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. In clinical trials, 2% of patients treated with paclitaxel experienced severe hypersensitivity. One of these reactions was fatal in a patient treated without premedication. 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 pretreatment 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 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.
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 pre-treatment. 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.
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).
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.
Effects on laboratory tests: No data available.
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.
Effects on ability to drive and use machines: The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.
Use in Children: The safety and effectiveness of paclitaxel in paediatric patients has not been established. There have been reports of central nervous system (CNS) toxicity (rarely associated with death) in a clinical trial in paediatric patients in which paclitaxel was infused intravenously over 3 hours at doses ranging from 350 mg/m2 to 420 mg/m2. 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. Although a direct effect of the paclitaxel itself cannot be discounted, the high doses used in this study (over twice the recommended adult dosage) must be considered in assessing the safety of paclitaxel for use in this population.
Use in the Elderly: Of 2228 patients who received paclitaxel in eight clinical studies evaluating its safety and efficacy in the treatment of advanced ovarian cancer, breast carcinoma or NSCLC and 1570 patients who were randomised to receive paclitaxel in the adjuvant breast cancer study, 649 patients (17%) were 65 years or older, including 49 patients (1%) 75 years or older. In most studies, severe myelosuppression was more frequent in elderly patients; in some studies, severe neuropathy was more common in elderly patients. In two clinical studies in NSCLC, the elderly patients treated with paclitaxel had a higher incidence of cardiovascular events. Estimates of efficacy appeared 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 a study of first line treatment of ovarian cancer, elderly patients had a lower median survival than younger patients, but no other efficacy parameters favoured the younger group.