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  • CLASSES

    Taxanes

    BOXED WARNING

    Bone marrow suppression, neutropenia, thrombocytopenia

    Bone marrow suppression (e.g., neutropenia, thrombocytopenia) is the dose-limiting toxicity of nanoparticle albumin-bound (nab) paclitaxel. Nab-paclitaxel is contraindicated in patients with a baseline absolute neutrophil count (ANC) of < 1500 cells/mm3. Obtain a complete blood count (CBC) panel prior to starting a new cycle of nab-paclitaxel therapy on day 1 in all patients and prior to therapy on day 8 and 15 in patients with non-small cell lung cancer and pancreatic cancer. Monitor CBC panel frequently to evaluate patients for myelotoxicity. Do not resume a new cycle of therapy until the ANC is >= 1500 cells/mm3 and the platelet count is >= 100,000 cells/mm3. In patients who develop severe neutropenia or thrombocytopenia, hold nab-paclitaxel and reduce the dose of therapy for subsequent cycles.

    Ensure correct formulation selection

    An albumin form of paclitaxel may substantially affect a drugs functional properties relative to those of drug in solution. Ensure correct formulation selection and do not substitute nanoparticle albumin-bound paclitaxel for or with other paclitaxel formulations.

    DEA CLASS

    Rx

    DESCRIPTION

    Nanoparticle albumin-bound taxane; a microtubule inhibitor
    Approved as a single-agent for the treatment of metastatic breast cancer; approved in combination with carboplatin for the first-line treatment of locally advanced or metastatic non-small cell lung cancer; approved in combination with gemcitabine for the treatment of metastatic adenocarcinoma of the pancreas
    Severe myelosuppression has been reported; monitoring is necessary

    COMMON BRAND NAMES

    Abraxane

    HOW SUPPLIED

    Abraxane Intravenous Inj Pwd F/Susp: 100mg

    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.
    NOTE: Prior therapy should have included an anthracycline unless clinically contraindicated. 
    Intravenous dosage
    Adults

    260 mg/m2 IV over 30 minutes every 3 weeks. The primary endpoint of overall response rate (ORR) was significantly improved with nab-paclitaxel compared with standard paclitaxel (33% vs. 19%; p = 0.001) administered every 3 weeks in patients with metastatic breast cancer in a multicenter, randomized, phase III trial (n = 460). Additionally, the median time to progression (TTP) was significantly longer with nab-paclitaxel compared with standard paclitaxel (23 weeks vs. 16.9 weeks; hazard ratio = 0.75; p = 0.006). The TTP was significantly longer in patients treated with nab-paclitaxel as second line or greater (20.9 weeks vs. 16.1 weeks; p = 0.02) but not as first line (24 weeks vs. 19.7 weeks) therapy. The median overall survival (OS) time was not significantly improved with nab-paclitaxel compared with standard paclitaxel (65 weeks vs. 55.7 weeks); however, the median OS time was significantly improved in the subpopulation of patients treated with nab-paclitaxel as second line or greater (56.4 weeks vs. 46.7 weeks; p = 0.024).

    For the treatment of taxane-refractory metastatic breast cancer†.
    Intravenous dosage
    Adults

    100 mg/m2 IV over 30 minutes once per week for 3 weeks, then 1 week off, every 28 days. In a phase II, open-label non-randomized study of taxane-refractory metastatic breast cancer patients, 14% achieved a response and 12% had stable disease.

    For the treatment of previously untreated metastatic breast cancer†.
    Intravenous dosage
    Adults

    100 mg/m2—150 mg/m2 IV over 30 minutes once per week for 3 weeks, then 1 week off, every 28 days. In a phase II trial, 302 patients with previously untreated metastatic breast cancer were randomized to receive nab-paclitaxel 100 mg/m2 or 150 mg/m2 weekly for 3 out of 4 weeks, nab-paclitaxel 300 mg/m2 once every 3 weeks, or docetaxel 100 mg/m2 once every 3 weeks. Overall response rate, the primary endpoint, was not significantly different between the groups. However, when reviewed by an independent radiologist, progression-free survival (PFS) was significantly improved in the nab-paclitaxel 150 mg/m2 arm vs. docetaxel (12.9 months vs. 7.5 months, p = 0.0065) and in the nab-paclitaxel 100 mg/m2 arm (12.8 months vs. 7.5 months, p value not provided); in the nab-paclitaxel 300 mg/m2 every 3 weeks arm PFS was 11 months (p value not provided).

    For the first-line treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who are not candidates for curative surgery or radiation, in combination with carboplatin.
    Intravenous dosage
    Adults

    100 mg/m2 IV over 30 minutes on days 1, 8, and 15 in combination with carboplatin (AUC 6 IV) on day 1 (immediately following the nab-paclitaxel infusion) of each 21-day cycle. The primary endpoint of overall response rate (ORR) assessed by independent radiologic review was significantly improved with nab-paclitaxel plus carboplatin (median number of cycles, 6; range, 1—31 cycles) compared with solvent-based (sb) paclitaxel plus carboplatin (33% vs. 25%; response rate ratio = 1.313; 95% CI, 1.082—1.593; p = 0.005) in patients with previously untreated non-resectable stage IIIB or stage IV non-small cell lung cancer (NSCLC) in a multicenter, randomized, phase III trial (n = 1052). All responding patients in the nab-paclitaxel arm had a partial response (PR); one patient in the sb-paclitaxel arm achieved a complete response, all others had a PR. In a subgroup analysis, the ORR was significantly improved with nab-paclitaxel plus carboplatin in patients with squamous cell histology (41% vs. 24%; p < 0.001) but not nonsquamous cell histology (26% vs. 25%). Although treatment with nab-paclitaxel plus carboplatin was not statistically superior compared with sb-paclitaxel plus carboplatin for the secondary endpoints of median progression-free survival (6.3 months vs. 5.8 months, HR = 0.902; 95% CI, 0.767—1.06) and overall survival (12.1 months vs 11.2 months, HR = 0.922; 95% CI, 0.797—1.066) times, noninferiority was demonstrated.

    For the first-line treatment of metastatic pancreatic cancer in combination with gemcitabine.
    Intravenous dosage
    Adults

    125 mg/m2 IV over 30—40 minutes on days 1, 8, and 15 followed by gemcitabine 1000 mg/m2 IV over 30—40 minutes on days 1, 8, and 15, every 28 days. In a multinational, randomized, open-label study, nab-paclitaxel plus gemcitabine (n = 431) was compared to gemcitabine 1000 mg/m2 IV weekly for 7 weeks with a 1 week rest period in cycle 1, and then on days 1, 8, and 15 of each subsequent 28 day cycle (n = 430) until disease progression or unacceptable toxicity in patients with metastatic adenocarcinoma of the pancreas. Median overall survival (8.5 months vs. 6.7 months; HR 0.72; 95% CI 0.62—0.83; p < 0.001) and median progression free survival (5.5 months vs. 3.7 months; HR 0.69; 95% CI 0.58—0.82; p < 0.001) were improved by the combination of nab-paclitaxel and gemcitabine. Additionally, 23% of patients treated with combination therapy had a confirmed complete or partial overall response, compared to 7% of patients treated with gemcitabine alone (p < 0.001).

    MAXIMUM DOSAGE

    Adults

    260 mg/m2 IV.

    Geriatric

    260 mg/m2 IV.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Metastatic Breast Cancer:
    Baseline mild hepatic impairment (AST level < 10X the upper limit of normal (ULN) and bilirubin level > ULN to <= 1.5x ULN): No initial dose adjustment is necessary; the need for dose adjustments in subsequent cycles depends on individual patient tolerance.
    Baseline moderate to severe hepatic impairment (AST level < 10X ULN and bilirubin level > 1.5x to 5x ULN): Initiate at a reduced nab-paclitaxel dose of 200 mg/m2; the need for further dose adjustments in subsequent cycles depends on individual patient tolerance. If the initial dose is well tolerated for 2 cycles, nab-paclitaxel may be increased to 260 mg/m2 in subsequent cycles.
    Baseline AST level > 10x ULN or bilirubin level > 5x ULN: Do NOT administer; nab-paclitaxel has not been studied in this population.
     
    Non-Small Cell Lung Cancer (NSCLC):
    NOTE: Patients with bilirubin levels > ULN were excluded from clinical trials for NSCLC)
    Baseline mild hepatic impairment (AST level < 10x ULN and bilirubin level ULN to <= 1.5x ULN): No initial dose adjustment is necessary; the need for dose adjustments in subsequent cycles depends on individual patient tolerance.
    Baseline moderate to severe hepatic impairment (AST level < 10x ULN and bilirubin level > 1.5x to 5x ULN): Initiate at a reduced nab-paclitaxel dose of 80 mg/m2; the need for further dose adjustments in subsequent cycles depends on individual patient tolerance. If the initial dose is well tolerated for 2 cycles, nab-paclitaxel may be increased to 100 mg/m2 in subsequent cycles.
    Baseline AST level > 10x ULN or bilirubin level > 5x ULN: Do NOT administer; nab-paclitaxel has not been studied in this population.
     
    Pancreatic Adenocarcinoma:
    (NOTE: patients with bilirubin levels > ULN were excluded from clinical trials for pancreatic cancer).
    Baseline mild hepatic impairment (AST level < 10x ULN and bilirubin level ULN to <= 1.5x ULN): No initial dose adjustment is necessary; the need for dose adjustments in subsequent cycles depends on individual patient tolerance.
    Baseline moderate to severe hepatic impairment (AST level < 10x ULN and bilirubin level > 1.5x ULN): Use not recommended
    Baseline AST level > 10x ULN or bilirubin level > 5x ULN: Do NOT administer; nab-paclitaxel has not been studied in this population.

    Renal Impairment

    CrCL >= 30 ml/min: Dosage adjustment is not necessary.
    CrCL < 30 ml/min: Insufficient data exist to make dosage recommendations.

    ADMINISTRATION

    CAUTION: Observe and exercise usual precautions for handling, preparing, and administering solutions of cytotoxic drugs. If nanoparticle albumin-bound (NAB) paclitaxel comes in contact with the skin, wash the affected area immediately and thoroughly with soap and water. Following topical exposure, tingling, burning, and redness may occur. If contact occurs with mucous membranes, flush the affected area thoroughly with water.
    For storage information, see specific product information within the How Supplied section.

    Injectable Administration

    Visually inspect parenteral product prior to administration; discard if proteinaceous strands, particulate matter, or discoloration are observed.

    Intravenous Administration

    Administer as an intravenous infusion.
    Substitution for (or with) other paclitaxel formulations is prohibited. The albumin formulation may significantly affect the pharmacokinetic and pharmacodynamic properties relative to those of paclitaxel injection.
    Prior to administration, patients should have documented neutrophil counts > 1500/mm3 and platelet count of 100,000/mm3.
    No premedication to prevent hypersensitivity reactions is required.
     
    Dilution and Preparation of Infusion
    Each single-use vial contains 100 mg of paclitaxel and approximately 900 mg of human albumin.
    Reconstitute lyophilized powder with 20 ml 0.9% Sodium Chloride Injection, USP prior to intravenous infusion. Slowly inject the sodium chloride over a minimum of 1 minute onto the inside wall of the vial; do not inject directly onto the lyophilized cakes of drug as this will result in foaming. Allow the vial to sit for a minimum of 5 minutes to ensure proper wetting of the lyophilized drug. Then, gently swirl and/or slowly invert the vial for at least 2 minutes until complete dissolution of any cake/powder occurs. Avoid the generation of foam. If foaming or clumping occurs, let the solution stand for at least 15 minutes until foam subsides. The resulting concentration is 5 mg/ml paclitaxel.
    The reconstituted suspension should be milky and homogenous without visible particulates. If particulates or settling are visible, gently invert the vial to ensure complete suspension prior to use.
    Inject the appropriate amount of reconstituted solution into an empty, sterile PVC-type IV bag. It is not necessary to use specialized DEHP-free solution containers or administration sets for preparation or administration. However, the use of medical devices containing silicone oil as a lubricant (i.e., syringes and IV bags) may result in the formation of proteinaceous strands.
    Storage of reconstituted suspension in the vial: Reconstituted solutions may be stored in the refrigerator, between 2 and 8 degrees C (36 and 46 degrees F), for up to 24 hours. If not used immediately, place each vial in the original carton to protect it from bright light. Discard any unused portion. Some settling of the reconstituted suspension may occur. Ensure complete resuspension by mild agitation before use. Discard the reconstituted suspension if precipitates are observed.
    Storage of reconstituted suspension in an infusion bag: Following drug transfer into an infusion bag, immediate administration is preferred. If needed, the suspension for infusion may be refrigerated at 2 to 8 degrees C (36 to 46 degrees F) and protected from bright light for a maximum of 24 hours. The total combined refrigerated storage time of reconstituted drug suspension in the vial and in the infusion bag is 24 hours. This may be followed by storage in the infusion bag at ambient temperature (approximately 25 degrees C) and lighting conditions for a maximum of 4 hours. Discard any unused portion. Some settling of the reconstituted suspension may occur. Ensure complete resuspension by mild agitation before use. Discard the reconstituted suspension if precipitates are observed.
     
    Intravenous Infusion
    Infuse weekly† and every 3-week doses IV over 30 minutes.

    STORAGE

    Abraxane:
    - Do not freeze
    - Do not refrigerate
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    - Store in original container

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    This product contains human albumin and carries a remote risk of viral disease or Creutzfeldt-Jakob disease transmission.

    Taxane hypersensitivity

    Severe hypersensitivity reactions (e.g., anaphylaxis) have been reported with nanoparticle albumin-bound (nab) paclitaxel use; some cases were fatal. Nab-paclitaxel is contraindicated in patients who have experienced a severe hypersensitivity to the product (taxane hypersensitivity); do not re-challenge patients who experience a severe hypersensitivity reaction with nab-paclitaxel.

    Bone marrow suppression, neutropenia, thrombocytopenia

    Bone marrow suppression (e.g., neutropenia, thrombocytopenia) is the dose-limiting toxicity of nanoparticle albumin-bound (nab) paclitaxel. Nab-paclitaxel is contraindicated in patients with a baseline absolute neutrophil count (ANC) of < 1500 cells/mm3. Obtain a complete blood count (CBC) panel prior to starting a new cycle of nab-paclitaxel therapy on day 1 in all patients and prior to therapy on day 8 and 15 in patients with non-small cell lung cancer and pancreatic cancer. Monitor CBC panel frequently to evaluate patients for myelotoxicity. Do not resume a new cycle of therapy until the ANC is >= 1500 cells/mm3 and the platelet count is >= 100,000 cells/mm3. In patients who develop severe neutropenia or thrombocytopenia, hold nab-paclitaxel and reduce the dose of therapy for subsequent cycles.

    Peripheral neuropathy

    Peripheral neuropathy has been reported commonly with nanoparticle albumin-bound (nab) paclitaxel use. In patients who develop grade 3 or higher peripheral neuropathy, hold nab-paclitaxel until symptoms improve/resolve and reduce the dose of therapy for subsequent cycles.

    Geriatric

    Use caution when treating patients older than age 65 with nanoparticle albumin-bound (nab) paclitaxel. An increased incidence of some adverse effects, including arthralgia, decreased appetite, dehydration, diarrhea, epistaxis, fatigue, myelosuppression, peripheral neuropathy, and peripheral edema were reported more often in patients >= 65 years compared with younger patients in 3 separate randomized trials (n = 1926). Toxicity was similar among geriatric patients and younger patients with metastatic breast cancer who received nab-paclitaxel in another randomized study (n = 229).

    Hepatic disease, jaundice

    Use nanoparticle albumin-bound (nab) paclitaxel cautiously in patients with hepatic disease, as they are at an increased risk of toxicity. If nab-paclitaxel is administered to patients with hepatic impairment, monitor closely for the development of severe myelosuppression. An initial nab-paclitaxel dose reduction is recommended in patients with moderate or severe hepatic impairment; the need for dose adjustments in subsequent cycles depends on individual patient tolerance. Patients who develop jaundice should be evaluated. Do not administer nab-paclitaxel to any patient with an AST level > 10X the upper limit of normal (ULN) or a bilirubin level > 5X ULN, or to patients with metastatic pancreatic cancer with an AST level <= 10X ULN but total bilirubin level > 1.5X ULN.

    Infertility, male-mediated teratogenicity, pregnancy

    Nanoparticle albumin-bound (nab) paclitaxel is classified as FDA pregnancy risk category D. In animal models, administration of nab-paclitaxel on gestation days 7 to 17 at doses of 6mg/m2 (approximately 2% of the daily maximum recommended human dose on a mg/m2 basis) caused embryo- and feto-toxicity, as indicated by intrauterine mortality, increased resorptions (up to 5-fold), reduced numbers of litters and live fetuses, reduction in fetal body weight and increase in fetal anomalies. Fetal anomalies included soft tissue and skeletal malformations, such as eye bulge, folded retina, microphthalmia, and dilation of brain ventricles. A lower incidence of soft tissue and skeletal malformations were also exhibited at 3 mg/m2 (approximately 1% of the daily maximum recommended human dose on a mg/m2 basis). There are no data concerning the effects in pregnant women; nab-paclitaxel should be avoided during pregnancy, and females of childbearing potential should be instructed to avoid becoming pregnant during nab-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. Men should be advised to not father a child while receiving treatment with nab-paclitaxel; the possibility of male infertility or of male-mediated teratogenicity cannot be excluded. Administration of nab-paclitaxel to male rats at 42 mg/m2 on a weekly basis (approximately 16% of the daily maximum recommended human exposure on a mg/m2 basis) for 11 weeks prior to mating with untreated female rats resulted in significant infertility accompanied by decreased pregnancy rates and increased loss of embryos in mated females. Testicular atrophy/degeneration has also been observed in single-dose toxicology studies in rodents administered NAB paclitaxel at 54 mg/m2 and dogs administered 175 mg/m2.

    Breast-feeding

    Adverse effects to the nursing infant are unknown. It also is unknown whether nanoparticle albumin-bound (NAB) 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 NAB paclitaxel therapy.

    Radiation therapy

    A radiation recall phenomenon has been reported with nanoparticle albumin-bound paclitaxel use. Patients who have received prior radiation therapy may be at increased risk for this reaction.

    Children, infants, neonates

    The safety and effectiveness of nanoparticle albumin-bound paclitaxel have not been evaluated in adolescents, children, infants, and neonates.

    Biliary obstruction, fever, sepsis

    In clinical trials, 5% of patients treated with nab-paclitaxel and gemcitabine, with or without neutropenia, developed severe infection or sepsis. Risk factors include biliary obstruction or the presence of a biliary stent. If a patient develops a fever (regardless of ANC), initiate appropriate broad spectrum antibiotics; if the patient is neutropenic, discontinue therapy with nab-paclitaxel and gemcitabine until resolution of neutropenic fever, then resume therapy at a reduced dose.

    Pneumonitis

    In clinical trials, 4% of patients treated with nab-paclitaxel and gemcitabine developed pneumonitis; some cases were fatal. Interrupt nab-paclitaxel and gemcitabine if patients develop shortness of breath, cough, and chest pain. Permanently discontinue treatment with nab-paclitaxel and gemcitabine if pneumonitis is diagnosed.

    Ensure correct formulation selection

    An albumin form of paclitaxel may substantially affect a drugs functional properties relative to those of drug in solution. Ensure correct formulation selection and do not substitute nanoparticle albumin-bound paclitaxel for or with other paclitaxel formulations.

    ADVERSE REACTIONS

    Severe

    neutropenia / Delayed / 34.0-47.0
    anemia / Delayed / 1.0-28.0
    thrombocytopenia / Delayed / 13.0-18.0
    fatigue / Early / 18.0-18.0
    peripheral neuropathy / Delayed / 3.0-17.0
    heart failure / Delayed / 0-10.0
    macular edema / Delayed / 0-10.0
    asthenia / Delayed / 7.0-8.0
    myalgia / Early / 1.0-8.0
    arthralgia / Delayed / 1.0-8.0
    dehydration / Delayed / 7.0-7.0
    diarrhea / Early / 1.0-6.0
    vomiting / Early / 4.0-6.0
    nausea / Early / 3.0-6.0
    anorexia / Delayed / 5.0-5.0
    hypokalemia / Delayed / 4.0-4.0
    cardiac arrest / Early / 3.0-3.0
    peripheral edema / Delayed / 3.0-3.0
    thromboembolism / Delayed / 3.0-3.0
    thrombosis / Delayed / 3.0-3.0
    fever / Early / 3.0-3.0
    rash (unspecified) / Early / 2.0-2.0
    bradycardia / Rapid / 0-1.0
    stomatitis / Delayed / 1.0-1.0
    alopecia / Delayed / 1.0-1.0
    epistaxis / Delayed / 0-1.0
    keratitis / Delayed / 1.0-1.0
    blurred vision / Early / 1.0-1.0
    headache / Early / 0-1.0
    depression / Delayed / 0-1.0
    pancytopenia / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    tissue necrosis / Early / Incidence not known
    stroke / Early / Incidence not known
    cranial nerve palsies / Delayed / Incidence not known
    ileus / Delayed / Incidence not known
    GI perforation / Delayed / Incidence not known
    pancreatitis / Delayed / Incidence not known
    GI obstruction / Delayed / Incidence not known
    typhlitis / Delayed / Incidence not known
    pulmonary fibrosis / Delayed / Incidence not known
    pulmonary embolism / Delayed / Incidence not known
    hepatic necrosis / Delayed / Incidence not known
    hepatic encephalopathy / Delayed / Incidence not known
    visual impairment / Early / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known

    Moderate

    elevated hepatic enzymes / Delayed / 36.0-39.0
    constipation / Delayed / 16.0-16.0
    dyspnea / Early / 12.0-12.0
    edema / Delayed / 10.0-10.0
    hypertension / Early / 0-10.0
    sinus tachycardia / Rapid / 0-10.0
    candidiasis / Delayed / 1.0-10.0
    hyperbilirubinemia / Delayed / 7.0-7.0
    hypotension / Rapid / 5.0-5.0
    pneumonitis / Delayed / 4.0-4.0
    chest pain (unspecified) / Early / 3.0-3.0
    supraventricular tachycardia (SVT) / Early / 3.0-3.0
    bleeding / Early / 2.0-2.0
    phlebitis / Rapid / Incidence not known
    erythema / Early / Incidence not known
    palmar-plantar erythrodysesthesia (hand and foot syndrome) / Delayed / Incidence not known
    radiation recall reaction / Delayed / Incidence not known
    paresis / Delayed / Incidence not known
    colitis / Delayed / Incidence not known
    conjunctivitis / Delayed / Incidence not known

    Mild

    infection / Delayed / 24.0-24.0
    cough / Delayed / 7.0-17.0
    metallic taste / Early / 16.0-16.0
    injection site reaction / Rapid / 0-1.0
    flushing / Rapid / 0-1.0
    pruritus / Rapid / Incidence not known
    photosensitivity / Delayed / Incidence not known
    nail discoloration / Delayed / Incidence not known
    maculopapular rash / Early / Incidence not known
    lacrimation / Early / Incidence not known

    DRUG INTERACTIONS

    Aliskiren; Amlodipine: Additive bradycardia may occur in patients receiving paclitaxel and other drugs known to cause bradycardia, such as calcium-channel blockers like amlodipine. These patients may require monitoring and information.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: Additive bradycardia may occur in patients receiving paclitaxel and other drugs known to cause bradycardia, such as calcium-channel blockers like amlodipine. These patients may require monitoring and information.
    Alpha interferons: Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Alteplase, tPA: An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
    Amlodipine: Additive bradycardia may occur in patients receiving paclitaxel and other drugs known to cause bradycardia, such as calcium-channel blockers like amlodipine. These patients may require monitoring and information.
    Amlodipine; Atorvastatin: Additive bradycardia may occur in patients receiving paclitaxel and other drugs known to cause bradycardia, such as calcium-channel blockers like amlodipine. These patients may require monitoring and information.
    Amlodipine; Benazepril: Additive bradycardia may occur in patients receiving paclitaxel and other drugs known to cause bradycardia, such as calcium-channel blockers like amlodipine. These patients may require monitoring and information.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: Additive bradycardia may occur in patients receiving paclitaxel and other drugs known to cause bradycardia, such as calcium-channel blockers like amlodipine. These patients may require monitoring and information.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: Additive bradycardia may occur in patients receiving paclitaxel and other drugs known to cause bradycardia, such as calcium-channel blockers like amlodipine. These patients may require monitoring and information.
    Amlodipine; Olmesartan: Additive bradycardia may occur in patients receiving paclitaxel and other drugs known to cause bradycardia, such as calcium-channel blockers like amlodipine. These patients may require monitoring and information.
    Amlodipine; Telmisartan: Additive bradycardia may occur in patients receiving paclitaxel and other drugs known to cause bradycardia, such as calcium-channel blockers like amlodipine. These patients may require monitoring and information.
    Amlodipine; Valsartan: Additive bradycardia may occur in patients receiving paclitaxel and other drugs known to cause bradycardia, such as calcium-channel blockers like amlodipine. These patients may require monitoring and information.
    Anticoagulants: Due to the thrombocytopenic effects of taxanes, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Antithrombin III: Due to the thrombocytopenic effects of taxanes, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Antithymocyte Globulin: 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: Due to the thrombocytopenic effects of taxanes, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Argatroban: Due to the thrombocytopenic effects of taxanes, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Azelastine; Fluticasone: 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.
    Bacillus Calmette-Guerin Vaccine, BCG: 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.
    Beclomethasone: 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: 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: 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.
    Bivalirudin: Due to the thrombocytopenic effects of taxanes, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Budesonide: 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: 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.
    Carvedilol: 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.
    Ciclesonide: 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.
    Clozapine: 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.
    Corticosteroids: 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: 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: 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.
    Cyclosporine: In vitro, the metabolism of paclitaxel is inhibited by cyclosporine, but cyclosporine concentrations used exceeded those found in vivo following normal therapeutic doses used. Additionally, cyclosporine and valspodar (PSC-833), a cyclosporine analog, block 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.
    Dabigatran: Due to the thrombocytopenic effects of taxanes, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Dalteparin: Due to the thrombocytopenic effects of taxanes, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Danaparoid: Due to the thrombocytopenic effects of taxanes, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: 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.
    Deferiprone: Avoid concomitant use of deferiprone with other drugs known to be associated with neutropenia or agranulocytosis, such as antineoplastic agents; however, if this is not possible, closely monitor the absolute neutrophil count and interrupt deferiprone therapy if neutropenia develops.
    Deflazacort: 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.
    Denosumab: The safety and efficacy of denosumab use in patients receiving antineoplastic agents have not been evaluated; in theory, such patients may be at a greater risk of developing osteonecrosis of the jaw, a rare condition that has been reported during denosumab therapy. Patients receiving antineoplastic agents known as angiogenesis inhibitors may particularly be at a greater risk of developing osteonecrosis of the jaw.
    Desirudin: Due to the thrombocytopenic effects of taxanes, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Dexamethasone: 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.
    Diazepam: Paclitaxel is metabolized by hepatic cytochrome P450 (CYP) isoenzymes 2C8 and 3A4. In vitro, the metabolism of paclitaxel is inhibited by diazepam but concentrations used exceeded those found in vivo following normal therapeutic doses.
    Digoxin: 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: Additive bradycardia may occur in patients receiving paclitaxel and other drugs known to cause bradycardia, such as calcium-channel blockers like diltiazem. These patients may require additional monitoring and information.
    Drospirenone; Ethinyl Estradiol: Paclitaxel is metabolized by hepatic cytochrome P450 (CYP) isoenzymes 2C8 and 3A4. In vitro, the metabolism of paclitaxel is inhibited by 17alpha-ethinyl estradiol; combining the drugs in clinical practice may require close monitoring to ensure proper therapeutic responses.
    Drospirenone; Ethinyl Estradiol; Levomefolate: Paclitaxel is metabolized by hepatic cytochrome P450 (CYP) isoenzymes 2C8 and 3A4. In vitro, the metabolism of paclitaxel is inhibited by 17alpha-ethinyl estradiol; combining the drugs in clinical practice may require close monitoring to ensure proper therapeutic responses.
    Echinacea: 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: Due to the thrombocytopenic effects of taxanes, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Eliglustat: 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.
    Enalapril; Felodipine: Additive bradycardia may occur in patients receiving paclitaxel and other drugs known to cause bradycardia, such as calcium-channel blockers like felodipine. These patients may require additional monitoring and information.
    Enoxaparin: Due to the thrombocytopenic effects of taxanes, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Erythromycin: 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: 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.
    Ethinyl Estradiol: Paclitaxel is metabolized by hepatic cytochrome P450 (CYP) isoenzymes 2C8 and 3A4. In vitro, the metabolism of paclitaxel is inhibited by 17alpha-ethinyl estradiol; combining the drugs in clinical practice may require close monitoring to ensure proper therapeutic responses.
    Ethinyl Estradiol; Desogestrel: Paclitaxel is metabolized by hepatic cytochrome P450 (CYP) isoenzymes 2C8 and 3A4. In vitro, the metabolism of paclitaxel is inhibited by 17alpha-ethinyl estradiol; combining the drugs in clinical practice may require close monitoring to ensure proper therapeutic responses.
    Ethinyl Estradiol; Ethynodiol Diacetate: Paclitaxel is metabolized by hepatic cytochrome P450 (CYP) isoenzymes 2C8 and 3A4. In vitro, the metabolism of paclitaxel is inhibited by 17alpha-ethinyl estradiol; combining the drugs in clinical practice may require close monitoring to ensure proper therapeutic responses.
    Ethinyl Estradiol; Etonogestrel: Paclitaxel is metabolized by hepatic cytochrome P450 (CYP) isoenzymes 2C8 and 3A4. In vitro, the metabolism of paclitaxel is inhibited by 17alpha-ethinyl estradiol; combining the drugs in clinical practice may require close monitoring to ensure proper therapeutic responses.
    Ethinyl Estradiol; Levonorgestrel: Paclitaxel is metabolized by hepatic cytochrome P450 (CYP) isoenzymes 2C8 and 3A4. In vitro, the metabolism of paclitaxel is inhibited by 17alpha-ethinyl estradiol; combining the drugs in clinical practice may require close monitoring to ensure proper therapeutic responses.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: Paclitaxel is metabolized by hepatic cytochrome P450 (CYP) isoenzymes 2C8 and 3A4. In vitro, the metabolism of paclitaxel is inhibited by 17alpha-ethinyl estradiol; combining the drugs in clinical practice may require close monitoring to ensure proper therapeutic responses.
    Ethinyl Estradiol; Norelgestromin: Paclitaxel is metabolized by hepatic cytochrome P450 (CYP) isoenzymes 2C8 and 3A4. In vitro, the metabolism of paclitaxel is inhibited by 17alpha-ethinyl estradiol; combining the drugs in clinical practice may require close monitoring to ensure proper therapeutic responses.
    Ethinyl Estradiol; Norethindrone Acetate: Paclitaxel is metabolized by hepatic cytochrome P450 (CYP) isoenzymes 2C8 and 3A4. In vitro, the metabolism of paclitaxel is inhibited by 17alpha-ethinyl estradiol; combining the drugs in clinical practice may require close monitoring to ensure proper therapeutic responses.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: Paclitaxel is metabolized by hepatic cytochrome P450 (CYP) isoenzymes 2C8 and 3A4. In vitro, the metabolism of paclitaxel is inhibited by 17alpha-ethinyl estradiol; combining the drugs in clinical practice may require close monitoring to ensure proper therapeutic responses.
    Ethinyl Estradiol; Norethindrone: Paclitaxel is metabolized by hepatic cytochrome P450 (CYP) isoenzymes 2C8 and 3A4. In vitro, the metabolism of paclitaxel is inhibited by 17alpha-ethinyl estradiol; combining the drugs in clinical practice may require close monitoring to ensure proper therapeutic responses.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: Paclitaxel is metabolized by hepatic cytochrome P450 (CYP) isoenzymes 2C8 and 3A4. In vitro, the metabolism of paclitaxel is inhibited by 17alpha-ethinyl estradiol; combining the drugs in clinical practice may require close monitoring to ensure proper therapeutic responses.
    Ethinyl Estradiol; Norgestimate: Paclitaxel is metabolized by hepatic cytochrome P450 (CYP) isoenzymes 2C8 and 3A4. In vitro, the metabolism of paclitaxel is inhibited by 17alpha-ethinyl estradiol; combining the drugs in clinical practice may require close monitoring to ensure proper therapeutic responses.
    Ethinyl Estradiol; Norgestrel: Paclitaxel is metabolized by hepatic cytochrome P450 (CYP) isoenzymes 2C8 and 3A4. In vitro, the metabolism of paclitaxel is inhibited by 17alpha-ethinyl estradiol; combining the drugs in clinical practice may require close monitoring to ensure proper therapeutic responses.
    Etoposide, VP-16: Paclitaxel is metabolized by hepatic cytochrome P450 (CYP) isoenzymes 2C8 and 3A4. In vitro, the metabolism of paclitaxel is inhibited by etoposide but concentrations used exceeded those found in vivo following normal therapeutic doses.
    Febuxostat: 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.
    Felodipine: Additive bradycardia may occur in patients receiving paclitaxel and other drugs known to cause bradycardia, such as calcium-channel blockers like felodipine. These patients may require additional monitoring and information.
    Flucytosine: Flucytosine can cause significant hematologic toxicity. It should be used cautiously with all antineoplastic agents, especially those that cause bone marrow depression.
    Fludrocortisone: 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: 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: 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: Paciltaxel is metabolized by cytochrome P450 3A enzymes. Drugs that inhibit the CYP3A enzymes, such as fluoxetine, can significantly reduce the metabolism of paclitaxel.
    Fluticasone: 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: 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: 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.
    Fondaparinux: Due to the thrombocytopenic effects of taxanes, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Formoterol; Mometasone: 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.
    Heparin: Due to the thrombocytopenic effects of taxanes, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Hydrocortisone: 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.
    Hydroxocobalamin: Medications known to cause bone marrow suppression (e.g., myelosuppressive antineoplastic agents) may result in a blunted or impeded response to hydroxocobalamin, vitamin B12 therapy. Antineoplastics that are antimetabolites for the vitamin may induce inadequate utilization of vitamin B12. However, cancer patients usually benefit from vitamin B12 supplementation.
    Ifosfamide: Paclitaxel is metabolized by hepatic cytochrome P450 (CYP) isoenzymes 2C8 and 3A4. Although some experts state that pharmacokinetic interactions between paclitaxel and ifosfamide do not appear to be clinically significant, combining the drugs in clinical practice may require close monitoring to ensure proper therapeutic responses.
    immunosuppressives: Both sirolimus and taxanes, like paclitaxel and docetaxel, decrease immune system function. Patients on both agents may be predisposed to over-immunosuppression resulting in an increased risk of infection or other side effects.
    Interferon Alfa-2a: 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: 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: 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: 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: Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Interferon Gamma-1b: Interferon gamma-1b can cause severe, reversible neutropenia and thrombocytopenia, which may be dose-related. Caution is recommended if interferon gamma-1b is used concurrently with myelosuppressive agents.
    Intranasal Influenza Vaccine: 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.
    Isradipine: Additive bradycardia may occur in patients receiving paclitaxel and other drugs known to cause bradycardia, such as calcium-channel blockers like isradipine. These patients may require additional monitoring and information.
    Ixabepilone: 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.
    Japanese Encephalitis Virus Vaccine: 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.
    Lepirudin: Due to the thrombocytopenic effects of taxanes, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Live Vaccines: 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 Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: 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: 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.
    Methylprednisolone: 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.
    Mometasone: 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: Paclitaxel is metabolized by cytochrome P450 2C8 and in vitro data indicate that montelukast is a potent inhibitor of CYP2C8. The manufacturer of montelukast advises caution when these drugs are coadministered; patients should be monitored for adverse effects of paclitaxel.
    Natalizumab: The concomitant use of natalizumab and antineoplastic agents may further increase the risk of infections, including progressive multifocal leukoencephalopathy and other opportunistic infections, over the risk observed with use of natalizumab alone. The safety and efficacy of natalizumab in combination with antineoplastic agents have not been established. Also, natalizumab for Crohn's disease should not be used in combination with immunosuppressants such as 6-mercaptopurine because of the potential for increased risk of progressive multifocal leukoencephalopathy and other infections.
    Nicardipine: Additive bradycardia may occur in patients receiving paclitaxel and other drugs known to cause bradycardia, such as calcium-channel blockers like nicardipine. These patients may require additional monitoring and information.
    Nifedipine: Additive bradycardia may occur in patients receiving paclitaxel and other drugs known to cause bradycardia, such as calcium-channel blockers like nifedipine. These patients may require additional monitoring and information.
    Nimodipine: Additive bradycardia may occur in patients receiving paclitaxel and other drugs known to cause bradycardia, such as calcium-channel blockers like nimodipine. These patients may require additional monitoring and information.
    Nisoldipine: Additive bradycardia may occur in patients receiving paclitaxel and other drugs known to cause bradycardia, such as calcium-channel blockers like nisoldipine. These patients may require additional monitoring and information.
    Ombitasvir; Paritaprevir; Ritonavir: 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.
    Palifermin: Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Pegfilgrastim: 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: 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: Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Peginterferon beta-1a: Due to its potential to decrease peripheral blood cell counts, proper monitoring of patients is required if peginterferon beta-1a is given in combination with immunosuppressives or antineoplastic agents.
    Penicillamine: Concomitant use of penicillamine with antineoplastic agents is contraindicated because of the increased risk of developing severe hematologic and renal toxicity. Antineoplastic agents have adverse reactions similar to those of penicillamine.
    Pentosan: Due to the thrombocytopenic effects of taxanes, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Perindopril; Amlodipine: Additive bradycardia may occur in patients receiving paclitaxel and other drugs known to cause bradycardia, such as calcium-channel blockers like amlodipine. These patients may require monitoring and information.
    Platelet Inhibitors: 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.
    Prednisolone: 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: 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.
    Protease inhibitors: Concurrent administration of paclitaxel (or nanoparticle albumin-bound paclitaxel) with protease inhibitors 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; protease inhibits are potent CYP3A4 inhibitors. In addition, paclitaxel is a substrate of the drug transporter P-glycoprotein (P-gp); some protease inhibitors also inhibit P-gp. Several case reports describe potential interactions between anti-retroviral protease inhibitors and paclitaxel. In one report, two patients on combined therapy with delavirdine, didanosine, and saquinavir developed unexpectedly severe paclitaxel toxicity, including mucositis and neutropenia, but a causal relationship was not established. These patients were previously treated with paclitaxel with only mild toxicity (i.e., nausea and alopecia). In another case, paclitaxel was given concomitantly with antiretroviral agents and no dosage adjustments of paclitaxel, indinavir, ritonavir, saquinavir or nevirapine were required.
    Reteplase, r-PA: An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
    Rifapentine: 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. Monitor for decresed paclitaxel efficacy.
    Rivaroxaban: Due to the thrombocytopenic effects of taxanes, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Rotavirus Vaccine: 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: 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.
    Sargramostim, GM-CSF: 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.
    Sipuleucel-T: 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: 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.
    Streptokinase: An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
    Telaprevir: 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.
    Tenecteplase, TNK-tPA: An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
    Testosterone: Paclitaxel is metabolized by hepatic cytochrome P450 (CYP) isoenzymes 2C8 and 3A4. Testosterone inhibited the formation of paclitaxel metabolites in vitro. Combining the drugs in clinical practice may require close monitoring to ensure proper therapeutic responses.
    Thrombolytic Agents: An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
    Tinzaparin: Due to the thrombocytopenic effects of taxanes, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Trandolapril; Verapamil: Coadministration of verapamil and paclitaxel may result in a significant decrease in paclitaxel clearance and an increase in paclitaxel toxicity. Paclitaxel metabolism was reduced in an in vitro study with supratherapeutic verapamil concentrations. Further studies are needed to clarify the actual clinical significance of these results. Combining these drugs in clinical practice may require close monitoring to ensure proper therapeutic responses.
    Triamcinolone: 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.
    Tuberculin Purified Protein Derivative, PPD: 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: 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.
    Urokinase: An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
    Varicella-Zoster Virus Vaccine, Live: 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.
    Vedolizumab: The concomitant use of vedolizumab and antineoplastic agents may further increase the risk of infections, including progressive multifocal leukoencephalopathy and other opportunistic infections, over the risk observed with use of vedolizumab alone. The safety and efficacy of vedolizumab in combination with antineoplastic agents have not been established. Also, vedolizumab should not be used in combination with immunosuppressants such as 6-mercaptopurine because of the potential for increased risk of progressive multifocal leukoencephalopathy and other infections.
    Verapamil: Coadministration of verapamil and paclitaxel may result in a significant decrease in paclitaxel clearance and an increase in paclitaxel toxicity. Paclitaxel metabolism was reduced in an in vitro study with supratherapeutic verapamil concentrations. Further studies are needed to clarify the actual clinical significance of these results. Combining these drugs in clinical practice may require close monitoring to ensure proper therapeutic responses.
    Warfarin: Due to the thrombocytopenic effects of taxanes, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Yellow Fever Vaccine, Live: 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.

    PREGNANCY AND LACTATION

    Pregnancy

    Nanoparticle albumin-bound (nab) paclitaxel is classified as FDA pregnancy risk category D. In animal models, administration of nab-paclitaxel on gestation days 7 to 17 at doses of 6mg/m2 (approximately 2% of the daily maximum recommended human dose on a mg/m2 basis) caused embryo- and feto-toxicity, as indicated by intrauterine mortality, increased resorptions (up to 5-fold), reduced numbers of litters and live fetuses, reduction in fetal body weight and increase in fetal anomalies. Fetal anomalies included soft tissue and skeletal malformations, such as eye bulge, folded retina, microphthalmia, and dilation of brain ventricles. A lower incidence of soft tissue and skeletal malformations were also exhibited at 3 mg/m2 (approximately 1% of the daily maximum recommended human dose on a mg/m2 basis). There are no data concerning the effects in pregnant women; nab-paclitaxel should be avoided during pregnancy, and females of childbearing potential should be instructed to avoid becoming pregnant during nab-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. Men should be advised to not father a child while receiving treatment with nab-paclitaxel; the possibility of male infertility or of male-mediated teratogenicity cannot be excluded. Administration of nab-paclitaxel to male rats at 42 mg/m2 on a weekly basis (approximately 16% of the daily maximum recommended human exposure on a mg/m2 basis) for 11 weeks prior to mating with untreated female rats resulted in significant infertility accompanied by decreased pregnancy rates and increased loss of embryos in mated females. Testicular atrophy/degeneration has also been observed in single-dose toxicology studies in rodents administered NAB paclitaxel at 54 mg/m2 and dogs administered 175 mg/m2.

    MECHANISM OF ACTION

    Mechanism of Action: Paclitaxel is an antimicrotubule chemotherapy agent with a unique mechanism of action. It promotes the assembly of microtubules and stabilizes them against depolymerization. These microtubules are extremely stable and block mitotic cellular functions, ultimately resulting in an inability of cells to replicate. Paclitaxel also prevents 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.Neutrophil functions inhibited by paclitaxel include chemotaxis, migration, polarization, and killing of phagocytosed microorganisms. 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. Cells treated with paclitaxel show distinctive morphologic effects. Paclitaxel shifts the equilibrium towards microtubule assembly, resulting in abnormal arrays or 'bundles' of microtubules throughout the cell cycle and multiple asters of microtubules 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 are 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. Nanoparticle albumin-bound (NAB) paclitaxel utilities a unique mechanism for transportation of paclitaxel into the cells. NAB paclitaxel utilizes a receptor-mediated (gp60) pathway on microvessel endothelial cells to transport the albumin-paclitaxel complex out of the blood stream and into the tumor interstitium. In addition, studies have shown an albumin-binding protein, SPARC, is over-expressed in breast tumors and may play a role in the accumulation of NAB paclitaxel in breast cancer cells. It is suggested that once the albumin-paclitaxel complex is in the tumor interstitium, this complex would bind to the SPARC protein and would be rapidly internalized by the tumor cell. Traditional formulations of paclitaxel are not transported into tumor cells via these mechanisms. Some reports have indicated that solvents used in traditional formulations of paclitaxel inhibit binding of paclitaxel to albumin, thereby limiting transport by these mechanisms.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

    Nanoparticle albumin-bound (NAB) paclitaxel is administered intravenously. In vitro studies of binding to human serum proteins, indicate that NAB paclitaxel is extensively protein bound (94%) to plasma proteins. In a within-patient comparison study, the fraction of unbound paclitaxel was significantly higher with nab-paclitaxel than with solvent-based paclitaxel (6.2% and 2.3%, respectively), contributing to higher unbound paclitaxel exposure with nab-paclitaxel. The mean volume of distribution is 1741 L/m2. The large volume of distribution indicates extensive extravascular distribution and/or tissue binding. Paclitaxel is metabolized via CYP2C8 to 6-alpha-hydroxypaclitaxel and via CYP3A4 to 3'-p-hydroxypaclitaxel and 6-alpha,3'-para-dihydroxypaclitaxel. Elimination is due to hepatic metabolism, biliary and fecal excretion, and tissue binding. Approximately 20% of the dose is eliminated in the feces. Only 4% of paclitaxel is eliminated unchanged in the urine with less than 1% of the total administered dose being excreted in the urine as the metabolites. The mean total clearance is 15 L/hr/m2. NAB paclitaxel undergoes biphasic elimination following IV administration (30 and 180 minutes infusions) of 80 to 375mg/m2 with an initial rapid decline representing distribution to the peripheral compartment and a slower second phase representing drug elimination. The terminal half-life is approximately 27 hours.
     
    In a pharmacokinetic comparison of NAB paclitaxel 260 mg/m2 administered over 30 minutes and paclitaxel 175 mg/m2 administered over 3 hours, the clearance of NAB paclitaxel was 43% slower than the clearance of paclitaxel, and the volume of distribution of NAB paclitaxel was 53% higher.
     
    Affected Cytochrome P450 (CYP450) isoenzymes and drug transporters: CYP2C8, CYP3A4
    The metabolism of paclitaxel is catalyzed by CYP2C8 and CYP3A4. Inducers or inhibitors of these CYP enzymes can affect the response to NAB.

    Intravenous Route

    The area under the curve (AUC) is dose proportional over 80—300 mg/m2 and the pharmacokinetics of NAB paclitaxel are independent of the duration of administration. NAB paclitaxel undergoes biphasic elimination following IV administration (30 and 180 minutes infusions) of 80 to 375 mg/m2 with an initial rapid decline representing distribution to the peripheral compartment and a slower second phase representing drug elimination. At clinical doses (80—300 mg/m2), the mean total clearance of paclitaxel ranges from 13 to 30 L/h/m2 and the terminal half-life is 13—27 hours.