Paclitaxel Injection, USP is indicated as subsequent therapy for the treatment of advanced carcinoma of the ovary. As first-line therapy, paclitaxel is indicated in combination with cisplatin. Paclitaxel is indicated for the adjuvant treatment of node-positive breast cancer administered sequentially to standard doxorubicin-containing combination chemotherapy. In the clinical trial, there was an overall favorable effect on disease-free and overall survival in the total population of patients with receptor-positive and receptor-negative tumors, but the benefit has been specifically demonstrated by available data (median follow-up 30 months) only in the patients with estrogen and progesterone receptornegative tumors.
(See CLINICAL STUDIES: Breast Carcinoma . ) Paclitaxel Injection, USP is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated. Paclitaxel, in combination with cisplatin, is indicated for the first-line treatment of nonsmall cell lung cancer in patients who are not candidates for potentially curative surgery and/or radiation therapy.
Paclitaxel is indicated for the second-line treatment of AIDS-related Kaposi’s sarcoma.
Contraindications
Paclitaxel Injection, USP is contraindicated in patients who have a history of hypersensitivity reactions to paclitaxel or other drugs formulated in Polyoxyl 35 Castor Oil, NF. Paclitaxel Injection, USP should not be used in patients with solid tumors who have baseline neutrophil counts of <1,500 cells/mm 3 or in patients with AIDS-related Kaposi’s sarcoma with baseline neutrophil counts of <1,000 cells/mm 3 .
Warnings and precautions
Anaphylaxis and severe hypersensitivity reactions characterized by dyspnea and hypotension requiring treatment, angioedema, and generalized urticaria have occurred in 2%-4% of patients receiving paclitaxel in clinical trials. Fatal reactions have occurred in patients despite premedication. All patients should be pretreated with corticosteroids, diphenhydramine, and H 2 antagonists. ( See DOSAGE AND ADMINISTRATION section .) Patients who experience severe hypersensitivity reactions to paclitaxel should not be rechallenged with the drug.
Bone marrow suppression (primarily neutropenia) is dose-dependent and is the dose- limiting toxicity. Neutrophil nadirs occurred at a median of 11 days. Paclitaxel should not be administered to patients with baseline neutrophil counts of less than 1,500 cells/mm 3 (<1,000 cells/mm 3 for patients with KS). Frequent monitoring of blood counts should be instituted during paclitaxel treatment. Patients should not be re-treated with subsequent cycles of paclitaxel until neutrophils recover to a level >1,500 cells/mm 3 (>1,000 cells/mm 3 for patients with KS) and platelets recover to a level >100,000 cells/mm 3 .
Severe conduction abnormalities have been documented in <1% of patients during paclitaxel therapy and in some cases requiring pacemaker placement. If patients develop significant conduction abnormalities during paclitaxel infusion, appropriate therapy should be administered and continuous cardiac monitoring should be performed during subsequent therapy with paclitaxel. Pregnancy: Paclitaxel can cause fetal harm when administered to a pregnant woman.
Administration of paclitaxel during the period of organogenesis to rabbits at doses of 3.0 mg/kg/day (about 0.2 the daily maximum recommended human dose on a mg/m 2 basis) caused embryo- and fetotoxicity, as indicated by intrauterine mortality, increased resorptions, and increased fetal deaths. Maternal toxicity was also observed at this dose. No teratogenic effects were observed at 1.0 mg/kg/day (about 1/15 the daily maximum recommended human dose on a mg/m 2 basis); teratogenic potential could not be assessed at higher doses due to extensive fetal mortality.
There are no adequate and well-controlled studies in pregnant women. If paclitaxel is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.
Interactions
Drug Interactions: In a Phase I trial using escalating doses of paclitaxel (110-200 mg/m 2 ) and cisplatin (50 or 75 mg/m 2 ) given as sequential infusions, myelosuppression was more profound when paclitaxel was given after cisplatin than with the alternate sequence (i.e., paclitaxel before cisplatin). Pharmacokinetic data from these patients demonstrated a decrease in paclitaxel clearance of approximately 33% when paclitaxel was administered following cisplatin.
The metabolism of paclitaxel is catalyzed by cytochrome P450 isoenzymes CYP2C8 and CYP3A4. In the absence of formal clinical drug interaction studies, caution should be exercised when administering paclitaxel concomitantly with known substrates or inhibitors of the cytochrome P450 isoenzymes CYP2C8 and CYP3A4. Caution should be exercised when paclitaxel is concomitantly administered with known substrates (eg, midazolam, buspirone, felodipine, lovastatin, eletriptan, sildenafil, simvastatin, and triazolam), inhibitors (eg, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin), and inducers (eg, rifampin and carbamazepine) of CYP3A4.
( See CLINICAL PHARMACOLOGY section. ) Caution should also be exercised when paclitaxel is concomitantly administered with known substrates (eg, repaglinide and rosiglitazone), inhibitors (eg, gemfibrozil), and inducers (eg, rifampin) of CYP2C8. ( See CLINICAL PHARMACOLOGY. ) Potential interactions between paclitaxel, a substrate of CYP3A4, and protease inhibitors (ritonavir, saquinavir, indinavir, and nelfinavir), which are substrates and/or inhibitors of CYP3A4, have not been evaluated in clinical trials.
Reports in the literature suggest that plasma levels of doxorubicin (and its active metabolite doxorubicinol) may be increased when paclitaxel and doxorubicin are used in combination.
Pregnancy and breastfeeding
PREGNANCY ( See WARNINGS section. )
Adverse reactions
Pooled Analysis of Adverse Event Experiences from Single-Agent Studies: Data in the following table are based on the experience of 812 patients (493 with ovarian carcinoma and 319 with breast carcinoma) enrolled in 10 studies who received single- agent Paclitaxel Injection, USP. Two hundred and seventy-five patients were treated in eight Phase 2 studies with paclitaxel doses ranging from 135 to 300 mg/m 2 administered over 24 hours (in four of these studies, G-CSF was administered as hematopoietic support).
Three hundred and one patients were treated in the randomized Phase 3 ovarian carcinoma study which compared two doses (135 or 175 mg/m 2 ) and two schedules (3 or 24 hours) of paclitaxel. Two hundred and thirty-six patients with breast carcinoma received paclitaxel (135 or 175 mg/m 2 ) administered over 3 hours in a controlled study. Table 10. Summarya of Adverse Events in Patients with Solid Tumors Receiving Single-Agent Paclitaxel None of the observed toxicities were clearly influenced by age.
Table 10 Disease-Specific Adverse Event Experiences First-Line Ovary in Combination: For the 1084 patients who were evaluable for safety in the Phase 3 first-line ovary combination therapy studies, Table 11 shows the incidence of important adverse events. For both studies, the analysis of safety was based on all courses of therapy (6 courses for the GOG-111 study and up to 9 courses for the Intergroup study). Table 11.
Frequency a of Important Adverse Events in the Phase 3 First-Line Ovarian Carcinoma Studies Second-Line Ovary: For the 403 patients who received single-agent Paclitaxel Injection, USP in the Phase 3 second-line ovarian carcinoma study, the following table shows the incidence of important adverse events. Table 12. Frequency a of Important Adverse Events in the Phase 3 Second- Line Ovarian Carcinoma Study Myelosuppression was dose and schedule related, with the schedule effect being more prominent.
The development of severe hypersensitivity reactions (HSRs) was rare; 1% of the patients and 0.2% of the courses overall. There was no apparent dose or schedule effect seen for the HSRs. Peripheral neuropathy was clearly dose-related, but schedule did not appear to affect the incidence Table 11 Table 12 Adjuvant Breast: For the Phase 3 adjuvant breast carcinoma study, the following table shows the incidence of important severe adverse events for the 3121 patients (total population) who were evaluable for safety as well as for a group of 325 patients (early population) who, per the study protocol, were monitored more intensively than other patients.
Table 13. Frequency a of Important Severe b Adverse Events in the Phase 3 Adjuvant Breast Carcinoma Study The incidence of an adverse event for the total population likely represents an underestimation of the actual incidence given that safety data were collected differently based on enrollment cohort. However, since safety data were collected consistently across regimens, the safety of the sequential addition of paclitaxel following AC therapy may be compared with AC therapy alone.
Compared to patients who received AC alone, patients who received AC followed by paclitaxel experienced more Grade III/IV neurosensory toxicity, more Grade III/IV myalgia/arthralgia, more Grade III/IV neurologic pain (5% vs 1%), more Grade III/IV flu-like symptoms (5% vs 3%), and more Grade III/IV hyperglycemia (3% vs 1%). During the additional 4 courses of treatment with paclitaxel, 2 deaths (0.1%) were attributed to treatment.
During paclitaxel treatment, Grade IV neutropenia was reported for 15% of patients, Grade II/III neurosensory toxicity for 15%, Grade II/III myalgias for 23%, and alopecia for 46%. The incidences of severe hematologic toxicities, infections, mucositis, and cardiovascular events increased with higher doses of doxorubicin. Breast Cancer After Failure of Initial Chemotherapy : For the 458 patients who received single-agent paclitaxel in the Phase 3 breast carcinoma study, the following table shows the incidence of important adverse events by treatment arm (each arm was administered by a 3-hour infusion).
Table 14. Frequency a of Important Adverse Events in the Phase 3 Study of Breast Cancer after Failure of Initial Chemotherapy or Within 6 Months of Adjuvant Chemotherapy Myelosuppression and peripheral neuropathy were dose related. There was one severe hypersensitivity reaction (HSR) observed at the dose of 135 mg/m 2 . First-Line NSCLC in Combination: In the study conducted by the Eastern Cooperative Oncology Group (ECOG), patients were randomized to either paclitaxel (T) 135 mg/m 2 as a 24-hour infusion in combination with cisplatin (c) 75 mg/m 2 , paclitaxel (T) 250 mg/m 2 as a 24-hour infusion in combination with cisplatin (c) 75 mg/m 2 with G- CSF support, or cisplatin (c) 75 mg/m 2 on day 1, followed by etoposide (VP) 100 mg/m 2 on days 1, 2, and 3 (control).
The following table shows the incidence of important adverse events. Table 15. Frequency a of Important Adverse Events in the Phase 3 Study for First-Line NSCLC Toxicity was generally more severe in the high-dose paclitaxel treatment arm (T250/c75) than in the low-dose paclitaxel arm (T135/c75). Compared to the cisplatin/etoposide arm, patients in the low-dose paclitaxel arm experienced more arthralgia/myalgia of any grade and more severe neutropenia.
The incidence of febrile neutropenia was not reported in this study. Table 13 Table 14 Table 15 Kaposis & Sarcoma: The following table shows the frequency of important adverse events in the 85 patients with KS treated with 2 different single-agent paclitaxel regimens. Table 16. Frequencya of Important Adverse Events in the Aids-Related Kaposi’s Sarcoma Studies As demonstrated in this table, toxicity was more pronounced in the study utilizing paclitaxel at a dose of 135 mg/m 2 every 3 weeks than in the study utilizing paclitaxel at a dose of 100 mg/m 2 every 2 weeks.
Notably, severe neutropenia (76% vs 35%), febrile neutropenia (55% vs 9%), and opportunistic infections (76% vs 54%) were more common with the former dose and schedule. The differences between the 2 studies with respect to dose escalation and use of hematopoietic growth factors, as described above, should be taken into account. ( See CLINICAL STUDIES: AIDS-Related Kaposi’s Sarcoma . ) Note also that only 26% of the 85 patients in these studies received concomitant treatment with protease inhibitors, whose effect on paclitaxel metabolism has not yet been studied.
Table 16 Adverse Event Experiences by Body System: The following discussion refers to the overall safety database of 812 patients with solid tumors treated with single-agent paclitaxel in clinical studies. Toxicities that occurred with greater severity or frequency in previously untreated patients with ovarian carcinoma or NSCLC who received paclitaxel in combination with cisplatin or in patients with breast cancer who received paclitaxel after doxorubicin/cyclophosphamide in the adjuvant setting and that occurred with a difference that was clinically significant in these populations are also described.
The frequency and severity of important adverse events for the Phase 3 ovarian carcinoma, breast carcinoma, NSCLC, and the Phase 2 Kaposi’s sarcoma carcinoma studies are presented above in tabular form by treatment arm. In addition, rare events have been reported from postmarketing experience or from other clinical studies. The frequency and severity of adverse events have been generally similar for patients receiving paclitaxel for the treatment of ovarian, breast, or lung carcinoma or Kaposi’s sarcoma, but patients with AIDS-related Kaposi’s sarcoma may have more frequent and severe hematologic toxicity, infections (including opportunistic infections, see Table 16), and febrile neutropenia.
These patients require a lower dose intensity and supportive care. ( See CLINICAL STUDIES: AIDS-Related Kaposi’s Sarcoma . ) Toxicities that were observed only in or we
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Composition
Active ingredients
PACLITAXEL 6MG/ML
Strengths and forms
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