Paclitaxel

Paclitaxel should be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available.

Anaphylaxis and severe hypersensitivity reactions characterized by dyspnea and hypotension requiring treatment, angioedema, and generalized urticaria have occurred in 2 to 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 H₂ antagonists (see

). Patients who experience severe hypersensitivity reactions to paclitaxel should not be rechallenged with the drug.

Paclitaxel therapy should not be given to patients with solid tumors who have baseline neutrophil counts of less than 1,500 cells/mm³ and should not be given to patients with AIDS-related Kaposi's sarcoma if the baseline neutrophil count is less than 1,000 cells/mm³. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving paclitaxel.

Paclitaxel Injection, USP is indicated as subsequent therapy for the treatment of advanced carcinoma of the ovary. As first-line therapy, Paclitaxel Injection, USP is indicated in combination with cisplatin.



Paclitaxel Injection, USP 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 receptor-negative tumors

see ).



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 Injection, USP, in combination with cisplatin, is indicated for the first-line treatment of non-small cell lung cancer in patients who are not candidates for potentially curative surgery and/or radiation therapy.



Paclitaxel Injection, USP is indicated for the second-line treatment of AIDS-related Kaposi's sarcoma.

Contact of the undiluted concentrate with plasticized PVC equipment or devices used to prepare solutions for infusion is not recommended. In order to minimize patient exposure to the plasticizer DEHP [di-(2-ethylhexyl)phthalate], which may be leached from PVC infusion bags or sets, diluted paclitaxel solutions should be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets.

All patients should be premedicated prior to paclitaxel administration in order to prevent severe hypersensitivity reactions. Such premedication may consist of dexamethasone 20 mg PO administered approximately 12 and 6 hours before paclitaxel, diphenhydramine (or its equivalent) 50 mg I.V. 30 to 60 minutes prior to paclitaxel, and cimetidine (300 mg) or ranitidine (50 mg) I.V. 30 to 60 minutes before paclitaxel.

For patients with, the following regimens are recommended (see ):

1) For previously untreated patients with carcinoma of the ovary, one of the following recommended regimens may be given every 3 weeks. In selecting the appropriate regimen, differences in toxicities should be considered (see in).

a. Paclitaxel administered intravenously over 3 hours at a dose of 175 mg/m² followed by cisplatin at a dose of 75 mg/m²; or

b. Paclitaxel administered intravenously over 24 hours at a dose of 135 mg/m² followed by cisplatin at a dose of 75 mg/m².

2) In patients previously treated with chemotherapy for carcinoma of the ovary, paclitaxel has been used at several doses and schedules; however, the optimal regimen is not yet clear (see ). The recommended regimen is paclitaxel   135 mg/m² or 175 mg/m² administered intravenously over 3 hours every 3 weeks.



For patients with, the following regimens are recommended (see

1) For the adjuvant treatment of node-positive breast cancer, the recommended regimen is paclitaxel, at a dose of 175 mg/m² intravenously over 3 hours every 3 weeks for 4 courses administered sequentially to doxorubicin-containing combination chemotherapy. The clinical trial used 4 courses of doxorubicin and cyclophosphamide (see ).

2) After failure of initial chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy, paclitaxel at a dose of 175 mg/m² administered intravenously over 3 hours every 3 weeks has been shown to be effective.

For patients with, the recommended regimen, given every 3 weeks, is paclitaxel administered intravenously over 24 hours at a dose of 135 mg/m² followed by cisplatin, 75 mg/m².

For patients with , paclitaxel administered at a dose of 135 mg/m² given intravenously over 3 hours every 3 weeks or at a dose of 100 mg/m² given intravenously over 3 hours every 2 weeks is recommended (dose intensity 45 to 50 mg/m²/week). In the 2 clinical trials evaluating these schedules (see ), the former schedule (135 mg/m² every 3 weeks) was more toxic than the latter. In addition, all patients with low performance status were treated with the latter schedule (100 mg/m² every 2 weeks).

Based upon the immunosuppression in patients with advanced HIV disease, the following modifications are recommended in these patients:

1) Reduce the dose of dexamethasone as 1 of the 3 premedication drugs to 10 mg PO (instead of 20 mg PO);

2) Initiate or repeat treatment with paclitaxel only if the neutrophil count is at least 1,000 cells/mm³;

3) Reduce the dose of subsequent courses of paclitaxel by 20% for patients who experience severe neutropenia (neutrophil <500 cells/mm³ for a week or longer); and

4) Initiate concomitant hematopoietic growth factor (G-CSF) as clinically indicated.

For the therapy of patients with solid tumors (ovary, breast, and NSCLC), courses of paclitaxel should not be repeated until the neutrophil count is at least 1,500 cells/mm³ and the platelet count is at least 100,000 cells/mm³. Paclitaxel should not be given to patients with AIDS-related Kaposi’s sarcoma if the baseline or subsequent neutrophil count is less than 1,000 cells/mm³.   Patients   who   experience   severe   neutropenia (neutrophil <500 cells/mm³ for a week or longer) or severe peripheral neuropathy during paclitaxel therapy should have dosage reduced by 20% for subsequent courses of paclitaxel. The incidence of neurotoxicity and the severity of neutropenia increase with dose.



Paclitaxel is a cytotoxic anticancer drug and, as with other potentially toxic compounds, caution should be exercised in handling paclitaxel. The use of gloves is recommended. If paclitaxel solution contacts the skin, wash the skin immediately and thoroughly with soap and water. Following topical exposure, events have included tingling, burning and redness. If paclitaxel contacts mucous membranes, the membranes should be flushed thoroughly with water. Upon inhalation, dyspnea, chest pain, burning eyes, sore throat, and nausea have been reported.

Patients with hepatic impairment may be at increased risk of toxicity, particularly grade III–IV myelosuppression (see

and ). Recommendations for dosage adjustment for the first course of therapy are shown in for both 3- and 24-hour infusions. Further dose reduction in subsequent courses should be based on individual tolerance. Patients should be monitored closely for the development of profound myelosuppression.

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. Two hundred and seventy-five patients were treated in 8, Phase 2 studies with paclitaxel doses ranging from 135 to 300 mg/m² administered over 24 hours (in 4 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 2 doses (135 or 175 mg/m²) and 2 schedules (3 or 24 hours) of paclitaxel. Two hundred and thirty-six patients with breast carcinoma received paclitaxel (135 or 175 mg/m²) administered over 3 hours in a controlled study.

		Percent of Patients (n=812)
·         B one Marrow   —Neutropenia	<2,000/mm3	90
	<500/mm3	52
—Leukopenia	<4,000/mm3	90
	<1,000/mm3	17
—Thrombocytopenia	<100,000/mm3	20
	<50,000/mm3	7
—Anemia	<11 g/dL	78
	<8 g/dL	16
—Infections		30
—Bleeding		14
—Red Cell Transfusions		25
—Platelet Transfusions  ·         Hy persensitivity Reactionb		2
—All		41
—Severe†		2
·         Card i ovascular   —Vital Sign Changesc
—Bradycardia (n=537)		3
—Hypotension (n=532)		12
—Significant Cardiovascular Events		1
·         A bnormal ECG
—All Pts		23
—Pts with normal baseline (n=559)		14
·         Peripheral Neuropathy
—Any symptoms		60
—Severe symptoms†		3
·         My algia/Arthralgia
—Any symptoms		60
—Severe symptoms†		8
·         G astrointestinal
—Nausea and vomiting		52
—Diarrhea		38
—Mucositis		31
·         Alopecia		87
·         Hep atic (Pts with normal baseline and on study data)
—Bilirubin elevations (n=765)		7
—Alkaline phosphatase elevations (n=575)		22
—AST (SGOT) elevations (n=591)		19
·         Injecti on Site Reaction		13

^a Based on worst course analysis.

^b All patients received premedication.

^c During the first 3 hours of infusion.

^†    Severe events are defined as at least Grade III toxicity.

None of the observed toxicities were clearly influenced by age.

For the 1084 patients who were evaluable for safety in the Phase 3 first-line ovary combination therapy studies, 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).

		Percent of Patients
		Intergroup		GOG-111
		T175/3b   c75c   (n = 339)	C750c   c75c   (n = 336)	T135/24b   c75c   (n = 196)	C750c   c75c   (n = 213)
·         B one Marrow   —Neutropenia	<2,000/mm3	91d	95d	96	92
	<500/mm3	33d	43d	81d	58d
—Thrombocytopenia	<100,000/mm3e	21d	33d	26	30
	<50,000/mm3	3d	7d	10	9
—Anemia	<11 g/dLf	96	97	88	86
	<8 g/dL	3d	8d	13	9
—Infections		25	27	21	15
—Febrile Neutropenia		4	7	15d	4d
·         Hypersensitivity Reaction
—All		11d	6d	8d.g	1d.g
—Severe†		1	1	3d.g	—d.g
·         Neurotoxicityh
—Any symptoms		87d	52d	25	20
—Severe symptoms†		21d	2d	3d	—d
·         Nausea and Vomiting
—Any symptoms		88	93	65	69
—Severe symptoms†		18	24	10	11
·         Myalgia/Arthralgia
—Any symptoms		60d	27d	9d	2d
—Severe symptoms†		6d	1d	1	—
·         Diarrhea
—Any symptoms		37d	29d	16d	8d
—Severe symptoms†		2	3	4	1
·         Asthenia
—Any symptoms		NC	NC	17d	10d
—Severe symptoms†		NC	NC	1	1
·         Alopecia
—Any symptoms		96d	89d	55d	37d
—Severe symptoms†		51d	21d	6	8

^a Based on worst course analysis.

^b Paclitaxel (T) dose in mg/m²/infusion duration in hours.

^c Cyclophosphamide (C) or cisplatin (c) dose in mg/m².

^d P<0.05 by Fisher exact test.

^e <130,000/mm³ in the Intergroup study.

^f <12 g/dL in the Intergroup study.

^g All patients received premedication.

^h In the GOG-111 study, neurotoxicity was collected as peripheral neuropathy and in the Intergroup study, neurotoxicity was collected as either neuromotor or neurosensory symptoms.

^†      Severe events are defined as at least Grade III toxicity.

NC  Not Collected

For the 403 patients who received single-agent paclitaxel in the Phase 3 second-line ovarian carcinoma study, the following table shows the incidence of important adverse events.

 In a Phase 1 trial using escalating doses of paclitaxel (110 to 200 mg/m²) and cisplatin (50 or 75 mg/m²) 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. Caution should be exercised when administering paclitaxel concomitantly with known substrates or inhibitors of the cytochrome P450 isoenzymes CTP2C8 and CYP3A4. Caution should be exercised when paclitaxel is concomitantly administered with known substrates (e.g, midazolam, buspirone, felodipine, lovastatin, eletriptan, sildenafil, simvastatin, and triazolam), inhibitors (e.g., atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin), and inducers (e.g., rifampin and carbamazepine) of CYP3A4. (see

).

Caution should also be exercised when paclitaxel is concomitantly administered with known substrates (e.g., repaglinide and rosiglitazone), inhibitors (e.g., gemfibrozil), and inducers (e.g., rifampin) of CYP2C8. (see ).

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.

Paclitaxel therapy should not be administered to patients with baseline neutrophil counts of less than 1,500 cells/mm³. In order to monitor the occurrence of myelotoxicity, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving paclitaxel. Patients should not be re-treated with subsequent cycles of paclitaxel until neutrophils recover to a level >1,500 cells/mm³ and platelets recover to a level >100,000 cells/mm³. In the case of severe neutropenia (<500 cells/mm³ for 7 days or more)during a course of paclitaxel therapy, a 20% reduction in dose for subsequent courses of therapy is recommended.



For patients with advanced HIV disease and poor-risk AIDS-related Kaposi's sarcoma, paclitaxel, at the recommended dose for this disease, can be initiated and repeated if the neutrophil count is at least 1,000 cells/mm³.



: Patients with a history of severe hypersensitivity reactions to products containing polyoxyl 35 castor oil (e.g., cyclosporin for injection concentrate and teniposide for injection concentrate) should not be treated with paclitaxel. In order to avoid the occurrence of severe hypersensitivity reactions, all patients treated with paclitaxel should be premedicated with corticosteroids (such as dexamethasone), diphenhydramine and H₂ antagonists (such as cimetidine or ranitidine). Minor symptoms such as flushing, skin reactions, dyspnea, hypotension, or tachycardia do not require interruption of therapy. However, severe reactions, such as hypotension requiring treatment, dyspnea requiring bronchodilators, angioedema, or generalized urticaria require immediate discontinuation of paclitaxel and aggressive symptomatic therapy. Patients who have developed severe hypersensitivity reactions should not be rechallenged with paclitaxel.





Hypotension, bradycardia, and hypertension have been observed during administration of paclitaxel, but generally do not require treatment. Occasionally paclitaxel infusions must be interrupted or discontinued because of initial or recurrent hypertension. Frequent vital sign monitoring, particularly during the first hour of paclitaxel infusion, is recommended. Continuous cardiac monitoring is not required except for patients with serious conduction abnormalities. (see). When paclitaxel is used in combination with doxorubicin for treatment of metastatic breast cancer, monitoring of cardiac function is recommended. (see ).



Although the occurrence of peripheral neuropathy is frequent, the development of severe symptomatology is unusual and requires a dose reduction of 20% for all subsequent courses of paclitaxel.

Paclitaxel contains dehydrated alcohol USP, 396 mg/mL; consideration should be given to possible CNS and other effects of alcohol. (see ).

There is limited evidence that the myelotoxicity of paclitaxel may be exacerbated in patients with serum total bilirubin >2 times ULN (see ). Extreme caution should be exercised when administering paclitaxel to such patients, with dose reduction as recommended in .

Injection site reactions, including reactions secondary to extravasation, were usually mild and consisted of erythema, tenderness, skin discoloration, or swelling at the injection site. These reactions have been observed more frequently with the 24-hour infusion than with the 3-hour infusion. Recurrence of skin reactions at a site of previous extravasation following administration of paclitaxel at a different site, i.e., ''recall'' has been reported.



More severe events such as phlebitis, cellulitis, induration, skin exfoliation, necrosis, and fibrosis have been reported. In some cases the onset of the injection site reaction either occurred during a prolonged infusion or was delayed by a week to 10 days.



A specific treatment for extravasation reactions 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.