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    Taxanes

    BOXED WARNING

    Bone marrow suppression, herpes infection, infection, Kaposi's sarcoma, neutropenia, requires a specialized care setting, requires an experienced clinician, thrombocytopenia, varicella, viral infection

    Paclitaxel is associated with dose-related bone marrow suppression. It should not be given to patients with severe thrombocytopenia or neutropenia, with solid tumors who have baseline neutrophil counts of less than 1,500 cells/mm3, with AIDS-related Kaposi's sarcoma, or with baseline neutrophil count is less than 1000 cells/mm3; these patients may have more frequent and severe hematologic toxicities, infections (including opportunistic infections), and febrile neutropenia compared to patients with solid tumors. In all patients, blood counts should be monitored frequently during treatment. Generally, the next cycle should not be given until neutrophils reach >= 1500/mm3 (1000/mm3 for Kaposi's sarcoma patients) and platelets recover to >= 100,000/mm3. In patients with a neutrophil count of < 500 cells/mm3 for longer than 1 week, consider adding colony-stimulating factor support or reducing subsequent paclitaxel doses by 20%. Due to these severe adverse reactions, paclitaxel requires an experienced clinician knowledgeable in the use of cancer chemotherapeutic agents. Administration requires a specialized care setting such as a hospital or treatment facility so that facilities are readily available for appropriate management of complications. Use cautiously in patients who have myelosuppression due to previous therapy such as other chemotherapy or radiotherapy; these patients may be more susceptible to the myelosuppressive effects of paclitaxel. Patients with active infection should be treated prior to receiving paclitaxel. Patients with a history of varicella zoster, other herpes infection (e.g., herpes simplex), or other viral infection are at risk for reactivation of the infection when treated with chemotherapy.

    DEA CLASS

    Rx

    DESCRIPTION

    Semisynthetic, diterpenoid taxane derivative from the bark of the Pacific yew tree; sequence of administration in combination with other agents is important in toxicity and efficacy; effective in numerous disease including breast, lung, ovarian, and bladder cancers, Kaposi's sarcoma alone or as part of combination regimens.

    COMMON BRAND NAMES

    Onxol, Taxol

    HOW SUPPLIED

    Onxol/Paclitaxel/Taxol Intravenous Inj Sol: 1mL, 6mg

    DOSAGE & INDICATIONS

    For the treatment of breast cancer.
    For metastatic breast cancer after the failure of combination chemotherapy or relapse within 6 months of adjuvant chemotherapy.
    Intravenous dosage
    Adults

    175 mg/m2 IV over 3 hours every 3 weeks. Doses of 135—175 mg/m2 IV over 3 hours, up to 250 mg/m2 IV over 24 hours, or 120—140 mg/m2 continuous IV for 96 hours (20—35 mg/m2/day for 5 days continuous IV infusion) once every 3 weeks and 80—100 mg/m2 IV over 1 hour weekly have been studied in patients with metastatic disease.

    For adjuvant treatment of node-positive breast cancer administered sequentially to standard doxorubicin-containing combination chemotherapy.
    Intravenous dosage
    Adults

    175 mg/m2 IV over 3 hours every 3 weeks for 4 courses following completion of standard doxorubicin-based combination chemotherapy. In a study completed by the Cancer and Leukemia Group B (CALGB) Cooperative Research Group, the addition of sequential paclitaxel following standard combination chemotherapy with doxorubicin and cyclophosphamide reduced mortality by 26% and reduced the risk of recurrent breast cancer by 22% as compared to the combination alone. Alternately, paclitaxel 80 mg/m2 IV over 1 hour weekly for 12 weeks† improved overall survival compared to every 3 week dosing (p = 0.01) in a phase III trial. Additionally, doxorubicin-based chemotherapy and sequential paclitaxel 175 mg/m2 IV have been administered every 14 days (dose-dense) for 4 courses. In patients with HER2-positive breast cancer, trastuzumab should be given in combination with paclitaxel.

    For first line treatment of metastatic breast cancer that overexpresses the HER2 protein in combination with trastuzumab.
    Intravenous dosage
    Adults

    175 mg/m2 IV over 3 hours every 3 weeks in combination with trastuzumab (4 mg/kg IV then 2 mg/kg IV weekly).

    For patients who have not previously received chemotherapy for metastatic HER2-negative breast cancer, in combination with bevacizumab†.
    Intravenous dosage

    NOTE: In February 2008, the FDA granted accelerated approval to bevacizumab for the treatment of previously untreated metastatic HER2-negative breast cancer in combination with paclitaxel. In December 2010, the FDA's Center for Drug Evaluation and Research (CDER), the agency which granted the accelerated approval, recommended removal of the breast cancer indication for bevacizumab. This recommendation came after reviewing the results of 4 clinical studies of bevacizumab in combination with various chemotherapy agents (e.g., an anthracycline, docetaxel, capecitabine, or paclitaxel) in women with breast cancer and determining that the data indicate that bevacizumab does not prolong overall survival in breast cancer patients or provide a sufficient benefit in slowing disease progression to outweigh the significant risk to patients. Genentech, the manufacturer of Avastin (bevacizumab), disagreed with this assessment and was granted a public hearing on CDER's withdrawal proposal, which took place in June 2011. A final decision to remove the breast cancer indication from the bevacizumab label was rendered by the FDA Commissioner in November 2011.

    Adults

    90 mg/m2 IV on days 1, 8, and 15 plus bevacizumab (10 mg/kg IV on days 1 and 15) given every 28 days has been studied. Treatment was continued until disease progression or unacceptable toxicity. Bevacizumab monotherapy could be continued at the discretion of the clinician, if unacceptable toxicity to paclitaxel developed while on combination treatment. In a phase III clinical trial of 722 patients with previously untreated metastatic breast cancer, paclitaxel was administered with or without bevacizumab. The primary end point, progression-free survival, was significantly improved in the bevacizumab/paclitaxel arm (11.8 months vs. 5.9 months, HR 0.60, 95% CI 0.51—0.7, p < 0.001), as was objective response rate (36.9% vs. 21.2%, p < 0.001). However, overall survival was not significantly different between the treatment arms (26.7 months vs. 25.2 months, p = 0.16). Grade 3 and 4 hypertension (14.8% vs. 0%, p < 0.001), proteinuria (3.5% vs. 0%, p < 0.001), neuropathy (23.6% vs. 17.6%, p = 0.03), infection (9.3% vs. 2.9%, p < 0.001), headaches (2.2% vs. 0%, p = 0.008), fatigue (8.5% vs. 4.9%, p = 0.04), and cerebrovascular ischemia (1.9% vs. 0%, p = 0.02) all occurred more frequently in the combination arm. Median duration of paclitaxel treatment in the combination arm was 7.1 months vs. 5.1 months in the paclitaxel alone arm. Of patients in the combination arm, 21.3% continued bevacizumab monotherapy for a median of 3.7 months after discontinuation of paclitaxel.

    For the front-line treatment of HER2-overexpressing metastatic breast cancer in combination with carboplatin and trastuzumab†.
    Intravenous dosage
    Adults

    175 mg/m2 IV in combination with carboplatin (AUC 6 IV) beginning in week 1 and repeated every 3 weeks for 6 cycles; alternatively, paclitaxel 80 mg/m2 IV and carboplatin (AUC 2 IV) may be administered weekly for 3 weeks with a 1 week rest to complete six 4-week cycles. Give either regimen with trastuzumab (4 mg/kg IV infused over 90 minutes in week 1, then 2 mg/kg IV infused over 30 minutes weekly starting in week 2); continue trastuzumab until disease progression or unacceptable toxicity. A phase III trial of 196 patients with previously untreated HER2-overexpressing metastatic breast cancer examined trastuzumab and paclitaxel with or without carboplatin. The primary end point, overall response rate, was signficantly increased with the addition of carboplatin (52% vs. 36%, p = 0.04). Progression-free survival was also superior in the carboplatin arm (10.7 months vs. 7.1 months, p = 0.03). Grade 4 neutropenia (36% vs. 12%, p = 0.0001) and grade 3 thrombocytopenia (9% vs. 1%) occurred more frequently in the carboplatin arm. A comparison of 2 parallel phase II studies revealed an increase in overall response rate, median time to disease progression, and overall survival with weekly administration of carboplatin/paclitaxel versus every 3 week administration.

    For the neoadjuvant treatment of HER2-positive breast cancer with trastuzumab, in sequence with fluorouracil, epirubicin, and cyclophosphamide (FEC regimen) plus trastuzumab†.
    Intravenous dosage
    Adults

    Paclitaxel 225 mg/m2 IV continuous infusion over 24 hours given in combination with trastuzumab and sequentially with fluorouracil, epirubicin, and cyclophosphamide (FEC regimen) plus trastuzumab. Give trastuzumab 4 mg/kg IV on week 1 just prior to paclitaxel, then, starting on week 2, trastuzumab 2 mg/kg IV once weekly for 23 weeks. Trastuzumab is given concomitantly with paclitaxel (225 mg/m2 IV continuous infusion over 24 hours on day 1) every 3 weeks for 4 cycles, followed by fluorouracil (500 mg/m2 IV on day 1), epirubicin (75 mg/m2 IV on day 1), and cyclophosphamide (500 mg/m2 IV on day 1) every 3 weeks for 4 cycles. Alternately, in a retrospective trial, paclitaxel 80 mg/m2 IV weekly for 12 weeks was substituted for every 3 week dosing in the above regimen.

    For the first line treatment of metastatic breast cancer in combination with carboplatin†.
    Intravenous dosage
    Adults

    175 mg/m2 IV over 3 hours on day 1 in combination with carboplatin AUC 6 IV on day 1, every 3 weeks for 6 cycles has been studied.

    For second line treatment of AIDS-related Kaposi's sarcoma.
    NOTE: Paclitaxel has been designated an orphan drug by the FDA for this indication.
    Intravenous dosage
    Adults

    135 mg/m2 IV infused over 3 hours once every 3 weeks or 100 mg/m2 IV over 3 hours every 2 weeks (dose intensity 45—50 mg/m2/week). In trials evaluating these schedules, the every 3-week regimen was more toxic than the other. In addition, all patients with low performance status were treated with the every 2-week schedule. Initiate or repeat paclitaxel treatment only if the absolute neutrophil count (ANC) is 1000/mm3 or higher. Reduce subsequent courses of paclitaxel by 20% for patients who experience severe neutropenia (ANC less than 500/mm3) for a week or longer; hematopoietic growth factor support may be required. Doses of 175 mg/m2 IV over 3 hours once every 3 weeks have been used. In a study of patients with treatment-resistant AIDS-related Kaposi's sarcoma, paclitaxel 100 mg/m2 IV over 3 hours every 2 weeks lead to a 59% overall response rate. As these patients had received extensive prior chemotherapy, G-CSF was required in 55% of paclitaxel cycles.

    For the treatment of non-small cell lung cancer (NSCLC).
    For first line treatment of NSCLC, in combination with cisplatin, in patients who are not candidates for potentially curative surgery and/or radiation therapy.
    Intravenous dosage
    Adults

    135 mg/m2 IV administered over 24 hours followed by cisplatin (75 mg/m2 IV) every 3 weeks based on clinical status of the patient.

    For the treatment of advanced or metastatic NSCLC in combination with carboplatin†.
    Intravenous dosage
    Adults

    Paclitaxel 200 mg/m2 IV on day 1 in combination with carboplatin (AUC 6 IV) on day 1 given every 21 days produced an overall survival of 12.3 months in a phase III comparison of 4 chemotherapy doublets in advanced NSCLC. In another similar 4-arm phase III comparison, paclitaxel 225 mg/m2 IV on day 1 in combination with carboplatin (AUC 6 IV) on day 1 given every 21 days, produced an overall survival of 7.8 months, which was similar to the reference regimen of cisplatin and paclitaxel.

    For the treatment of advanced or metastatic NSCLC in combination with gemcitabine†.
    Intravenous dosage
    Adults

    Paclitaxel 200 mg/m2 IV on day 1 in combination with gemcitabine 1000 mg/m2 IV on days 1 and 8, every 3 weeks has been given. Alternately, paclitaxel 175 mg/m2 IV on day 1 in combination with gemcitabine 1250 mg/m2 IV on days 1 and 8, every 3 weeks has also been given.

    For the treatment of ovarian cancer.
    For first line treatment of ovarian cancer in combination with cisplatin.
    Intravenous dosage
    Adults

    135 mg/m2 IV over 24 hours or 175 mg/m2 IV over 3 hours once every 3 weeks, followed by cisplatin (75 mg/m2 IV). This combination improves duration of progression-free survival and overall survival of these women as compared to the combination of cyclophosphamide and cisplatin. The 3-hour paclitaxel infusion is associated with less myelosuppression but increased neurotoxicity versus the 24-hour infusion. The combination of paclitaxel (175 mg/m2 IV over 3 hours) and carboplatin (AUC 5—6) is better tolerated than the paclitaxel-cisplatin combination and also appears to yield a survival advantage.

    For the first line treatment of ovarian cancer in combination with carboplatin†.
    Intravenous dosage
    Adults

    175 to 185 mg/m2 IV over 3 hours on day 1 in combination with carboplatin (AUC 5—7.5 IV on day 1), every 3 weeks for 6 cycles. In clinical trials, carboplatin/paclitaxel has been shown to be less toxic and produce similar efficacy to cisplatin/paclitaxel as first line treatment of patients with advanced ovarian cancer. Additionally, paclitaxel 80 mg/m2 IV on days 1, 8, and 15 in combination with carboplatin (AUC 6 IV on day 1), every 3 weeks for 6 cycles has been given. This dose-dense combination was compared to conventional carboplatin/paclitaxel in 631 patients with advanced ovarian cancer. Progression-free survival, the primary end point, was significantly higher in the dose-dense arm (28 months vs. 17.2 months, p = 0.0015).

    For refractory or metastatic ovarian cancer.
    Intravenous dosage
    Adults

    135 mg/m2 or 175 mg/m2 IV over 3 hours once every 3 weeks. The optimal regimen has not yet been determined. Alternately, paclitaxel 80 mg/m2 IV over 1 hour weekly for an initial 12 weeks, followed by 4-week courses of 3 weekly doses with 1 week off, has been given until disease progression or unacceptable toxicity†. In 48 patients with platinum and paclitaxel-resistant ovarian cancer, the objective response rate was 20.9%.

    For the first line treatment of optimally debulked, stage III ovarian cancer as an intraperitoneal and intravenous infusion in combination with intraperitoneal cisplatin†.
    Intravenous dosage and Intraperitoneal dosage†
    Adults

    Paclitaxel 135 mg/m2 intravenously over 24 hours on day 1 followed by cisplatin 100 mg/m2 intraperitoneally on day 2 and paclitaxel 60 mg/m2 intraperitoneally on day 8. Administer every 3 weeks for 6 cycles. Extended overall survival and progression-free survival in a phase III trial compared to cisplatin IV/paclitaxel IV.

    For the first line treatment of advanced transitional-cell bladder cancer†, in combination with carboplatin.
    Intravenous dosage
    Adults

    225 mg/m2 IV over 3 hours on day 1 followed by carboplatin (AUC of 6) IV over 30 minutes on day 1 repeated every 21 days (CP regimen) for 6 cycles was compared with methotrexate 30 mg/m2 on days 1, 15, and 22, vinblastine 3 mg/m2 IV on days 2, 15, and 22, doxorubicin 30 mg/m2 on day 2, and cisplatin 70 mg/m2 on day 2 (MVAC regimen) in a randomized, phase III trial. In this study, the median overall survival (OS) times were 13.8 and 15.4 months with CP and MVAC, respectively (p = 0.75) in 85 patients (median follow-up of 32.5 months). This study was halted because of slow patient accrual and was therefore underpowered to detect a difference in the primary end point of OS. The progression-free survival time was 5.2 months in the CP arm and 8.7 months in the MVAC arm (p = 0.24). Grade 3 or higher toxicity reported less often with CP compared with MVAC included neutropenia (29% vs. 67%), anemia (5% vs. 38%), thrombocytopenia (10% vs. 21%), fatigue (10% vs. 24%), and dyspnea (2% vs. 14% ); grade 3 sensory neuropathy occurred more often with CP (15% vs. 2%). Additionally, worst degree toxicity of grade 4 or higher occurred in fewer patients in the CP arm (15% vs. 33%) and there was 1 treatment-related death in each study arm.

    For the treatment of unresectable or metastatic squamous cell esophageal cancer†, in combination with cisplatin.
    Intravenous dosage
    Adults

    175 mg/m2 IV over greater than 2 hours followed by cisplatin 75 mg/m2 IV over 1 hour (with 2—3 L of a electrolyte hydration solution over 8 hours daily for 3 days) on day 1 repeated every 21 days (mean of 3 cycles) and paclitaxel 90 mg/m2 IV over 3 hours plus cisplatin 50 mg/m2 IV over 3 hours (with 1 L of prehydration and 3 L of post hydration) repeated every 2 weeks for up to 8 cycles (median of 5 cycles; range, 2—8 cycles) have been evaluated in patients with unresectable or metastatic squamous cell carcinoma of the esophagus in nonrandomized clinical trials. All patients received premedications with a 5-HT3 antagonist prior to chemotherapy and dexamethasone and antihistamines 30 minutes prior to paclitaxel.

    For the treatment of advanced squamous cell head and neck cancer†, in combination with carboplatin and radiotherapy.
    Intravenous dosage
    Adults

    40—45 mg/m2 IV weekly in combination with carboplatin (100 mg/m2 IV weekly). Chemotherapy was administered weekly prior to radiation therapy. In a clinical trial, 62 patients were administered carboplatin/paclitaxel concomitantly with radiation therapy. An overall survival of 33 months was achieved. A complete response (CR) occurred in 75% of patients; among patients with a CR, an overall survival of 49 months was achieved. At a follow-up of 30 months, a local control rate of 63% was observed.

    For peripheral blood stem cell (PBSC) mobilization† in hematologic malignancies.
    Intravenous dosage
    Adults

    200 mg/m2 IV has been given in combination with etoposide, cyclophosphamide, and dexamethasone, followed by filgrastim for peripheral blood stem cell mobilization (d-TEC regimen). Alternately, paclitaxel 250 mg/m2 IV has been given on day 1, followed by filgrastim starting on day 2 and continued through the completion of leukapheresis.

    For the treatment of advanced or recurrent endometrial cancer in combination with doxorubicin and cisplatin†.
    Intravenous dosage
    Adults

    160 mg/m2 IV on day 2, in combination with doxorubicin (45 mg/m2) immediately followed by cisplatin (50 mg/m2) on day 1; give every 21 days. In clinical trials treatment was continued for up to 7 cycles or until disease progression, and filgrastim (5 mcg/kg) was administered on days 3—12. A phase III trial showed an increase in response rate, progression-free survival, and overall survival in patients receiving paclitaxel, doxorubicin, and cisplatin (TAP) vs. cisplatin and doxorubicin alone. Thrombocytopenia and neuropathy were higher in the TAP arm.

    For the first line treatment of unresectable, advanced thymoma†, in combination with carboplatin.
    Intravenous dosage
    Adults

    225 mg/m2 IV over 3 hours followed by carboplatin AUC of 6 IV over 30 minutes on day 1 repeated every 21 days for up to 6 cycles resulted in an objective response rate (ORR) of 42.9% (complete response rate, 14.3%; median duration of response, 16.9 months) in 21 patients with invasive, recurrent, or metastatic thymoma in a multicenter, phase II study. This ORR was less than the prespecified ORR of 60% that would warrant further study of this regimen. At a median follow-up of 59.4 months, the median progression-free survival time was 16.7 months and the median overall survival time was not reached. Serious toxicity reported in this study included grade 4 neutropenia and grade 3 sensory neuropathy.

    For the first line treatment of unresectable, advanced thymic carcinoma†, in combination with carboplatin.
    Intravenous dosage
    Adults

    225 mg/m2 IV over 3 hours followed by carboplatin AUC of 6 IV over 30 minutes on day 1 administered every 21 days for up to 6 cycles resulted in an objective response rate (ORR) of 21.7% (all partial responses; median duration of response, 4.5 months) in 23 patients with invasive, recurrent, or metastatic thymic carcinoma in a multicenter, phase II study. This ORR was less than the prespecified ORR of 45% that would warrant further study of this regimen. At a median follow-up of 63.8 months, the median progression-free survival and overall survival times were 5 and 20 months, respectively. Serious toxicity reported in this study included grade 4 neutropenia and grade 3 sensory neuropathy.

    For the treatment of small cell lung cancer (SCLC)†.
    For chemotherapy-naive, extensive-stage SCLC in combination with topotecan†.
    Intravenous dosage
    Adults

    Paclitaxel 135 mg/m2 IV as a 24-hour infusion on day 5 following topotecan (given as 1 mg/m2 IV days 1—5) every 28 days was evaluated in a phase II trial for the treatment of chemotherapy-naive extensive stage SCLC. Initially, topotecan dosing was 1.25 mg/m2 IV on days 1—5; however, because of excessive hematologic toxicity in the first 3 patients, the dose was reduced as above. Patients received an average of 4 cycles of chemotherapy. The overall response rate was 69%, overall median survival was 54 weeks with a 1-year survival rate of 50%. Despite the use of prophylactic G-CSF, the incidence of grade 4 neutropenia was 31%, which may have been increased because of 24-hour administration of paclitaxel. Overall, response rates and tolerability of this regimen were comparable to platinum/etoposide.

    For the treatment of relapsed SCLC as a single agent†.
    Intravenous dosage
    Adults

    Paclitaxel can be given weekly or every 3 weeks as a single agent. Paclitaxel 175 mg/m2 IV on day 1, repeated every 3 weeks up to a maximum of 5 cycles has been given to patients with SCLC relapsed within 3 months of chemotherapy. Alternately, paclitaxel 80 mg/m2 IV once weekly for 6 weeks on and 2 weeks off has been given to patients refractory to chemotherapy or relapsed within 4 weeks of chemotherapy.

    For the treatment of relapsed SCLC in combination with carboplatin†.
    Intravenous dosage
    Adults

    175 mg/m2 IV on day 1 in combination with carboplatin AUC 7 IV on day 1, every 3 weeks for 5 cycles.

    For the neoadjuvant treatment of locally advanced or metastatic penile cancer† in combination with cisplatin and ifosfamide.
    Intravenous dosage
    Adults

    175 mg/m2 IV over 3 hours on day 1 in combination with cisplatin 25 mg/m2/day IV over 2 hours on days 1—3 and ifosfamide 1200 mg/m2/day IV over 2 hours on days 1—3, repeated every 3—4 weeks.

    †Indicates off-label use

    MAXIMUM DOSAGE

    The suggested maximum tolerated dose (MTD) for paclitaxel is dependent on performance status, other chemotherapy agents or radiation given in combination, and disease state. The optimal dose or infusion duration of paclitaxel has not been determined. Therefore, dosing may vary from protocol to protocol. If questions arise, clinicians should consult the appropriate references to verify the dose.

    Adults

    135—175 mg/m2 IV over 3 hours or up to 250 mg/m2 IV over 24 hours every 3 weeks. Weekly paclitaxel at doses of 80—100 mg/m2 IV over 1 hour are under investigation. Studies of weekly doses have given paclitaxel for 3 consecutive weeks with 1 week off, 6 weeks consecutively with 2 weeks off, or weekly for >12 weeks continuously. Higher doses may be given as part of preparative regimens for bone marrow transplantation. For intraperitoneal administration, the maximum tolerated dose was 175 mg/m2 IP every 3—4 weeks. When given IP weekly, significant Grade 2 toxicities were seen at 75 mg/m2; the recommended dose for weekly IP administration is 60—65 mg/m2 IP.

    DOSING CONSIDERATIONS

    Dosage adjustments for hematologic and non-hematologic toxicities:
    If neutrophil count < 500/mm3 for > 7 days or neutropenic fever: Consider adding colony-stimulating factor support with next cycle or dose reducing paclitaxel by 20%.
    Severe peripheral neuropathy: Reduce paclitaxel dose by 20%.

    Hepatic Impairment

    NOTE: Recommended dose reductions are for the first course of therapy; subsequent dose reductions should be based on individual tolerance. 
    Dose reduction for 135 mg/m2 24-hour intravenous infusion:
    AST/ALT 2—10 x ULN and total bilirubin <= 1.5 mg/dl: 100 mg/m2.
    AST/ALT < 10 x ULN and total bilirubin 1.6—7.5 mg/dl: 50 mg/m2.
    AST/ALT >= 10 x ULN or total bilirubin > 7.5 mg/dl: Not recommended.
     
    Dose reduction for 175 mg/m2 3-hour intravenous infusion:
    AST/ALT < 10 x ULN and total bilirubin 1.26—2 x ULN: 135 mg/m2.
    AST/ALT < 10 x ULN and total bilirubin 2.01—5 x ULN: 90 mg/m2.
    AST/ALT >= 10 x ULN or total bilirubin > 5 x ULN: Not recommended.
     
    Dose adjustments of paclitaxel are required in patients with hepatic dysfunction, although exact guidelines are not available for other dosage regimens. In general, dosage reductions of at least 50% are recommended in patients with moderate or severe hyperbilirubinemia or substantially increased serum transferase levels. The results of a study of patients with elevated serum bilirubin and/or liver enzymes indicate that the dose of paclitaxel should not exceed 50—75 mg/m2 IV over 24 hours or 75—100 mg/m2 IV over 3 hours. In addition, patients with AST > 2 times the upper limit of normal should not be treated with doses > 50 mg/m2 IV over 24 hours.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

     
    CAUTION: Observe and exercise usual precautions for handling, preparing, and administering solutions of cytotoxic drugs.

    Injectable Administration

    Administer as an intravenous infusion. In clinical studies, paclitaxel has been administered intraperitoneally.
    Prior to administration, patients should have documented neutrophil counts > 1500/mm3 and platelet counts > 100,000/mm3. Patients with AIDS-related Kaposi's sarcoma should have neutrophil counts > 1000/mm3.
    To prevent hypersensitivity reactions, all patients should be premedicated with dexamethasone 20 mg PO approximately 12 and 6 hours before paclitaxel, diphendydramine (or its equivalent) 50 mg IV 30—60 minutes prior to paclitaxel, and cimetidine 300 mg IV, famotidine 20 mg IV, or ranitidine 50 mg IV 30—60 minutes before paclitaxel. In patients with advanced HIV disease, reduce the dose of dexamethasone to 10 mg PO.
    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
     
    Dilution:
    Withdraw the appropriate dose of paclitaxel from the vial and dilute to a concentration of 0.3—1.2 mg/ml with either NS, D5W, D5NS, or dextrose in Lactated Ringer's solution.
    The Chemo Dispensing Pin device or similar devices with spikes should not be used in vials of Taxol since they can cause the stopper to collapse resulting in loss of sterility of the solution.
    It is recommended that the infusion be prepared in glass or polypropylene bottles or polypropylene or polyolefin plastic bags and administered through polyethylene-lined administration sets. Do not use PVC administration sets or containers.
    Diluted solutions are stable at room temperature for up to 27 hours.

    Intravenous Administration

    Use of an in-line filter of not greater than 0.22 micron pore size is required during administration.
    Infuse IV according to the prescriber's directions as infusion times may vary according to indication (see Dosage). Paclitaxel has been administered as a 3-hour or a 24-hour IV infusion. Paclitaxel doses up to 100 mg/m2 IV weekly have been given as a 1-hour IV infusion.

    Other Injectable Administration

    Intraperitoneal infusion:
    Paclitaxel is not approved by the FDA for intraperitoneal administration.
    Dilute into 1—2 liters of 0.9% Sodium Chloride (NS), depending upon patient tolerability.
    Warm to 37 degrees C and infuse as rapidly as tolerated into the peritoneal cavity
    Patients should change positions at 15 minute intervals for 2 hours to ensure adequate intraabdominal distribution.

    STORAGE

    Onxol :
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Protect from light
    - See package insert for detailed storage information
    - Store at controlled room temperature (between 68 and 77 degrees F)
    - Store in original package until time of use
    Taxol:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Protect from light
    - See package insert for detailed storage information
    - Store at controlled room temperature (between 68 and 77 degrees F)
    - Store in original package until time of use

    CONTRAINDICATIONS / PRECAUTIONS

    Polyoxyethylated castor oil hypersensitivity, risk of serious hypersensitivity reactions or anaphylaxis, taxane hypersensitivity

    Paclitaxel is contraindicated in patients who have a history of severe paclitaxel hypersensitivity; those patients with a history of other taxane hypersensitivity should be given paclitaxel with caution. A risk of serious hypersensitivity reactions or anaphylaxis has been reported in patients receiving paclitaxel. Patients with known polyoxyethylated castor oil hypersensitivity should not receive the Taxol formulation or should receive it cautiously and with premedication. Polyoxyethylated compound (Cremophor EL) is believed to be responsible for anaphylactoid reactions. Severe hypersensitivity reactions (e.g., acute bronchospasm and/or hypotension) have occurred despite antihistamine (H1- and H2-blockers) and corticosteroid premedication. Hypersensitivity reactions may occur within minutes of beginning an infusion. Severe may reactions necessitate the immediate discontinuation of the infusion. Patients should be monitored closely.

    Bone marrow suppression, herpes infection, infection, Kaposi's sarcoma, neutropenia, requires a specialized care setting, requires an experienced clinician, thrombocytopenia, varicella, viral infection

    Paclitaxel is associated with dose-related bone marrow suppression. It should not be given to patients with severe thrombocytopenia or neutropenia, with solid tumors who have baseline neutrophil counts of less than 1,500 cells/mm3, with AIDS-related Kaposi's sarcoma, or with baseline neutrophil count is less than 1000 cells/mm3; these patients may have more frequent and severe hematologic toxicities, infections (including opportunistic infections), and febrile neutropenia compared to patients with solid tumors. In all patients, blood counts should be monitored frequently during treatment. Generally, the next cycle should not be given until neutrophils reach >= 1500/mm3 (1000/mm3 for Kaposi's sarcoma patients) and platelets recover to >= 100,000/mm3. In patients with a neutrophil count of < 500 cells/mm3 for longer than 1 week, consider adding colony-stimulating factor support or reducing subsequent paclitaxel doses by 20%. Due to these severe adverse reactions, paclitaxel requires an experienced clinician knowledgeable in the use of cancer chemotherapeutic agents. Administration requires a specialized care setting such as a hospital or treatment facility so that facilities are readily available for appropriate management of complications. Use cautiously in patients who have myelosuppression due to previous therapy such as other chemotherapy or radiotherapy; these patients may be more susceptible to the myelosuppressive effects of paclitaxel. Patients with active infection should be treated prior to receiving paclitaxel. Patients with a history of varicella zoster, other herpes infection (e.g., herpes simplex), or other viral infection are at risk for reactivation of the infection when treated with chemotherapy.

    Angina, AV block, bradycardia, cardiac arrhythmias, cardiac disease, heart failure, myocardial infarction

    Severe conduction abnormalities have been documented in during paclitaxel therapy and in some cases requiring pacemaker placement. If patients develop significant cardiac conduction abnormalities during paclitaxel infusion, appropriate therapy should be administered and continuous cardiac monitoring should be performed during subsequent therapy with paclitaxel. Patients with cardiac disease including angina, cardiac arrhythmias including AV block, history of congestive heart failure, or myocardial infarction within the past 6 months should be carefully monitored during paclitaxel therapy due to the potential for serious cardiac complications. In addition, patients receiving paclitaxel in combination with doxorubicin for metastatic breast cancer should be considered for cardiac monitoring. In a review of gynecologic cancer patients with major risk factors who received paclitaxel, no evidence of additive adverse effects was noted. As many of the reports of severe cardiac events were seen in early trials of paclitaxel as a result of hypersensitivity reactions, appropriate premedication appears to have decreased the incidence of these effects. It should be noted that patients with severe conduction abnormalities were not included in this review. Because bradycardia is a common adverse reaction, patients receiving drugs known to cause bradycardia, such as beta-blockers, calcium-channel blockers, and digoxin, also should be monitored carefully.

    Peripheral neuropathy

    Preexisting peripheral neuropathy is not a contraindication for paclitaxel; although, these patients may be at increased risk to develop paclitaxel-induced neurotoxicity. Exacerbation of pre-existing neuropathies may occur at relatively low paclitaxel doses. Patients who have been exposed to agents that may cause neurotoxicity, such as cisplatin, may also be at increased risk for paclitaxel-induced neurotoxicity. Patients with severe neurotoxic symptoms should have their paclitaxel doses reduced by 20%.

    Geriatric

    Geriatric patients are at increased risk for adverse reactions to paclitaxel therapy. In most studies, severe myelosuppression was more frequent in elderly patients; in some studies, severe neuropathy was more common in the elderly. In two clinical studies of non-small cell lung cancer (NSCLC), the elderly patients treated with paclitaxel had a higher incidence of cardiovascular events.

    Hepatic disease

    Paclitaxel should be used cautiously in patients with known hepatic disease. Because paclitaxel is extensively metabolized through cytochrome P-450 system, excessive toxicity may occur in patients with hyperbilirubinemia and elevated liver enzymes. Limited data suggest myelotoxicity may be increased in patients with serum bilirubin > 2 times ULN. Patients with hepatic disease may require dose reductions (see Dosage).

    Pregnancy

    Paclitaxel is classified as FDA pregnancy risk category D and has been shown to produce toxic effects, including death, in fetal animal studies. There are no data concerning the effects in pregnant women. Therefore, paclitaxel should be avoided during pregnancy, and females of childbearing potential should be instructed to avoid becoming pregnant during paclitaxel therapy. If a women becomes pregnant while receiving this drug, she should be counseled of the potential harm to the fetus and the possibility of loss of pregnancy.

    Breast-feeding

    It is unknown whether paclitaxel is excreted into human breast milk; paclitaxel was excreted into the breast milk of lactating rats at concentrations higher than those seen in plasma. Because of the potential for serious adverse reactions in nursing infants, patients should be instructed to discontinue breast-feeding during paclitaxel therapy.

    Radiation therapy

    Patients who have received prior radiation therapy are at risk for radiation recall reactions when receiving paclitaxel. These patients should be monitored closely. In addition, paclitaxel may increase the efficacy and/or the adverse reactions of radiation therapy.

    Intramuscular injections

    Intramuscular injections should be avoided in patients with platelet counts < 50,000/mm3 who are receiving paclitaxel. IM injections can cause bleeding, bruising, or hematomas in patients with paclitaxel-induced thrombocytopenia.

    Dental disease, dental work

    Myelosuppressive effects of paclitaxel can increase the risk of infection or bleeding; therefore, dental work should be delayed until blood counts have returned to normal. Patients, especially those with dental disease, should be instructed in proper oral hygiene, including caution in use of regular toothbrushes, dental floss, and toothpicks.

    Alcoholism, driving or operating machinery

    The Taxol formulation of paclitaxel contains a high concentration of ethanol (49.7% (v/v)). Consideration should be given to the CNS effects and other effects of alcohol. Special consideration may be prudent in individuals with alcoholism or a history of substance abuse. Patients should be cautioned regarding driving or operating machinery following infusion of Taxol as the high alcohol content infused over a short period of time may theoretically cause impairment in some persons.

    Children

    The safe and effective use of paclitaxel in children has not been established. There have been reports of central nervous system toxicity, rarely associated with death, in a pediatric clinical trial in which Taxol was infused at doses ranging from 350—420 mg/m2 IV over 3 hours. The toxicity is thought to be due to the high concentration of alcohol in the Taxol vehicle and the short infusion time. However, the effect of antihistamine premedication and the high dose of paclitaxel used in this study, over twice the adult recommended dose, cannot be discounted as possible attributing factors.

    Extravasation, intramuscular administration, subcutaneous administration

    Paclitaxel is considered a vesicant. Extravasation of paclitaxel infusions should be avoided as tissue necrosis has been reported following paclitaxel extravasation. Patients should be closely monitored during IV infusions for signs and symptoms of extravasation such as pain, swelling and poor blood return. In some cases the onset of the extravasation reaction either occurred during a prolonged infusion or was delayed by 7 to 10 days. Patients who have previously experienced a paclitaxel extravasation may have a 'recall' reaction at the previous extravasation site during subsequent paclitaxel infusions. It is recommended that prolonged paclitaxel infusions not be given through peripheral lines due to the potential for severe reactions if extravasated. Intramuscular administration and subcutaneous administration of paclitaxel should be avoided.

    Accidental exposure, ocular exposure

    Use care to avoid accidental exposure to paclitaxel during preparation, handling and administration. The use of protective gowns, gloves and goggles is recommended. Avoid ocular exposure of paclitaxel solutions. If exposure occurs, the eye should be rinsed immediately and thoroughly; seek medical attention.

    Vaccination

    Vaccination during chemotherapy with paclitaxel or radiation therapy should be avoided because the antibody response is suboptimal. When chemotherapy is being planned, vaccination should precede the initiation of chemotherapy by >= 2 weeks. The administration of live vaccines to immunocompromised patients should be avoided. Those undergoing chemotherapy should not be exposed to others who have recently received the oral poliovirus vaccine (OPV). Measles-mumps-rubella (MMR) vaccination is not contraindicated for the close contacts, including health care professionals, of immunocompromised patients. Passive immunoprophylaxis with immune globulins may be indicated for immunocompromised persons instead of, or in addition to, vaccination. When exposed to a vaccine-preventable disease such as measles, severely immunocompromised children should be considered susceptible regardless of their vaccination history.

    ADVERSE REACTIONS

    Severe

    neutropenia / Delayed / 52.0-52.0
    leukopenia / Delayed / 17.0-17.0
    anemia / Delayed / 16.0-16.0
    arthralgia / Delayed / 8.0-8.0
    myalgia / Early / 8.0-8.0
    thrombocytopenia / Delayed / 7.0-7.0
    angioedema / Rapid / 2.0-4.0
    anaphylactoid reactions / Rapid / 2.0-4.0
    bradycardia / Rapid / 3.0-3.0
    peripheral neuropathy / Delayed / 3.0-3.0
    leukoencephalopathy / Delayed / 2.0-2.0
    thromboembolism / Delayed / 1.0-1.0
    AV block / Early / 1.0-1.0
    ventricular tachycardia / Early / 1.0-1.0
    seizures / Delayed / 0-1.0
    anaphylactic shock / Rapid / Incidence not known
    tissue necrosis / Early / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    myocardial infarction / Delayed / Incidence not known
    atrial fibrillation / Early / Incidence not known
    typhlitis / Delayed / Incidence not known
    pulmonary fibrosis / Delayed / Incidence not known
    pleural effusion / Delayed / Incidence not known
    exfoliative dermatitis / Delayed / Incidence not known
    pulmonary embolism / Delayed / Incidence not known
    hepatic necrosis / Delayed / Incidence not known
    hepatic encephalopathy / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    ileus / Delayed / Incidence not known
    hearing loss / Delayed / Incidence not known

    Moderate

    stomatitis / Delayed / 31.0-31.0
    elevated hepatic enzymes / Delayed / 19.0-22.0
    edema / Delayed / 21.0-21.0
    bleeding / Early / 14.0-14.0
    sinus tachycardia / Rapid / 14.0-14.0
    hypotension / Rapid / 4.0-12.0
    candidiasis / Delayed / 7.0-9.0
    hyperbilirubinemia / Delayed / 7.0-7.0
    dyspnea / Early / 2.0-4.0
    hypertension / Early / 1.0-1.0
    encephalopathy / Delayed / 0-1.0
    ataxia / Delayed / 0-1.0
    chest pain (unspecified) / Early / Incidence not known
    erythema / Early / Incidence not known
    phlebitis / Rapid / Incidence not known
    supraventricular tachycardia (SVT) / Early / Incidence not known
    hyperesthesia / Delayed / Incidence not known
    esophagitis / Delayed / Incidence not known
    ascites / Delayed / Incidence not known
    constipation / Delayed / Incidence not known
    pneumonitis / Delayed / Incidence not known
    radiation recall reaction / Delayed / Incidence not known
    confusion / Early / Incidence not known
    scotomata / Delayed / Incidence not known
    conjunctivitis / Delayed / Incidence not known
    photopsia / Delayed / Incidence not known

    Mild

    alopecia / Delayed / 87.0-87.0
    infection / Delayed / 30.0-61.0
    vomiting / Early / 52.0-52.0
    nausea / Early / 52.0-52.0
    diarrhea / Early / 38.0-38.0
    flushing / Rapid / 28.0-28.0
    asthenia / Delayed / 17.0-17.0
    injection site reaction / Rapid / 13.0-13.0
    fever / Early / 12.0-12.0
    rash (unspecified) / Early / 12.0-12.0
    nail discoloration / Delayed / 2.0-2.0
    syncope / Early / 1.0-1.0
    paresthesias / Delayed / 60.0
    malaise / Early / Incidence not known
    anorexia / Delayed / Incidence not known
    diaphoresis / Early / Incidence not known
    abdominal pain / Early / Incidence not known
    chills / Rapid / Incidence not known
    back pain / Delayed / Incidence not known
    maculopapular rash / Early / Incidence not known
    pruritus / Rapid / Incidence not known
    dizziness / Early / Incidence not known
    headache / Early / Incidence not known
    lacrimation / Early / Incidence not known
    tinnitus / Delayed / Incidence not known
    vertigo / Early / Incidence not known

    DRUG INTERACTIONS

    Alpha interferons: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Alteplase, tPA: (Moderate) An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
    Amoxicillin; Clarithromycin; Lansoprazole: (Minor) Paclitaxel is partially metabolized by CYP3A4. The systemic clearance of paclitaxel may be decreased if coadministered with clarithromycin, an inhibitor of CYP3A4.
    Amoxicillin; Clarithromycin; Omeprazole: (Minor) Paclitaxel is partially metabolized by CYP3A4. The systemic clearance of paclitaxel may be decreased if coadministered with clarithromycin, an inhibitor of CYP3A4.
    Amprenavir: (Minor) Amprenavir may inhibit the metabolism of other medications that are metabolized via cytochrome P450 3A4 including paclitaxel. The serum concentration of paclitaxel may be increased with concomitant administration of amprenavir.
    Anticoagulants: (Moderate) Due to the thrombocytopenic effects of taxanes, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Antithrombin III: (Moderate) Due to the thrombocytopenic effects of taxanes, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Antithymocyte Globulin: (Moderate) Because antithymocyte globulin is an immunosuppressant, additive affects may be seen with other immunosuppressives or antineoplastic agents. While therapy is designed to take advantage of this effect, patients may be predisposed to over-immunosuppression resulting in an increased risk of infection or other side effects.
    Apixaban: (Moderate) Due to the thrombocytopenic effects of taxanes, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Aprepitant, Fosaprepitant: (Moderate) Aprepitant, fosaprepitant is indicated for the prophylaxis of chemotherapy-induced nausea/vomiting and is often used in combination with paclitaxel. However, use caution and monitor for a possible increase in non-emetogenic paclitaxel-related adverse effects for several days after administration of a multi-day aprepitant regimen. Paclitaxel is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer. The AUC of another CYP3A4 substrate, midazolam, was significantly increased when coadministered with oral aprepitant; theoretically, this could also occur with paclitaxel. However, oral aprepitant was commonly administered with paclitaxel in clinical trials without dose adjustments for potential drug interactions; the aprepitant manufacturer does not recommend a paclitaxel dose adjustment. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction.
    Argatroban: (Moderate) Due to the thrombocytopenic effects of taxanes, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Atazanavir: (Moderate) Due to atazanavir-induced inhibition of CYP3A4 isoenzymes, atazanavir may inhibit the metabolism and thus, increase the serum concentrations of drugs that are largely metabolized via CYP3A4 including paclitaxel. If atazanavir and paclitaxel must be coadministered, the dosage of paclitaxel may need to be downwardly adjusted and conversely, upward dosage adjustment of paclitaxel may be required when atazanavir is discontinued.
    Atazanavir; Cobicistat: (Moderate) Due to atazanavir-induced inhibition of CYP3A4 isoenzymes, atazanavir may inhibit the metabolism and thus, increase the serum concentrations of drugs that are largely metabolized via CYP3A4 including paclitaxel. If atazanavir and paclitaxel must be coadministered, the dosage of paclitaxel may need to be downwardly adjusted and conversely, upward dosage adjustment of paclitaxel may be required when atazanavir is discontinued. (Minor) Plasma concentrations of paclitaxel may be elevated when administered concurrently with cobicistat. Cobicistat is a CYP3A4 and P-glycoprotein (P-gp) inhibitor, while paclitaxel is a CYP3A4 and P-gp substrate. Some experts state that pharmacokinetic interactions between paclitaxel and some CYP3A4 inhibitors do not appear to be clinically significant. However, combining the drugs in clinical practice may require close monitoring to ensure proper therapeutic responses.
    Azelastine; Fluticasone: (Moderate) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. In addition, Cabazitaxel is a CYP3A4 substrate and concomitant use with strong CYP3A4 inducers such as dexamethasone may lead to reduced concentrations of cabazitaxel. Avoid concomitant use of cabazitaxel and strong CYP3A4 inducers. Consider alternative therapies with low enzyme induction potential.
    Azithromycin: (Moderate) Paclitaxel is a substrate of P-glycoprotein (P-gp) and azithromycin is a P-gp inhibitor; therefore, paclitaxel concentrations could be increased with coadministration. Monitor patients for increased side effects if these drugs are given together.
    Bacillus Calmette-Guerin Vaccine, BCG: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Barbiturates: (Minor) Paclitaxel is metabolized by hepatic cytochrome P450 isoenzymes 2C8 and 3A4. Potential interactions may occur in vivo with any agent that induces CYP2C8 or CYP3A4 isoenzymes including barbiturates.
    Beclomethasone: (Moderate) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. In addition, Cabazitaxel is a CYP3A4 substrate and concomitant use with strong CYP3A4 inducers such as dexamethasone may lead to reduced concentrations of cabazitaxel. Avoid concomitant use of cabazitaxel and strong CYP3A4 inducers. Consider alternative therapies with low enzyme induction potential.
    Bepridil: (Minor) Additive bradycardia may occur in patients receiving paclitaxel and other drugs known to cause bradycardia, such as calcium-channel blockers like bepridil. These patients may require additional monitoring and information.
    Betamethasone: (Moderate) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. In addition, Cabazitaxel is a CYP3A4 substrate and concomitant use with strong CYP3A4 inducers such as dexamethasone may lead to reduced concentrations of cabazitaxel. Avoid concomitant use of cabazitaxel and strong CYP3A4 inducers. Consider alternative therapies with low enzyme induction potential.
    Betrixaban: (Moderate) Due to the thrombocytopenic effects of taxanes, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Medications with significant alcohol content should not be ingested during therapy with metronidazole and should be avoided for 3 days after therapy is discontinued. Some formulations of paclitaxel contain a high level of ethanol. Administration to patients receiving or who have recently received metronidazole may result in disulfiram-like reactions. A disulfiram reaction would not be expected to occur with non-ethanol containing formulations.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Medications with significant alcohol content should not be ingested during therapy with metronidazole and should be avoided for 3 days after therapy is discontinued. Some formulations of paclitaxel contain a high level of ethanol. Administration to patients receiving or who have recently received metronidazole may result in disulfiram-like reactions. A disulfiram reaction would not be expected to occur with non-ethanol containing formulations.
    Bivalirudin: (Moderate) Due to the thrombocytopenic effects of taxanes, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Boceprevir: (Moderate) Close clinical monitoring is advised when administering paclitaxel with boceprevir due to an increased potential for paclitaxel-related adverse events. If paclitaxel dose adjustments are made, re-adjust the dose upon completion of boceprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of paclitaxel. Paclitaxel is a substrate of the drug efflux transporter P-glycoprotein (PGP) and of the hepatic isoenzyme CYP3A4; boceprevir is an inhibitor of both the efflux protein and the isoenzyme. Coadministration may result in elevated paclitaxel plasma concentrations.
    Bortezomib: (Minor) Monitor patients for the development of peripheral neuropathy when receiving bortezomib in combination with other drugs that can cause peripheral neuropathy like paclitaxel; the risk of peripheral neuropathy may be additive.
    Bosentan: (Minor) Co-administration of bosentan with other drugs which are metabolized by hepatic enzymes has not been studied. Bosentan is an inducer of cytochrome P450 enzymes, specifically the CYP2C9 and CYP3A4 isoenzymes, and may decrease concentrations of drugs metabolized by these enzymes including paclitaxel.
    Brigatinib: (Moderate) Monitor for decreased efficacy of paclitaxel if coadministration with brigatinib is necessary. Paclitaxel is a CYP3A substrate and brigatinib induces CYP3A in vitro; plasma concentrations of paclitaxel may decrease.
    Budesonide: (Moderate) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. In addition, Cabazitaxel is a CYP3A4 substrate and concomitant use with strong CYP3A4 inducers such as dexamethasone may lead to reduced concentrations of cabazitaxel. Avoid concomitant use of cabazitaxel and strong CYP3A4 inducers. Consider alternative therapies with low enzyme induction potential.
    Budesonide; Formoterol: (Moderate) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. In addition, Cabazitaxel is a CYP3A4 substrate and concomitant use with strong CYP3A4 inducers such as dexamethasone may lead to reduced concentrations of cabazitaxel. Avoid concomitant use of cabazitaxel and strong CYP3A4 inducers. Consider alternative therapies with low enzyme induction potential.
    Cabozantinib: (Moderate) Monitor for an increase in paclitaxel-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of paclitaxel may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and paclitaxel is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Carbamazepine: (Moderate) Paclitaxel is metabolized by hepatic cytochrome P450 isoenzymes 2C8 and 3A4. Potential interactions may occur in vivo with any agent that induces CYP2C8 or CYP3A4 isoenzymes including carbamazepine. Clinicians should be alert to changes in the clinical effects of paclitaxel. Dosage adjustments may be necessary, and closer monitoring of clinical and/or adverse effects is warranted when carbamazepine is used with paclitaxel.
    Carboplatin: (Minor) In vitro studies have shown an increase in cytotoxicity with either the simultaneous or sequential administration of paclitaxel and carboplatin. It appears that paclitaxel followed by carboplatin is more cytotoxic. The pharmacokinetics of either agent is not affected by this sequence of administration.
    Carvedilol: (Moderate) Increased concentrations of paclitaxel may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and paclitaxel is a P-gp substrate.
    Celecoxib: (Major) Due to the thrombocytopenic effects of paclitaxel, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Ceritinib: (Moderate) Monitor for an increase in paclitaxel-related adverse reactions if coadministration with ceritinib is necessary. Ceritinib is a CYP3A4 inhibitor and paclitaxel is metabolized by CYP3A4. In vitro, coadministration with both strong and moderate CYP3A4 inhibitors increased paclitaxel exposure; however, the concentrations used exceeded those found in vivo following normal therapeutic doses. The pharmacokinetics of paclitaxel may also be altered in vivo as a result of interactions with CYP3A4 inhibitors.
    Ciclesonide: (Moderate) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. In addition, Cabazitaxel is a CYP3A4 substrate and concomitant use with strong CYP3A4 inducers such as dexamethasone may lead to reduced concentrations of cabazitaxel. Avoid concomitant use of cabazitaxel and strong CYP3A4 inducers. Consider alternative therapies with low enzyme induction potential.
    Cisplatin: (Moderate) A sequence-related interaction occurs when paclitaxel is given in combination with cisplatin. When cisplatin is administered prior to paclitaxel, the clearance of paclitaxel is decreased up to 33% and increases the severity of myelosuppression. It is recommended that paclitaxel administration precede cisplatin when these agents are given in combination. Additive neurotoxicity may occur with concurrent paclitaxel/cisplatin therapy. When paclitaxel is administered following previous cisplatin therapy, paclitaxel induces the onset of or worsens existing peripheral neuropathy. Higher paclitaxel doses have been associated with more severe neurotoxic effects in patients previously treated with cisplatin.
    Clarithromycin: (Minor) Paclitaxel is partially metabolized by CYP3A4. The systemic clearance of paclitaxel may be decreased if coadministered with clarithromycin, an inhibitor of CYP3A4.
    Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Cobicistat: (Minor) Plasma concentrations of paclitaxel may be elevated when administered concurrently with cobicistat. Cobicistat is a CYP3A4 and P-glycoprotein (P-gp) inhibitor, while paclitaxel is a CYP3A4 and P-gp substrate. Some experts state that pharmacokinetic interactions between paclitaxel and some CYP3A4 inhibitors do not appear to be clinically significant. However, combining the drugs in clinical practice may require close monitoring to ensure proper therapeutic responses.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Minor) Plasma concentrations of paclitaxel may be elevated when administered concurrently with cobicistat. Cobicistat is a CYP3A4 and P-glycoprotein (P-gp) inhibitor, while paclitaxel is a CYP3A4 and P-gp substrate. Some experts state that pharmacokinetic interactions between paclitaxel and some CYP3A4 inhibitors do not appear to be clinically significant. However, combining the drugs in clinical practice may require close monitoring to ensure proper therapeutic responses.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Minor) Plasma concentrations of paclitaxel may be elevated when administered concurrently with cobicistat. Cobicistat is a CYP3A4 and P-glycoprotein (P-gp) inhibitor, while paclitaxel is a CYP3A4 and P-gp substrate. Some experts state that pharmacokinetic interactions between paclitaxel and some CYP3A4 inhibitors do not appear to be clinically significant. However, combining the drugs in clinical practice may require close monitoring to ensure proper therapeutic responses.
    Conivaptan: (Major) Avoid coadministration of conivaptan, a CYP3A4/P-glycoprotein (P-gp) inhibitor and paclitaxel, a CYP3A4/P-gp substrate. Concurrent use may result in elevated paclitaxel serum concentrations. According to the manufacturer of conivaptan, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as paclitaxel, should be avoided. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with paclitaxel. Treatment with paclitaxel may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Corticosteroids: (Moderate) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. In addition, Cabazitaxel is a CYP3A4 substrate and concomitant use with strong CYP3A4 inducers such as dexamethasone may lead to reduced concentrations of cabazitaxel. Avoid concomitant use of cabazitaxel and strong CYP3A4 inducers. Consider alternative therapies with low enzyme induction potential.
    Corticotropin, ACTH: (Moderate) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. In addition, Cabazitaxel is a CYP3A4 substrate and concomitant use with strong CYP3A4 inducers such as dexamethasone may lead to reduced concentrations of cabazitaxel. Avoid concomitant use of cabazitaxel and strong CYP3A4 inducers. Consider alternative therapies with low enzyme induction potential.
    Cortisone: (Moderate) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. In addition, Cabazitaxel is a CYP3A4 substrate and concomitant use with strong CYP3A4 inducers such as dexamethasone may lead to reduced concentrations of cabazitaxel. Avoid concomitant use of cabazitaxel and strong CYP3A4 inducers. Consider alternative therapies with low enzyme induction potential.
    Crizotinib: (Moderate) Monitor for an increase in paclitaxel-related adverse reactions if coadministration with crizotinib is necessary. Paclitaxel is a CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor.
    Cyclophosphamide: (Minor) Use caution if cyclophosphamide is used concomitantly with paclitaxel; increased hemotoxicity has been reported when cyclophosphamide was administered after paclitaxel infusion.
    Cyclosporine: (Major) In vitro, the metabolism of paclitaxel is inhibited by cyclosporine, but cyclosporine concentrations used exceeded those found in vivo following normal therapeutic doses used in transplantation. Additionally, cyclosporine blocks the multidrug resistance (MDR) P-glycoprotein, which is a mechanism of resistance to naturally occurring (non-synthetic) chemotherapy agents. These agents could enhance paclitaxel's activity and toxicity. Paclitaxel has poor oral availability due to its high affinity for P-glycoprotein present in high levels in the GI tract. In clinical studies, oral paclitaxel has been given in combination with cyclosporine to improve the bioavailability of paclitaxel, due to cyclosporine-induced blockade of P-glycoprotein located in the in GI tract. The bioavailability of oral paclitaxel was 8-fold higher when given in combination with cyclosporine than after oral paclitaxel alone. Therapeutic concentrations were achieved within 7.4 hours, comparable to an equivalent IV dose.
    Dabigatran: (Moderate) Due to the thrombocytopenic effects of taxanes, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Daclatasvir: (Moderate) Systemic exposure of paclitaxel, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of paclitaxel; monitor patients for potential adverse effects.
    Dalteparin: (Moderate) Due to the thrombocytopenic effects of taxanes, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Danaparoid: (Moderate) Due to the thrombocytopenic effects of taxanes, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Darunavir; Cobicistat: (Minor) Plasma concentrations of paclitaxel may be elevated when administered concurrently with cobicistat. Cobicistat is a CYP3A4 and P-glycoprotein (P-gp) inhibitor, while paclitaxel is a CYP3A4 and P-gp substrate. Some experts state that pharmacokinetic interactions between paclitaxel and some CYP3A4 inhibitors do not appear to be clinically significant. However, combining the drugs in clinical practice may require close monitoring to ensure proper therapeutic responses.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Minor) Concurrent administration of paclitaxel (or nanoparticle albumin-bound paclitaxel) with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in increased paclitaxel plasma concentrations and risk for toxicity. Caution and close monitoring are advised if these drugs are administered together. Paclitaxel is metabolized by the hepatic isoenzymes CYP2C8 and CYP3A4; ritonavir is a potent CYP3A4 inhibitor. In addition, paclitaxel is a substrate of the drug transporter P-glycoprotein (P-gp), and ritonavir also inhibits P-gp. Paritaprevir also inhibits P-gp. (Minor) Due to ritonavir's potential inhibitory effects on various hepatic isoenzymes, numerous drug interactions may occur with ritonavir. Close monitoring of serum drug concentrations and/or therapeutic and adverse effects is required when paclitaxel (a CYP2C8 and CYP3A4 substrate) is coadministered with ritonavir (a CYP3A4 inhibitor). In addition, paclitaxel is a substrate of the drug transporter P-glycoprotein (P-gp), and ritonavir also inhibits P-gp.
    Dasatinib: (Moderate) Dasatinib is a time-dependent, weak inhibitor of CYP3A4. Therefore, caution is warranted when drugs that are metabolized by this enzyme like paclitaxel are administered concurrently with dasatinib as increased adverse reactions may occur.
    Deferasirox: (Moderate) Deferasirox inhibits CYP2C8. Paclitaxel is a substrate for CYP2C8. The concomitant administration of deferasirox and the CYP2C8 substrate repaglinide (single dose of 0.5 mg) resulted in an increase in repaglinide Cmax by 62% and an increase in AUC 2.3-fold. Although specific drug interaction studies of deferasirox and paclitaxel are not available, a similar interaction may occur. The dose of paclitaxel may need to be decreased if coadministered with deferasirox.
    Deflazacort: (Moderate) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. In addition, Cabazitaxel is a CYP3A4 substrate and concomitant use with strong CYP3A4 inducers such as dexamethasone may lead to reduced concentrations of cabazitaxel. Avoid concomitant use of cabazitaxel and strong CYP3A4 inducers. Consider alternative therapies with low enzyme induction potential.
    Delavirdine: (Minor) Delavirdine is a potent inhibitor of the CYP3A4 and increased plasma concentrations of drugs extensively metabolized by this enzyme, such as paclitaxel, should be expected with concurrent use of delavirdine.
    Desirudin: (Moderate) Due to the thrombocytopenic effects of taxanes, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Dexamethasone: (Moderate) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. In addition, Cabazitaxel is a CYP3A4 substrate and concomitant use with strong CYP3A4 inducers such as dexamethasone may lead to reduced concentrations of cabazitaxel. Avoid concomitant use of cabazitaxel and strong CYP3A4 inducers. Consider alternative therapies with low enzyme induction potential.
    Diclofenac: (Major) Due to the thrombocytopenic effects of paclitaxel, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Diclofenac; Misoprostol: (Major) Due to the thrombocytopenic effects of paclitaxel, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Diflunisal: (Major) Due to the thrombocytopenic effects of paclitaxel, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Digoxin: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy.
    Diltiazem: (Minor) Additive bradycardia may occur in patients receiving paclitaxel and other drugs known to cause bradycardia, such as certain calcium-channel blockers, such as diltiazem. These patients should be monitored carefully. Paclitaxel is metabolized by hepatic cytochrome P450 (CYP) isoenzymes 2C8 and 3A4. Paclitaxel metabolism may be inhibited by diltiazem, a moderate CYP3A4 inhibitor. Combining the drugs in clinical practice may require close monitoring to ensure proper therapeutic responses; monitor patients for symptoms and signs of toxicity, such as myelosuppression and peripheral neuropathy.
    Diphenhydramine; Ibuprofen: (Major) Due to the thrombocytopenic effects of paclitaxel, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Diphenhydramine; Naproxen: (Major) Due to the thrombocytopenic effects of paclitaxel, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Disulfiram: (Major) Some formulations of paclitaxel injection contain a high level of ethanol. Administration to patients receiving or who have recently received disulfiram may result in disulfiram-like reactions. A disulfiram reaction would not be expected to occur with non-ethanol containing formulations.
    Doxorubicin: (Moderate) Use paclitaxel and doxorubicin together with caution. Administer doxorubicin prior to paclitaxel; the AUC values of doxorubicin and its metabolites may increase if paclitaxel is given first. Paclitaxel and doxorubicin are both CYP3A4 substrates.
    Dronedarone: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A; dronedarone also inhibits P-gp. Paclitaxel is a substrate for CYP3A4 and P-gp. The concomitant administration of dronedarone with CYP3A4 and P-gp substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Echinacea: (Major) Echinacea possesses immunostimulatory activity and may theoretically reduce the response to drugs that alter immune system activity like antineoplastic drugs. Although documentation is lacking, coadministration of echinacea with immunosuppressants is not recommended by some resources.
    Edoxaban: (Moderate) Due to the thrombocytopenic effects of taxanes, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Efavirenz: (Moderate) Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as paclitaxel.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as paclitaxel.
    Elbasvir; Grazoprevir: (Moderate) Administering paclitaxel with elbasvir; grazoprevir may result in elevated paclitaxel plasma concentrations. Paclitaxel is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
    Eliglustat: (Major) Coadministration of paclitaxel (including nanoparticle albumin-bound paclitaxel) and eliglustat may result in increased plasma concentrations of paclitaxel. If coadministration is necessary, use caution and monitor closely. Paclitaxel is a P-glycoprotein (P-gp) substrate; eliglustat is a P-gp inhibitor.
    Enoxaparin: (Moderate) Due to the thrombocytopenic effects of taxanes, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Enzalutamide: (Moderate) Monitor for decreased efficacy of paclitaxel if coadministration with enzalutamide is necessary. Paclitaxel is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer.
    Epirubicin: (Major) When paclitaxel was administered prior to epirubicin, patients experienced a lower neutrophil and platelet nadir and a statistically significant slower neutrophil recovery as compared to patients given epirubicin followed by paclitaxel. The AUC of epirubicin was higher in the patients given paclitaxel followed by epirubicin. Epirubicin should be given prior to paclitaxel in clinical practice.
    Erythromycin: (Minor) Paclitaxel is metabolized by hepatic cytochrome P450 (CYP) isoenzymes 2C8 and 3A4. Erythromycin is a CYP3A4 inhibitor. In vitro, the metabolism of paclitaxel is inhibited by various agents (e.g., ketoconazole, verapamil, diazepam, quinidine, dexamethasone, tenopiside, etoposide, and vincristine) but concentrations used exceeded those found in vivo following normal therapeutic doses. Closely monitor patients for toxicity when administering paclitaxel with any of these agents.
    Erythromycin; Sulfisoxazole: (Minor) Paclitaxel is metabolized by hepatic cytochrome P450 (CYP) isoenzymes 2C8 and 3A4. Erythromycin is a CYP3A4 inhibitor. In vitro, the metabolism of paclitaxel is inhibited by various agents (e.g., ketoconazole, verapamil, diazepam, quinidine, dexamethasone, tenopiside, etoposide, and vincristine) but concentrations used exceeded those found in vivo following normal therapeutic doses. Closely monitor patients for toxicity when administering paclitaxel with any of these agents.
    Esomeprazole; Naproxen: (Major) Due to the thrombocytopenic effects of paclitaxel, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Etodolac: (Major) Due to the thrombocytopenic effects of paclitaxel, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Etravirine: (Moderate) Etravirine is a CYP3A4 inducer/substrate and a P-glycoprotein (PGP) inhibitor and paclitaxel is a CYP3A4 and PGP substrate. Caution is warranted if these drugs are coadministered.
    Famotidine; Ibuprofen: (Major) Due to the thrombocytopenic effects of paclitaxel, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Febuxostat: (Major) Coadministration of febuxostat and cytotoxic antineoplastic agents has not been studied. After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and calculi.
    Fenofibrate: (Minor) Paclitaxel is a substrate of CYP2C8, and fenofibrate is a CYP2C8 inhibitor. If coadministration is necessary, use caution and monitor for increased paclitaxel side effects, including myelosuppression and peripheral neuropathy.
    Fenofibric Acid: (Minor) Paclitaxel is a substrate of CYP2C8, and fenofibric acid is a weak CYP2C8 inhibitor. If coadministration is necessary, use caution and monitor for increased paclitaxel side effects, including myelosuppression and peripheral neuropathy.
    Fenoprofen: (Major) Due to the thrombocytopenic effects of paclitaxel, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Filgrastim, G-CSF: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert their toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.
    Fluconazole: (Minor) Paclitaxel is metabolized by hepatic cytochrome P450 isoenzymes 2C8 and 3A4. The metabolism of paclitaxel may be inhibited by drugs that inhibit these enzymes, including fluconazole. Closely monitor patients for toxicity when administering paclitaxel with fluconazole.
    Flucytosine: (Minor) Flucytosine can cause significant hematologic toxicity. It should be used cautiously with all antineoplastic agents, especially those that cause bone marrow depression.
    Fludrocortisone: (Moderate) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. In addition, Cabazitaxel is a CYP3A4 substrate and concomitant use with strong CYP3A4 inducers such as dexamethasone may lead to reduced concentrations of cabazitaxel. Avoid concomitant use of cabazitaxel and strong CYP3A4 inducers. Consider alternative therapies with low enzyme induction potential.
    Flunisolide: (Moderate) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. In addition, Cabazitaxel is a CYP3A4 substrate and concomitant use with strong CYP3A4 inducers such as dexamethasone may lead to reduced concentrations of cabazitaxel. Avoid concomitant use of cabazitaxel and strong CYP3A4 inducers. Consider alternative therapies with low enzyme induction potential.
    Fluoxetine: (Minor) Paciltaxel is metabolized by cytochrome P450 3A enzymes. Drugs that inhibit the CYP3A enzymes, such as fluoxetine, can significantly reduce the metabolism of paclitaxel.
    Fluoxetine; Olanzapine: (Minor) Paciltaxel is metabolized by cytochrome P450 3A enzymes. Drugs that inhibit the CYP3A enzymes, such as fluoxetine, can significantly reduce the metabolism of paclitaxel.
    Flurbiprofen: (Major) Due to the thrombocytopenic effects of paclitaxel, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Fluticasone: (Moderate) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. In addition, Cabazitaxel is a CYP3A4 substrate and concomitant use with strong CYP3A4 inducers such as dexamethasone may lead to reduced concentrations of cabazitaxel. Avoid concomitant use of cabazitaxel and strong CYP3A4 inducers. Consider alternative therapies with low enzyme induction potential.
    Fluticasone; Salmeterol: (Moderate) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. In addition, Cabazitaxel is a CYP3A4 substrate and concomitant use with strong CYP3A4 inducers such as dexamethasone may lead to reduced concentrations of cabazitaxel. Avoid concomitant use of cabazitaxel and strong CYP3A4 inducers. Consider alternative therapies with low enzyme induction potential.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. In addition, Cabazitaxel is a CYP3A4 substrate and concomitant use with strong CYP3A4 inducers such as dexamethasone may lead to reduced concentrations of cabazitaxel. Avoid concomitant use of cabazitaxel and strong CYP3A4 inducers. Consider alternative therapies with low enzyme induction potential.
    Fluticasone; Vilanterol: (Moderate) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. In addition, Cabazitaxel is a CYP3A4 substrate and concomitant use with strong CYP3A4 inducers such as dexamethasone may lead to reduced concentrations of cabazitaxel. Avoid concomitant use of cabazitaxel and strong CYP3A4 inducers. Consider alternative therapies with low enzyme induction potential.
    Fluvoxamine: (Minor) Paclitaxel is metabolized by hepatic cytochrome P450 isoenzymes 2C8 and 3A4. Inhibitors of these enzymes, such as fluvoxamine, may increase the serum concentration of paclitaxel. Closely monitor patients for toxicity when administering paclitaxel with fluvoxamine.
    Fondaparinux: (Moderate) Due to the thrombocytopenic effects of taxanes, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Formoterol; Mometasone: (Moderate) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. In addition, Cabazitaxel is a CYP3A4 substrate and concomitant use with strong CYP3A4 inducers such as dexamethasone may lead to reduced concentrations of cabazitaxel. Avoid concomitant use of cabazitaxel and strong CYP3A4 inducers. Consider alternative therapies with low enzyme induction potential.
    Fosamprenavir: (Minor) Caution is advised when administering paclitaxel with fosamprenavir, as concurrent use may alter the plasma concentrations of paclitaxel. Paclitaxel is a substrate for the hepatic isoenzyme CYP3A4 and the drug transporter P-glycoprotein (P-gp). Amprenavir, the active metabolite of fosamprenavir, is an inducer of P-gp and a potent inhibitor and moderate inducer of CYP3A4.
    Gadobenate Dimeglumine: (Moderate) Gadobenate dimeglumine is a substrate for the canalicular multi-specific organic anion transporter (MOAT). Use with other MOAT substrates, such as paclitaxel, may result in prolonged systemic exposure of the coadministered drug. Caution is advised if these drugs are used together.
    Gemfibrozil: (Major) Paclitaxel is a substrate of CYP2C8 and gemfibrozil is a potent CYP2C8 inhibitor. Paclitaxel concentrations are expected to increase with the co-use of gemfibrozil. Consider alternative therapy to gemfibrozil. If coadministration is necessary, use caution and monitor for increased paclitaxel side effects, including myelosuppression and peripheral neuropathy.
    Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with the coadministration of glecaprevir and paclitaxel as coadministration may increase serum concentrations of paclitaxel and increase the risk of adverse effects. Paclitaxel is a substrate of P-glycoprotein (P-gp); glecaprevir is a P-gp inhibitor. (Moderate) Caution is advised with the coadministration of pibrentasvir and paclitaxel as coadministration may increase serum concentrations of paclitaxel and increase the risk of adverse effects. Paclitaxel is a substrate of P-glycoprotein (P-gp); pibrentasvir is a P-gp inhibitor.
    Heparin: (Moderate) Due to the thrombocytopenic effects of taxanes, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Hydantoins: (Minor) Paclitaxel is metabolized by hepatic cytochrome P450 isoenzymes 2C8 and 3A4. Potential interactions may occur in vivo with any agent that induces CYP2C8 or CYP3A4 isoenzymes including hydantoins. This combination could potentially decrease chemotherapy efficacy.
    Hydrocodone; Ibuprofen: (Major) Due to the thrombocytopenic effects of paclitaxel, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Hydrocortisone: (Moderate) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. In addition, Cabazitaxel is a CYP3A4 substrate and concomitant use with strong CYP3A4 inducers such as dexamethasone may lead to reduced concentrations of cabazitaxel. Avoid concomitant use of cabazitaxel and strong CYP3A4 inducers. Consider alternative therapies with low enzyme induction potential.
    Ibuprofen: (Major) Due to the thrombocytopenic effects of paclitaxel, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Ibuprofen; Oxycodone: (Major) Due to the thrombocytopenic effects of paclitaxel, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Ibuprofen; Pseudoephedrine: (Major) Due to the thrombocytopenic effects of paclitaxel, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with paclitaxel, a CYP3A substrate, as paclitaxel toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
    Imatinib: (Minor) Imatinib is a potent inhibitor of cytochrome P450 3A4 and may increase concentrations of other drugs metabolized by this enzyme. Caution is recommended when administering imatinib with other CYP3A4 substrates including paclitaxel.
    Indinavir: (Minor) Indinavir inhibits cytochrome P450 3A4. Although specific interactions have not been studied, Indinavir may reduce the metabolism of CYP3A4 substrates, such as paclitaxel, and caution is warranted with coadministration.
    Indomethacin: (Major) Due to the thrombocytopenic effects of paclitaxel, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Interferon Alfa-2a: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Interferon Alfa-2b: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Interferon Alfa-2b; Ribavirin: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Interferon Alfacon-1: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Interferon Alfa-n3: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Intranasal Influenza Vaccine: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with paclitaxel may result in increased serum concentrations of paclitaxel. Paclitaxel is a substrate of the hepatic isoenzyme CYP3A4 and drug transporter P-glycoprotein (P-gp); isavuconazole, the active moiety of isavuconazonium, is an inhibitor of CYP3A4 and P-gp. Caution and close monitoring are advised if these drugs are used together.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Minor) Paclitaxel is metabolized by hepatic cytochrome P450 isoenzymes 2C8 and 3A4. Closely monitor patients for possibly decreased efficacy when administering paclitaxel with any agent that induces CYP2C8 or CYP3A4 isoenzymes, such as rifampin.
    Isoniazid, INH; Rifampin: (Minor) Paclitaxel is metabolized by hepatic cytochrome P450 isoenzymes 2C8 and 3A4. Closely monitor patients for possibly decreased efficacy when administering paclitaxel with any agent that induces CYP2C8 or CYP3A4 isoenzymes, such as rifampin.
    Itraconazole: (Minor) Due to itraconazole-induced inhibition of cytochrome P450 3A4, interactions are possible with agents that are substrates of this enzyme including paclitaxel.
    Ivacaftor: (Moderate) Use caution when administering ivacaftor and paclitaxel concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (Pgp). Co-administration of ivacaftor with CYP3A and Pgp substrates, such as paclitaxel, can increase paclitaxel exposure leading to increased or prolonged therapeutic effects and adverse events.
    Ixabepilone: (Minor) Ixabepilone is a weak inhibitor of P-glycoprotein (Pgp). Paclitaxel is a Pgp substrate, and concomitant use of ixabepilone with a Pgp substrate may cause an increase in paclitaxel concentrations. Use caution if ixabepilone is coadministered with a Pgp substrate.
    Ketoconazole: (Minor) Paclitaxel is metabolized by hepatic cytochrome P450 isoenzymes 2C8 and 3A4. The metabolism of paclitaxel is inhibited by inhibitors of CYP3A4, such as ketoconazole. Closely monitor patients for toxicity when administering paclitaxel with ketoconazole.
    Ketoprofen: (Major) Due to the thrombocytopenic effects of paclitaxel, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Ketorolac: (Major) Due to the thrombocytopenic effects of paclitaxel, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Lansoprazole; Naproxen: (Major) Due to the thrombocytopenic effects of paclitaxel, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Lapatinib: (Moderate) In vitro, lapatinib, at clinically relevant concentrations, inhibits CYP3A4 and CYP2C8. Also, lapatinib is a substrate and inhibitor of the efflux transporter P-glycoprotein (Pgp, ABCB1). Paclitaxel is a CYP3A4 substrate, a CYP2C8 substrate, and a P-glycoprotein substrate. As increased paclitaxel concentrations are likely, cautious coadministration is recommended, and consider a paclitaxel dose reduction.
    Ledipasvir; Sofosbuvir: (Minor) Caution and close monitoring of paclitaxel-associated adverse reactions is advised with concomitant administration of ledipasvir. Paclitaxel is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor. Taking these drugs together may increase paclitaxel plasma concentrations.
    Lepirudin: (Moderate) Due to the thrombocytopenic effects of taxanes, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Live Vaccines: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Lopinavir; Ritonavir: (Minor) Due to ritonavir's potential inhibitory effects on various hepatic isoenzymes, numerous drug interactions may occur with ritonavir. Close monitoring of serum drug concentrations and/or therapeutic and adverse effects is required when paclitaxel (a CYP2C8 and CYP3A4 substrate) is coadministered with ritonavir (a CYP3A4 inhibitor). In addition, paclitaxel is a substrate of the drug transporter P-glycoprotein (P-gp), and ritonavir also inhibits P-gp.
    Lumacaftor; Ivacaftor: (Major) Lumacaftor; ivacaftor may alter the therapeutic effects of paclitaxel; caution and close monitoring are advised if these drugs are used together. The paclitaxel dosage may need to be adjusted. Paclitaxel is metabolized by CYP3A4 (and CYP2C8) and is a substrate of the P-glycoprotein (P-gp) efflux transporter. Lumacaftor is a strong CYP3A inducer; in vitro data also suggest lumacaftor; ivacaftor may induce and/or inhibit P-gp. Although induction of paclitaxel through the CYP3A pathway may lead to decreased drug efficacy, the net effect of lumacaftor; ivacaftor on P-gp transport is not clear. Monitor the patient for chemotherapeutic efficacy and adverse effects. In a study designed to determine the maximum tolerated dose of paclitaxel, patients receiving concomitant enzyme-inducing anticonvulsants (e.g., phenytoin, carbamazepine, phenobarbital) tolerated significantly higher doses of paclitaxel as compared to those who were not. Although no prospectively validated dosage adjustment regimen is available, this study suggested a possible need to increase the dose of paclitaxel as much as 50% in patients receiving concurrent enzyme-inducing anticonvulsant therapy. Of note, patients receiving enzyme-inducing anticonvulsants experienced a dose-limiting toxicity of central neurotoxicity while those not receiving anticonvulsants experienced dose-limiting toxicities of myelosuppression, GI toxicity, and fatigue.
    Lumacaftor; Ivacaftor: (Moderate) Use caution when administering ivacaftor and paclitaxel concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (Pgp). Co-administration of ivacaftor with CYP3A and Pgp substrates, such as paclitaxel, can increase paclitaxel exposure leading to increased or prolonged therapeutic effects and adverse events.
    Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Measles/Mumps/Rubella Vaccines, MMR: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Meclofenamate Sodium: (Major) Due to the thrombocytopenic effects of paclitaxel, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Mefenamic Acid: (Major) Due to the thrombocytopenic effects of paclitaxel, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Meloxicam: (Major) Due to the thrombocytopenic effects of paclitaxel, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Methylprednisolone: (Moderate) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. In addition, Cabazitaxel is a CYP3A4 substrate and concomitant use with strong CYP3A4 inducers such as dexamethasone may lead to reduced concentrations of cabazitaxel. Avoid concomitant use of cabazitaxel and strong CYP3A4 inducers. Consider alternative therapies with low enzyme induction potential.
    Metronidazole: (Major) Medications with significant alcohol content should not be ingested during therapy with metronidazole and should be avoided for 3 days after therapy is discontinued. Some formulations of paclitaxel contain a high level of ethanol. Administration to patients receiving or who have recently received metronidazole may result in disulfiram-like reactions. A disulfiram reaction would not be expected to occur with non-ethanol containing formulations.
    Mitotane: (Major) Concomitant use of mitotane with paclitaxel should be undertaken with caution as it could result in decreased plasma concentrations of paclitaxel, leading to reduced efficacy. Mitotane is a strong CYP3A4 inducer and paclitaxel is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of paclitaxel.
    Mometasone: (Moderate) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. In addition, Cabazitaxel is a CYP3A4 substrate and concomitant use with strong CYP3A4 inducers such as dexamethasone may lead to reduced concentrations of cabazitaxel. Avoid concomitant use of cabazitaxel and strong CYP3A4 inducers. Consider alternative therapies with low enzyme induction potential.
    Montelukast: (Minor) Montelukast potently inhibits CYP2C8 and is expected to decrease the metabolism of paclitaxel, a CYP2C8 substrate.
    Nabumetone: (Major) Due to the thrombocytopenic effects of paclitaxel, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Naproxen: (Major) Due to the thrombocytopenic effects of paclitaxel, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Naproxen; Pseudoephedrine: (Major) Due to the thrombocytopenic effects of paclitaxel, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Naproxen; Sumatriptan: (Major) Due to the thrombocytopenic effects of paclitaxel, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Nefazodone: (Minor) Paclitaxel is metabolized by hepatic cytochrome P450 isoenzymes 2C8 and 3A4. Inhibitors of these enzymes, such as nefazodone, may cause increased serum concentration and side effects of paclitaxel. Closely monitor patients for toxicity when administering paclitaxel with any of these agents.
    Nelfinavir: (Minor) Nelfinavir may inhibit the metabolism of other substrates of cytochrome P450 3A4 such as paclitaxel.
    Netupitant; Palonosetron: (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4, such as paclitaxel. The plasma concentrations of CYP3A4 substrates can increase when co-administered with netupitant. The inhibitory effect on CYP3A4 can last for multiple days. If coadministration is necessary, use caution and monitor for chemotherapeutic related adverse reactions.
    Nevirapine: (Minor) Metabolism of nevirapine to hydroxylated metabolites occurs primarily via the cytochrome P450 3A family of hepatic enzymes. Nevirapine is an inducer of the cytochrome P4503A enzyme. Concomitant administration of nevirapine with drugs that are extensively metabolized by this enzyme, such as paclitaxel, may require dosage adjustments.
    Nicardipine: (Minor) Paclitaxel is a substrate of CYP2C8 and 3A4; in vitro, nicardipine is a moderate inhibitor of both CYP2C8 and 3A4. If coadministration is necessary, use caution and monitor for increased paclitaxel side effects, including myelosuppression and peripheral neuropathy.
    Nilotinib: (Major) Concomitant use of nilotinib, a substrate and moderate inhibitor of CYP3A4 and P-glycoprotein (P-gp) and an inducer and inhibitor of CYP2C8, and paclitaxel, a CYP3A4, Pgp, and CYP28C substrate with a narrow therapeutic range, may result in altered paclitaxel levels. In vivo, nilotinib inhibited CYP2C8-mediated metabolism of paclitaxel. If these agents are used together, monitor these patients closely for paclitaxel toxicity; a paclitaxel dose adjustment may be necessary.
    Nonsteroidal antiinflammatory drugs: (Major) Due to the thrombocytopenic effects of paclitaxel, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Ombitasvir; Paritaprevir; Ritonavir: (Minor) Concurrent administration of paclitaxel (or nanoparticle albumin-bound paclitaxel) with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in increased paclitaxel plasma concentrations and risk for toxicity. Caution and close monitoring are advised if these drugs are administered together. Paclitaxel is metabolized by the hepatic isoenzymes CYP2C8 and CYP3A4; ritonavir is a potent CYP3A4 inhibitor. In addition, paclitaxel is a substrate of the drug transporter P-glycoprotein (P-gp), and ritonavir also inhibits P-gp. Paritaprevir also inhibits P-gp. (Minor) Due to ritonavir's potential inhibitory effects on various hepatic isoenzymes, numerous drug interactions may occur with ritonavir. Close monitoring of serum drug concentrations and/or therapeutic and adverse effects is required when paclitaxel (a CYP2C8 and CYP3A4 substrate) is coadministered with ritonavir (a CYP3A4 inhibitor). In addition, paclitaxel is a substrate of the drug transporter P-glycoprotein (P-gp), and ritonavir also inhibits P-gp.
    Oritavancin: (Moderate) Paclitaxel is metabolized by CYP3A4; oritavancin is a weak CYP3A4 inducer. Plasma concentrations and efficacy of paclitaxel may be reduced if these drugs are administered concurrently.
    Oxaprozin: (Major) Due to the thrombocytopenic effects of paclitaxel, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Pazopanib: (Moderate) Coadministration of pazopanib (800 mg by mouth once daily) and paclitaxel (80 mg/m2 IV once weekly) resulted in a mean increase of 26% and 31% in paclitaxel AUC and Cmax, respectively.
    Pegfilgrastim: (Major) Pegfilgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert their toxic effects against rapidly growing cells, pegfilgrastim should not be given 14 days before or for 24 hours after cytotoxic chemotherapy.
    Peginterferon Alfa-2a: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Peginterferon Alfa-2b: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Pentosan: (Moderate) Due to the thrombocytopenic effects of taxanes, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Piroxicam: (Major) Due to the thrombocytopenic effects of paclitaxel, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Platelet Inhibitors: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as docetaxel and paclitaxel.
    Posaconazole: (Moderate) Posaconazole and paclitaxel should be coadministered with caution due to an increased potential for adverse events. Posaconazole is a potent inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of paclitaxel. Further, both paclitaxel and posaconazole are substrates of the drug efflux protein, P-glycoprotein, which when administered together may increase the absorption or decrease the clearance of the other drug. This complex interaction may cause alterations in the plasma concentrations of both posaconazole and paclitaxel, ultimately resulting in an increased risk of adverse events.
    Prednisolone: (Moderate) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. In addition, Cabazitaxel is a CYP3A4 substrate and concomitant use with strong CYP3A4 inducers such as dexamethasone may lead to reduced concentrations of cabazitaxel. Avoid concomitant use of cabazitaxel and strong CYP3A4 inducers. Consider alternative therapies with low enzyme induction potential.
    Prednisone: (Moderate) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. In addition, Cabazitaxel is a CYP3A4 substrate and concomitant use with strong CYP3A4 inducers such as dexamethasone may lead to reduced concentrations of cabazitaxel. Avoid concomitant use of cabazitaxel and strong CYP3A4 inducers. Consider alternative therapies with low enzyme induction potential.
    Regorafenib: (Minor) Paclitaxel is a substrate of CYP2C8 and 3A4; in vitro, regorafenib is a mild inhibitor of CYP2C8 and 3A4. Monitor for increased paclitaxel side effects, including myelosuppression and peripheral neuropathy.
    Reteplase, r-PA: (Moderate) An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
    Ribociclib: (Moderate) Use caution if coadministration of ribociclib with paclitaxel is necessary, as the systemic exposure of paclitaxel may be increased resulting in increase in treatment-related adverse reactions. Ribociclib is a moderate CYP3A4 inhibitor. Paclitaxel is a substrate of CYP2C8 and CYP3A4.
    Ribociclib; Letrozole: (Moderate) Use caution if coadministration of ribociclib with paclitaxel is necessary, as the systemic exposure of paclitaxel may be increased resulting in increase in treatment-related adverse reactions. Ribociclib is a moderate CYP3A4 inhibitor. Paclitaxel is a substrate of CYP2C8 and CYP3A4.
    Rifabutin: (Minor) Paclitaxel is metabolized by hepatic cytochrome P450 isoenzymes 2C8 and 3A4. Potential interactions may occur in vivo with any agent that induces CYP2C8 or CYP3A4 isoenzymes including rifabutin.
    Rifampin: (Minor) Paclitaxel is metabolized by hepatic cytochrome P450 isoenzymes 2C8 and 3A4. Closely monitor patients for possibly decreased efficacy when administering paclitaxel with any agent that induces CYP2C8 or CYP3A4 isoenzymes, such as rifampin.
    Rifapentine: (Minor) Paclitaxel is metabolized by hepatic cytochrome P450 (CYP) isoenzymes 2C8 and 3A4. Potential interactions may occur in vivo with any agent that induces CYP2C8 or CYP3A4 isoenzymes including rifapentine. Closely monitor patients for possibly decreased efficacy when administering paclitaxel with any of these agents.
    Ritonavir: (Minor) Due to ritonavir's potential inhibitory effects on various hepatic isoenzymes, numerous drug interactions may occur with ritonavir. Close monitoring of serum drug concentrations and/or therapeutic and adverse effects is required when paclitaxel (a CYP2C8 and CYP3A4 substrate) is coadministered with ritonavir (a CYP3A4 inhibitor). In addition, paclitaxel is a substrate of the drug transporter P-glycoprotein (P-gp), and ritonavir also inhibits P-gp.
    Rivaroxaban: (Moderate) Due to the thrombocytopenic effects of taxanes, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Rofecoxib: (Major) Due to the thrombocytopenic effects of paclitaxel, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Rolapitant: (Moderate) Use caution if paclitaxel and rolapitant are used concurrently, and monitor for paclitaxel-related adverse effects. Paclitaxel is a P-glycoprotein (P-gp) substrate, where an increase in exposure may significantly increase adverse effects; rolapitant is a P-gp inhibitor. When rolapitant was administered with another P-gp substrate, digoxin, the day 1 Cmax and AUC were increased by 70% and 30%, respectively; the Cmax and AUC on day 8 were not studied.
    Rotavirus Vaccine: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Rubella Virus Vaccine Live: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Rufinamide: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as paclitaxel, may occur during concurrent use with rufinamide.
    Sapropterin: (Moderate) Caution is advised with the concomitant use of sapropterin and paclitaxel as coadministration may result in increased systemic exposure of paclitaxel. Paclitaxel is a substrate for the drug transporter P-glycoprotein (P-gp); in vitro data show that sapropterin may inhibit P-gp. If these drugs are used together, closely monitor for increased side effects of paclitaxel.
    Saquinavir: (Minor) Although saquinavir does not inhibit cytochrome-based metabolism to the same degree as ritonavir, saquinavir may cause elevated plasma concentrations of drugs which are substrates for CYP3A4 isoenzymes including paclitaxel. Patients should be monitored for toxicities associated with paclitaxel.
    Sargramostim, GM-CSF: (Major) Sargramostim induces the proliferation of hematopoietic progenitor cells, and, because antineoplastic agents exert their toxic effects against rapidly growing cells, sargramostim is contraindicated for use in patients during the 24 hours before or after cytotoxic chemotherapy.
    Simeprevir: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of paclitaxel, which is a CYP3A4 substrate. Monitor patients for adverse effects of paclitaxel, such as myelosuppression, myalgia/arthralgia, and peripheral neuropathy.
    Sipuleucel-T: (Major) Concomitant use of sipuleucel-T and antineoplastic agents should be avoided. Concurrent administration of antineoplastic agents with the leukapheresis procedure that occurs prior to sipuleucel-T infusion has not been studied. Sipuleucel-T stimulates the immune system and patients receiving antineoplastic agents may have a diminished response to sipuleucel-T. When appropriate, consider discontinuing or reducing the dose of antineoplastic agents prior to initiating therapy with sipuleucel-T.
    Smallpox Vaccine, Vaccinia Vaccine: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Plasma concentrations of paclitaxel, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with voxilaprevir, a P-gp inhibitor. Monitor patients for increased side effects if these drugs are administered concurrently.
    Streptokinase: (Moderate) An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
    Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Minor) Paclitaxel is a substrate of CYP2C8; in vitro, trimethoprim is a mild inhibitor of CYP2C8. If coadministration is necessary, use caution and monitor for increased paclitaxel side effects, including myelosuppression and peripheral neuropathy. This interaction may also be applicable to combination products containing trimethoprim, including sulfamethoxazole; trimethoprim (also known as SMX-TMP or cotrimoxazole).
    Sulindac: (Major) Due to the thrombocytopenic effects of paclitaxel, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Tbo-Filgrastim: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert their toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.
    Telaprevir: (Moderate) Close clinical monitoring is advised when administering paclitaxel with telaprevir due to an increased potential for paclitaxel-related adverse events. If paclitaxel dose adjustments are made, re-adjust the dose upon completion of telaprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of paclitaxel. Paclitaxel is a substrate of the drug efflux transporter P-glycoprotein (PGP) and of the hepatic isoenzyme CYP3A4; telaprevir is an inhibitor of both the efflux protein and the isoenzyme. Coadministration may result in elevated paclitaxel plasma concentrations.
    Telithromycin: (Moderate) Concentrations of paclitaxel may be increased with concomitant use of telithromycin. Paclitaxel is a CYP3A4 and P-glycoprotein (PGP) substrate and telithromycin is a strong CYP3A4 inhibitor and potential PGP inhibitor. Caution is warranted if these drugs are coadministered.
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and paclitaxel is necessary, as the systemic exposure of paclitaxel may be decreased resulting in reduced efficacy. If these drugs are used together, monitor patients for suboptimal efficacy of paclitaxel. Paclitaxel is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when co-administered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate.
    Temsirolimus: (Moderate) Use caution if coadministration of temsirolimus with paclitaxel is necessary, and monitor for an increase in paclitaxel-related adverse reactions. Temsirolimus is a P-glycoprotein (P-gp) inhibitor in vitro, and paclitaxel is a P-gp substrate. Pharmacokinetic data are not available for concomitant use of temsirolimus with P-gp substrates, but exposure to paclitaxel is likely to increase.
    Tenecteplase, TNK-tPA: (Moderate) An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
    Teriflunomide: (Moderate) Increased monitoring is recommended if teriflunomide is administered concurrently with CYP2C8 substrates, such as paclitaxel. In vivo studies demonstrated that teriflunomide is an inhibitor of CYP2C8. Coadministration may lead to increased exposure to CYP2C8 substrates; however, the clinical impact of this has not yet been determined. Monitor for increased adverse effects.
    Thalidomide: (Moderate) Thalidomide and other agents that cause peripheral neuropathy such as paclitaxel should be used cautiously due to the potential for additive effects.
    Thrombolytic Agents: (Moderate) An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
    Tinidazole: (Severe) Medicines with significant alcohol content, including Taxol injection, should be avoided during tinidazole therapy and for three days after stopping therapy. Taking these drugs concurrently may cause disulfiram-like reactions. A disulfiram reaction would not be expected to occur with non-ethanol containing formulations of paclitaxel.
    Tinzaparin: (Moderate) Due to the thrombocytopenic effects of taxanes, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Tolmetin: (Major) Due to the thrombocytopenic effects of paclitaxel, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Trametinib: (Minor) Paclitaxel is a substrate of CYP2C8; in vitro, trametinib is a mild inhibitor of CYP2C8. If coadministration is necessary, use caution and monitor for increased paclitaxel side effects, including myelosuppression and peripheral neuropathy.
    Trandolapril; Verapamil: (Minor) Additive bradycardia may occur in patients receiving paclitaxel and other drugs known to cause bradycardia, such as certain calcium-channel blockers. In vitro, the metabolism of paclitaxel via CYP3A4 was inhibited by verapamil, a moderate CYP3A4 inhibitor. However, the verapamil concentrations used exceeded those found in vivo following normal therapeutic doses. Verapamil also blocks the multidrug resistance (MDR) P-glycoprotein, which is a mechanism of resistance to naturally occurring (non-synthetic) chemotherapy agents. Verapamil could enhance paclitaxel's activity and toxicity through this mechanism as well. Small clinical trials have indicated that the coadministration of r-verapamil, an isomer of verapamil, and paclitaxel results in a significant decrease in paclitaxel clearance and an increase in paclitaxel toxicity. Some experts state that pharmacokinetic interactions between paclitaxel and verapamil do not appear to be clinically significant in vivo. However, combining the drugs in clinical practice may require close monitoring; monitor for paclitaxel induced side effects such as myelosuppression, infection, or peripheral neuropathy.
    Triamcinolone: (Moderate) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents. In addition, Cabazitaxel is a CYP3A4 substrate and concomitant use with strong CYP3A4 inducers such as dexamethasone may lead to reduced concentrations of cabazitaxel. Avoid concomitant use of cabazitaxel and strong CYP3A4 inducers. Consider alternative therapies with low enzyme induction potential.
    Trimethoprim: (Minor) Paclitaxel is a substrate of CYP2C8; in vitro, trimethoprim is a mild inhibitor of CYP2C8. If coadministration is necessary, use caution and monitor for increased paclitaxel side effects, including myelosuppression and peripheral neuropathy. This interaction may also be applicable to combination products containing trimethoprim, including sulfamethoxazole; trimethoprim (also known as SMX-TMP or cotrimoxazole).
    Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
    Typhoid Vaccine: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Ulipristal: (Minor) In vitro data indicate that ulipristal may be an inhibitor of P-glycoprotein (P-gp) at clinically relevant concentrations. Thus, co-administration of ulipristal and P-gp substrates such as paclitaxel may increase paclitaxel concentrations; use caution. With single doses of ulipristal for emergency contraception it is not clear this interaction will have clinical consequence. In the absence of clinical data, co-administration of ulipristal (when given daily) and P-gp substrates is not recommended.
    Urokinase: (Moderate) An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
    Valdecoxib: (Major) Due to the thrombocytopenic effects of paclitaxel, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Vandetanib: (Moderate) Use caution if coadministration of vandetanib with paclitaxel is necessary, due to a possible increase in paclitaxel-related adverse reactions. Paclitaxel is primarily metabolized by CYP2C8, but is also a substrate of P-glycoprotein (P-gp). Coadministration with vandetanib increased the Cmax and AUC of digoxin, another P-gp substrate, by 29% and 23%, respectively.
    Varicella-Zoster Virus Vaccine, Live: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Vemurafenib: (Major) Avoid the concomitant use of vemurafenib and paclitaxel; increased paclitaxel exposure may occur. If co-administration is unavoidable, consider a paclitaxel dose reduction and monitor patients carefully for signs and symptoms of paclitaxel toxicity (e.g., neutropenia, peripheral neuropathy). Vemurafenib is a substrate and weak inducer of CYP3A4 and a substrate and inhibitor of P-glycoprotein (P-gp); paclitaxel is a CYP3A4 and P-gp substrate with a narrow therapeutic index.
    Verapamil: (Minor) Additive bradycardia may occur in patients receiving paclitaxel and other drugs known to cause bradycardia, such as certain calcium-channel blockers. In vitro, the metabolism of paclitaxel via CYP3A4 was inhibited by verapamil, a moderate CYP3A4 inhibitor. However, the verapamil concentrations used exceeded those found in vivo following normal therapeutic doses. Verapamil also blocks the multidrug resistance (MDR) P-glycoprotein, which is a mechanism of resistance to naturally occurring (non-synthetic) chemotherapy agents. Verapamil could enhance paclitaxel's activity and toxicity through this mechanism as well. Small clinical trials have indicated that the coadministration of r-verapamil, an isomer of verapamil, and paclitaxel results in a significant decrease in paclitaxel clearance and an increase in paclitaxel toxicity. Some experts state that pharmacokinetic interactions between paclitaxel and verapamil do not appear to be clinically significant in vivo. However, combining the drugs in clinical practice may require close monitoring; monitor for paclitaxel induced side effects such as myelosuppression, infection, or peripheral neuropathy.
    Vinorelbine: (Moderate) Paclitaxel may produce additive peripheral neuropathies when given with vinorelbine. Patients previously treated with paclitaxel may also develop worsening peripheral neuropathies during treatment with vinorelbine. The risk of developing severe neuropathies increases with continued therapy.
    Voriconazole: (Minor) Voriconazole is an inhibitor of CYP3A4 isoenzyme. Drugs that are substrates for CYP3A4, such as paclitaxel, when combined with voriconazole, may theoretically have reduced metabolism, and therefore higher serum concentrations resulting in toxicity.
    Warfarin: (Moderate) Due to the thrombocytopenic effects of taxanes, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Yellow Fever Vaccine, Live: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Zafirlukast: (Moderate) Published data indicate zafirlukast inhibits CYP2C8 rather potently. Until further data are available to confirm the absence of drug interactions, CYP2C8 metabolized drugs, such as paclitaxel, may require closer monitoring when used in conjunction with zafirlukast.
    Zonisamide: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and paclitaxel is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.

    PREGNANCY AND LACTATION

    Pregnancy

    Paclitaxel is classified as FDA pregnancy risk category D and has been shown to produce toxic effects, including death, in fetal animal studies. There are no data concerning the effects in pregnant women. Therefore, paclitaxel should be avoided during pregnancy, and females of childbearing potential should be instructed to avoid becoming pregnant during paclitaxel therapy. If a women becomes pregnant while receiving this drug, she should be counseled of the potential harm to the fetus and the possibility of loss of pregnancy.

    It is unknown whether paclitaxel is excreted into human breast milk; paclitaxel was excreted into the breast milk of lactating rats at concentrations higher than those seen in plasma. Because of the potential for serious adverse reactions in nursing infants, patients should be instructed to discontinue breast-feeding during paclitaxel therapy.

    MECHANISM OF ACTION

    Mechanism of Action: Paclitaxel is an antimicrotubule chemotherapy agent. Although both bind to tubulin, the mechanism of action of paclitaxel differs from the vinca alkaloids. Paclitaxel promotes the assembly of microtubules and stabilizes their formation by inhibiting depolymerization. These microtubules are extremely stable and non-functional. In addition to functioning as components of the spindle apparatus within the cell, normal microtubules also maintain cell shape, assist in cellular motility, attachment, and intracellular transport, and modulate interactions with growth factors. The primary effect of paclitaxel is to inhibit the cell cycle during mitosis. Paclitaxel also inhibits the transition from G0 to S phase by disrupting tubulin in the cell membrane and/or direct inhibition of the disassembly of the cytoskeleton interrupting intracellular transport and communications.Microtubules are in equilibrium with tubulin heterodimers, the building blocks of microtubules, which consist of alpha- and beta-subunits. Paclitaxel reversibly binds to the N-terminal 31 amino acids of the beta-tubulin subunit of the microtubule rather than the tubulin subunits. The binding site of paclitaxel is different from the binding site of colchicine, epipodophyllotoxins, and vinblastine. Paclitaxel shifts the equilibrium towards microtubule assembly. Cells treated with paclitaxel show distinctive morphologic effects. Multiple bundles of microtubules are noted in paclitaxel treated cells. These bundles form during all phases of the cell cycle. Abnormal spindle asters are formed during mitosis. Paclitaxel also induces the expression of tumor necrosis factor-alpha and inhibits angiogenesis, although the exact roles of these actions in the cytotoxic effects of paclitaxel is not known. Paclitaxel acts as a radiation sensitizer due to its ability to stop the cell cycle during the premitotic G2 and mitotic phases, which are the most sensitive to the effects of radiation.Paclitaxel will induce varying intracellular effects depending upon the intracellular concentration and cell type. In vitro studies have shown a minimum concentration for cytotoxic effects. As the taxane concentration increases, the dose-response decreases. Prolonged exposure to taxanes is critical to cytotoxicity and is more important than increasing the drug concentration.Resistance to paclitaxel may develop via two different mechanisms. Alterations in the alpha- and beta-tubulin subunits can decrease the rate of polymerization into microtubules. When this occurs, administration of taxanes may actually normalize the rate of microtubule assembly. The second mechanism is through multidrug resistance (MDR), which results in decreased intracellular drug accumulation and retention. This mechanism of resistance primarily affects naturally occurring chemotherapy agents. MDR is due to overexpression of the mdr-1 gene, which encodes for a membrane P-glycoprotein (P-gp) that acts as a drug efflux pump. The degree of resistance is proportional to the amount of P-gp. There is not complete cross-resistance between the taxanes and anthracyclines; the exact role of MDR in paclitaxel resistance has not been determined.

    PHARMACOKINETICS

    Paclitaxel is given by IV administration; an oral formulation is undergoing clinical evaluation. Paclitaxel undergoes nonlinear pharmacokinetics due to saturable distribution and/or metabolism. Nonlinear pharmacokinetics are especially evident when administered over shorter periods (i.e., 3 hours) versus initial studies of 24-hour or longer infusions. Clinical implications of the nonlinear pharmacokinetics include disproportionate increases in AUC, peak plasma concentrations, and toxicity with dose increases, while dose reductions may lead to decreased cytotoxicity. Tissue sites are saturated at relatively low concentrations (those achieved with < 175 mg/m2 over 3 hours) and metabolism is saturated at higher doses (>= 175 mg/m2 over 3 hours). Peak tissue concentrations do not change significantly doses are increased from 135 to 250 mg/m2 administered as 3- or 24-hour infusions. The rate and extent of tissue saturation are greater with shorter infusion schedules. Neutropenia and, to a lesser extent, neurotoxicity have been associated with exposure of cells above a critical plasma concentration (> 0.05 micromolar/L) or increased duration of exposure and do not correlate to dosage.
     
    Paclitaxel is extensively protein bound (95—98%) to tissue proteins, especially tubulin. It is widely distributed throughout the body except for the brain and testes. Following a 3-hour infusion the alpha-half-life is 16 minutes, beta-half life is 140 minutes, and final elimination half-life is about 19 hours. Paclitaxel is metabolized primarily via cytochrome P-450 (CYP) isoenzymes 2C8 to 6-alpha-hydroxypaclitaxel, and to a lesser extent by 3A4 to minor metabolites 3'-p-hydroxypaclitaxel and 6-alpha,3'-para-dihydroxypaclitaxel. Alterations of metabolism may occur when drugs affecting the CYP system are given concurrently. In addition, sequence-dependent drug interactions have been documented with paclitaxel and other chemotherapy agents. Elimination is due to hepatic metabolism, biliary and fecal excretion, and tissue binding. Approximately 70—80% of the dose is eliminated in the feces within 1 week. Only 1—8% of paclitaxel is eliminated unchanged in the urine.
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, CYP2C8, P-gp
    Paclitaxel is a substrate of the cytochrome P450 (CYP) isoenzymes 2C8 and 3A4, and of the multidrug resistance protein, P-glycoprotein (P-gp).

    Oral Route

    Paclitaxel has poor oral availability due to its high affinity for P-glycoprotein, a multi-drug transport enzyme present in high levels in the GI tract. In clinical studies, oral paclitaxel has been given in combination with cyclosporine to improve the bioavailability, as cyclosporine blocks the activity of P-glycoprotein (see Drug Interactions).

    Other Route(s)

    Intraperitoneal route
    When given intraperitoneally (IP), exposure to the peritoneal cavity exceeds plasma exposure by about 1000-times. Paclitaxel is slowly cleared from the peritoneal cavity resulting in significant concentrations persisted within the peritoneal cavity for > 24—48 hours after a single IP administration. The prolonged terminal half-life when given IP is thought to be due to Cremophor El diluent used in the Taxol product. In one small trial, the terminal half life of IP paclitaxel was 28.7 +/- 8.72 hours versus a terminal IV half-life of 17 +/- 11.3 hours. The systemic bioavailability of IP paclitaxel in this study was 31.4 +/- 5.18%. Elimination from ascites fluid is also extremely slow with detectable levels still present after 18 days and an apparent disappearance half-life in ascites fluid of about 140 hours.