Paclib Special Precautions

5 mL & 16.67 mL: General: Paclitaxel has a low therapeutic index. Therapeutic response is not likely to occur without evidence of toxicity.
Cardiovascular: Hypotension, hypertension and bradycardia have been reported but patients are usually asymptomatic and generally do not require treatment. Severe cases of conduction abnormalities have been reported in <1% of patients receiving paclitaxel. In severe cases, paclitaxel infusions may need to be interrupted or discontinued at the discretion of the physician. Cardiac function monitoring is recommended in patients with preexisting cardiac abnormalities and when paclitaxel is co-administered with doxorubicin in patients with metastatic breast cancer.
If patients develop significant cardiac function abnormalities during administration, appropriate therapy should be administered and continuous electrocardiographic monitoring should be performed during subsequent therapy with paclitaxel.
Hepatic: Patients with hepatic impairment may be at an increased risk of toxicity mainly grade III to IV myelosuppression. Increased myelosuppression may be observed in patients with moderate to severe hepatic impairment. Paclitaxel is not recommended in patients with severely impaired hepatic function (transaminase levels ≥10 x ULN or bilirubin levels >7.5 mg/dL or >5 x ULN; see Dosage & Administration).
Neurologic: Peripheral neuropathy (dose-dependent) may occur frequently. Carefully monitor patient with pre-existing peripheral neuropathy and in severe cases, reduce all subsequent doses by 20% (see Dosage & Administration).
Hypersensitivity: Patients with a history of severe hypersensitivity reaction to products containing Cremophor EL should not be treated with paclitaxel (see Contraindications). Minor symptoms such as flushing, skin reactions, dyspnea, hypotension or tachycardia do not require interruption of therapy. However, immediate discontinuation of paclitaxel and aggressive symptomatic therapy should be done in cases of severe reactions such as hypotension requiring treatment, dyspnea requiring bronchodilators, angioedema or generalized urticaria.
Injection Site Reaction: Erythema, tenderness, skin discoloration, or swelling at the injection site may occur. Recurrence of skin reactions at a previous site of extravasation (i.e., "recall" reactions) after paclitaxel administration at a different injection site has been reported rarely. More severe events such as phlebitis, cellulitis, induration, skin exfoliation, necrosis, and fibrosis have also been reported rarely (see Dosage & Administration).
Gastrointestinal: Exclude bowel perforation in patients receiving paclitaxel who complain of abdominal pain with other signs and symptoms.
Infectious Complications: Patients should be informed to take extra precautions to reduce the risk of infection or bleeding (e.g., avoiding people with infection, getting cut or bruised).
The risk-benefit should be considered when administering paclitaxel to patients with the following conditions: Varicella or recent exposure to such disease; Herpes Zoster; Infection; Precaution must be taken in patients who have undergone therapies with cytotoxic drugs, including radiotherapy.
Effects on the Ability to Drive or Use Machines: The alcohol content in the product may impair the ability to perform hazardous activities requiring mental alertness following paclitaxel infusion, particularly when high doses of the drug are administered over short periods (e.g., 3 hours). Concomitant use with CNS depressants should be done with caution.
Hepatic and Renal Impairment: The use of paclitaxel in patients with impaired renal and hepatic function has not been fully established. Since paclitaxel is metabolized in the liver, dose reduction is recommended in patients with moderate to severe liver failure. Dose reduction may not be necessary in patients with renal failure. (See Dosage & Administration.)
Carcinogenicity, Mutagenicity, Fertility: There is no study on the carcinogenic potential of paclitaxel. Paclitaxel has been shown to be clastogenic in vitro (chromosome aberrations in human lymphocytes) and in vivo (micronucleus test in mice) mammalian test system but was not mutagenic in the Ames test or the CHO/HGPRT gene mutation assay.
Reproduction studies in rats and rabbits showed evidence of maternal toxicity, embryotoxicity and fetotoxicity during organogenesis at IV doses of 1 mg/kg (6 mg/m² or systemic exposures approximately equivalent to 0.04 times the maximum recommended human dose on a mg/m² basis) and 3 mg/kg (33 mg/m² or systemic exposures approximately equivalent to 0.2 times the maximum recommended human dose on a mg/m² basis), respectively. These resulted in intrauterine mortality, increased resorptions, increased fetal deaths and reduced fertility.
Paclitaxel produced low fertility in rats at an IV dose of 1 mg/kg (6 mg/m²).
43.4 mL: 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, close monitoring of the infusion site for possible infiltration during administration of the drug is recommended.
Patients must be pretreated with corticosteroids, antihistamines and H₂ antagonists.
Paclitaxel should be given before Cisplatin when used in combination.
Significant hypersensitivity reactions characterized by dyspnea and hypotension requiring treatment, angioedema and generalized 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 (≥1,000/mm³ for KS patients) and platelets recover to ≥100,000/mm³ (≥75,000/mm³ for KS patients). In the KS clinical study, the majority of patients were receiving granulocyte colony stimulating factor (G-CSF). 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. Inadequate data are available to recommend dosage alterations in patients with mild to moderate hepatic impairments.
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 cardiac 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. 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, 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. If further treatment is administered, monitoring of cardiac function should be more frequent (e.g. every 1-2 cycles).
Although 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) for all subsequent courses of Paclitaxel is recommended. 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 of the lung, irrespective of their chronological order, may contribute to the development of interstitial pneumonitis. Since Paclitaxel concentrate for solution for infusion contains anhydrous ethanol (391 mg/mL), consideration should be given to possible CNS and other effects.
Paclitaxel concentrate for solution for infusion contains Polyoxyl 35 Castor oil, which may cause severe allergic reactions.
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 diarrhea occurring during or shortly after treatment with Paclitaxel.
In KS patients, severe mucositis is rare. If severe reactions occur, the paclitaxel dose should be reduced by 25%.
Paclitaxel has shown to be teratogenic, embryotoxic and mutagenic in many experimental systems.
Therefore, sexually active fertile female and male patients should use effective methods of contraception during treatment and up to six months after treatment for men and women. Hormonal contraception is contraindicated in hormone receptor positive tumors.
Use in Children: 5 mL & 16.67 mL: The safety and efficacy of paclitaxel in children have not been established. In a clinical trial in children, high dose paclitaxel (350 to 420 mg/m² or more than two times the recommended dose) infused over 3 hours caused CNS toxicity (rarely associated with death). The toxicity is attributed to the high dose alcohol content (vehicle) given over a short infusion time. Concomitant use of antihistamines may intensify this effect.
Use in the Elderly: 5 mL & 16.67 mL: The safety and efficacy of paclitaxel in elderly patients have not been clearly established. However, most of the patients treated for refractory metastatic ovarian carcinoma are older than 60 years. There is no evidence of age-related differences in the safety or dose tolerance between young and old patients. However, clinical studies show that severe myelosuppression, severe neuropathy and cardiovascular events were more frequent in elderly patients. Estimates of efficacy appeared similar between elderly and younger patients but comparative efficacy could not be determined due to a small number of elderly patients studied.