 (eg, every 3 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 (eg, every 1-2 cycles).
Anaphylaxis and severe hypersensitivity reactions: Severe hypersensitivity (anaphylactoid) reactions characterised by dyspnoea and hypotension requiring treatment, angioedema and generalised urticaria have occurred rarely in premedicated patients receiving paclitaxel. Rare fatal reactions have occurred in patients despite pretreatment. Cross-hypersensitivity between Anzatax and other taxane products has been reported and may include severe reactions such as anaphylaxis. Patients with a previous history of hypersensitivity to other taxanes should be closely monitored during initiation of ANZATAX therapy.
Since significant hypersensitivity reactions may occur, appropriate supportive equipment should be available. Patients receiving paclitaxel should be under continuous observation for at least the first 30 mins following the start of the infusion and frequently thereafter. In case of a severe hypersensitivity reaction, paclitaxel infusion should be discontinued immediately and appropriate treatment given as indicated for anaphylaxis. The patient should not be rechallenged with the drug. Minor hypersensitivity reactions such as flushing, skin reactions, etc. do not require interruption of therapy [see Adverse Reactions].
Gastrointestinal: In patients receiving paclitaxel who complain of abdominal pain with other signs and symptoms, bowel perforation should be excluded.
Administration: Anzatax Injection Concentrate is administered by intravenous infusion only; it must not be administered by the intracerebral, intrapleural or intraperitoneal routes. Anzatax Injection Concentrate must be diluted before intravenous infusion. Prior to intravenous infusion of paclitaxel, it must be ensured that the indwelling catheter is in the correct position as extravasation, necrosis and/or thrombophlebitis may result with incorrect administration (see Dosage & Administration).
Patients receiving paclitaxel should be under continuous observation for at least the first 30 minutes following the start of the infusion and frequently thereafter. In case of a severe hypersensitivity reaction, paclitaxel infusion should be discontinued immediately and appropriate treatment given as indicated for anaphylaxis. The patient should not be rechallenged with the drug. Minor hypersensitivity reactions such as flushing, skin reactions, etc. do not require interruption of therapy (see also Adverse Reactions).
In some patients, temporary discontinuation of the infusion is sufficient to resolve the symptoms. Other patients may require therapy with bronchodilators, adrenaline, antihistamines and corticosteroids, either alone or in combination.
Injection site reaction: A specific treatment for extravasation reaction is unknown at this time. Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug administration.
Nervous system: Patients with pre-existing neuropathy should be carefully monitored. Peripheral neuropathy is frequently reported in patients receiving paclitaxel and the severity is dose dependent. A 20% reduction in paclitaxel dose is recommended for patients who develop peripheral neuropathy during therapy [see Adverse Reactions].
In NSCLC patients, the administration of paclitaxel in combination with cisplatin resulted in a greater incidence of neurotoxicity than usually seen in patients receiving single agent paclitaxel.
Paclitaxel contains ethanol, 396 mg/mL; consideration should be given to possible CNS and other effects of alcohol.
Children may be more sensitive than adults to the effects of ethanol.
Interstitial pneumonia: Paclitaxel in combination with radiation of the lung, irrespective of their chronological order, may contribute to the development of interstitial pneumonia.
Pseudomembranous colitis: Pseudomembranous colitis has been reported 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.
Mucositis: Severe mucositis has been reported which requires dose reduction (see Dosage & Administration).
Ophthalmology: There have been reports of reduced visual acuity due to cystoid macular oedema (CMO) during treatment with paclitaxel as well as with other taxanes [see Adverse Reactions]. Patients with visual impairment during paclitaxel treatment should seek a prompt and complete ophthalmologic examination. Paclitaxel should be discontinued if a CMO diagnosis is confirmed.
Effects on laboratory tests: No data available.
Effects on ability to drive and use machine: The effect of paclitaxel on the ability to drive or use machines has not been systematically evaluated. Patients should refrain from driving or using machines until they know that paclitaxel does not negatively affect these abilities. It should be noted that paclitaxel contains ethanol.
Use in hepatic impairment: The effect of hepatic impairment on the pharmacokinetics of paclitaxel has not been established. However, as the liver is thought to be the primary site for metabolism of the drug, paclitaxel should be given cautiously to patients with decreased liver function. Paclitaxel has been shown to cause a dose related elevation of liver enzymes.
When paclitaxel is given as a 24 hour infusion to patients with moderate to severe hepatic impairment, increased myelosuppression may be seen as compared to patients with mildly elevated liver function tests given 24 hour infusions.
Use in renal impairment: The effect of renal impairment on the pharmacokinetics of paclitaxel has not been established.
Use in Children: The safety and effectiveness of Anzatax Injection Concentrate in children has not been established. Central nervous system (CNS) toxicity (rarely associated with death) has been associated with administration of higher doses (350 mg/m2 to 420 mg/m2) in paediatric patients. The toxicity is most likely attributable to the high dose of the ethanol component of the paclitaxel vehicle given over a short infusion time. The use of concomitant antihistamines may intensify this effect. A direct effect of paclitaxel itself cannot be discounted. The risk associated with the use of high doses in paediatric patients must be considered in assessing the safety of paclitaxel for use in this population.
Use in the Elderly: It is reported that severe myelosuppression, severe neuropathy and cardiovascular events are observed more frequently in elderly patients. Efficacy appears to be similar in elderly patients and in younger patients; however comparative efficacy cannot be determined with confidence due to the small number of elderly patients studied. In one report of first line treatment in ovarian cancer, elderly patients had a lower median survival than younger patients, but no other efficacy parameters favoured the younger group.
