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  • CLASSES

    Vinca Alkaloids and Analogs

    BOXED WARNING

    Anemia, bleeding, bone marrow suppression, infection, neutropenia, thrombocytopenia

    Monitor complete blood counts prior to each dose of vinorelbine, as a dose reduction or delay in treatment may be necessary; do not administer vinorelbine to patients with neutrophil counts < 1000 neutrophils/mm3 on the day of treatment. Advise patients to promptly report any signs of infection such as fever, sore throat, or abnormal pain to their healthcare provider. Bone marrow suppression, including neutropenia, anemia, and thrombocytopenia, have been reported with vinorelbine treatment; this may increase the incidence of fungal, viral, and bacterial infections, bleeding and fatigue. Neutropenia is the major dose-limiting toxicity; use vinorelbine with caution in patients who have had previous myelosuppressive therapy such as chemotherapy or radiotherapy.

    DEA CLASS

    Rx

    DESCRIPTION

    Semi-synthetic vinca alkaloid antineoplastic agent
    Used for the treatment of metastatic non-small cell lung cancer
    Vesicant; closely monitor for signs and symptoms of extravasation

    COMMON BRAND NAMES

    Navelbine

    HOW SUPPLIED

    Navelbine/Vinorelbine/Vinorelbine Tartrate Intravenous Inj Sol: 1mL, 10mg

    DOSAGE & INDICATIONS

    For the treatment of non-small cell lung cancer (NSCLC).
    As a single agent for the treatment of metastatic non-small cell lung cancer (NSCLC).
    Intravenous dosage
    Adults

    30 mg/m2 IV administered over 6 to 10 minutes once weekly. In a randomized, multicenter, open-label clinical trial of patients with treatment-naive stage IV NSCLC (n = 211), the primary outcome of median overall survival was improved to 30 weeks in patients treated with vinorelbine compared with 22 weeks in patients who received 5-fluorouracil plus leucovorin (p = 0.06); partial responses were obtained in 11.1% and 3.5% of patients, respectively.

    For the first-line treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in combination with every-4-week cisplatin.
    Intravenous dosage
    Adults

    25 mg/m2 IV over 6 to 10 minutes on days 1, 8, 15, and 21 in combination with cisplatin (100 mg/m2 IV on day 1) every 28 days. In a randomized, multicenter, open-label clinical trial of patients with treatment-naive stage 3b or stage IV NSCLC, the addition of vinblastine to cisplatin (n = 214) significantly improved median overall survival (7.8 months vs. 6.2 months) and overall response rate (19% vs. 8%) compared to cisplatin alone (n = 218).

    For adjuvant treatment of resected non-small cell lung cancer (NSCLC) in combination with cisplatin†.
    Intravenous dosage
    Adults

    25 or 30 mg/m2 IV once weekly for up to 16 doses in combination with cisplatin has been evaluated in randomized, phase 3 studies. Adjuvant therapy with vinorelbine (30 mg/m2 IV once weekly starting on day 1 for up to 16 doses) plus cisplatin (100 mg/m2 on days 1, 29, 57, and 85) led to significantly improved median overall survival (OS) (65.7 vs. 43.7 months) and disease-free survival (DFS) (36.3 vs. 20.7 months) compared with surgery +/- radiotherapy alone in a multinational, randomized, phase 3 study in 840 patients with completely resected stage IB-IIIA NSCLC. The absolute OS improvement at 2- and 5-years was 4.7% and 8.4%, respectively. In the adjuvant chemotherapy arm, grade 3 or 4 neutropenia was reported in 85% of patients and there were 7 (2%) treatment-related deaths. In another randomized, phase 3 study, adjuvant therapy with vinorelbine (25 mg/m2 IV weekly for 16 weeks) plus cisplatin (50 mg/m2 on days 1 and 8 repeated every 4 weeks for 4 cycles) resulted in significantly improved median OS (94 vs. 73 months) and relapse-free survival (not reached vs. 46.7 months) compared with surgery alone in 482 patients with stage IB or II NSCLC. The absolute improvement in 5-year OS was 11% at a median follow-up time of 9.3 years. In a post-hoc analysis, no OS benefit was observed in patients with stage IB disease. Grade 3 and 4 neutropenia was reported in 73% of patients and there were 2 (0.8%) treatment-related deaths.

    For the first-line treatment of advanced non-small cell lung cancer (NSCLC) in combination with cisplatin and cetuximab†.
    Intravenous dosage
    Adults

    25 mg/m2 IV on days 1 and 8 in combination with cisplatin (80 mg/m2 IV on day 1) every 21 days, and cetuximab (400 mg/m2 IV the first week with subsequent weekly infusions of 250 mg/m2 IV). Cisplatin and vinorelbine are given up to 6 cycles. Weekly cetuximab should continue until unacceptable toxicity or disease progression. In a phase III trial of 1125 patients with advanced EGFR-detectable non-small cell lung cancer, the addition of cetuximab to the doublet cisplatin and vinorelbine significantly improved the primary endpoint overall survival (11.3 months vs. 10.1 months). Response rate (36% vs. 29%) and time to treatment failure (4.2 months vs. 3.7 months) were also significantly greater in the cetuximab arm. Patients who received cetuximab had a significantly higher incidence of febrile neutropenia (22% vs. 15%). Multiple previous trials of EGFR-targeted tyrosine kinase inhibitors in combination with chemotherapy in the front-line treatment of patients with non-small cell lung cancer have generally shown no additional survival benefit with the addition of the tyrosine kinase inhibitor. Consideration should be given to the use of molecular markers to aid in patient selection as further information about this practice continues to become available.

    For the first-line treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in combination with every-6-week cisplatin.
    Intravenous dosage
    Adults

    30 mg/m2 IV over 6 to 10 minutes once weekly in combination with cisplatin (120 mg/m2 IV on days 1 and 29, then every 6 weeks). In a randomized, multicenter, open-label clinical trial of treatment-naive stage III or IV NSCLC, median overall survival was improved in patients treated with vinorelbine plus cisplatin (n = 206; 9.2 months) compared with vindesine plus cisplatin (n = 200; 7.4 months) and vinorelbine alone (n = 206; 7.2 months). The overall response rate was also significantly improved in the group that received vinorelbine plus cisplatin (28% vs. 19% vs. 14%).

    For the treatment of metastatic breast cancer†.
    For the treatment of HER2-positive metastatic breast cancer in combination with trastuzumab†.
    Intravenous dosage
    Adults

    30 mg/m2 or 35 mg/m2 IV on days 1 and 8, every 3 weeks, in combination with trastuzumab (8 mg/kg IV over 90 minutes on day 1 (of cycle 1 only), followed 3 weeks later by 6 mg/kg IV over 30 minutes repeated every 3 weeks). Alternatively, administer vinorelbine 25 mg/m2 IV once weekly, in combination with trastuzumab (4 mg/kg IV over 90 minutes on week 1 (of first cycle only), then 2 mg/kg IV over 30 minutes once weekly). In a phase 3 clinical trial, treatment with vinorelbine (30 mg/m2 or 35 mg/m2) plus trastuzumab did not significantly improve time to progression (15.3 months vs. 12.4 months) or overall survival (38.8 months vs. 35.7 months) compared with docetaxel plus trastuzumab in patients with previously untreated locally advanced or metastatic breast cancer. In a phase 2 clinical trial, the overall response rate was 58% and median time to treatment failure was 5.6 months in patients treated with vinorelbine (25 mg/m2 IV weekly) plus trastuzumab. This regimen was also shown to be similar to taxane-trastuzumab combinations in another phase 2 clinical trial.

    For the treatment of metastatic breast cancer, in patients previously treated with anthracyline and/or taxane therapy†.
    Intravenous dosage
    Adults

    30 mg/m2 IV over 6 to 10 minutes weekly, repeated every 21 days; alternatively, 30 mg/m2 IV over 6 to 10 minutes on days 1 and 8, every 21 days. The addition of gemcitabine to vinorelbine significantly improved median progression-free survival (PFS) compared with vinorelbine alone (6 months vs. 4 months) in a multicenter, randomized, phase 3 study in patients with locally recurrent and metastatic breast cancer who had previously received anthracyclines and taxanes; however, neither the median overall survival (OS) nor the objective response rate (ORR) were significantly different. In another multicenter, randomized, phase 3 study of patients with taxane-refractory, locally advanced or metastatic breast cancer, treatment with an investigator choice regimen consisting of either single-agent vinorelbine or mitomycin C plus vinblastine did not significantly improve median PFS (2.5 months vs. 2.9 months), median OS (9 months vs. 10.4 months), or ORR (12% vs. 10%) compared with pegylated liposomal doxorubicin. The median time to disease progression (105 vs. 84 days) and median OS (283 vs. 284 days) were not significantly different with single-agent docetaxel or vinorelbine in yet another randomized study in patients with metastatic breast cancer in patients who had previously received doxorubicin, epirubicin, or mitoxantrone.

    For the treatment of HER2-positive, trastuzumab-resistant, advanced breast cancer in patients previously treated with a taxane, in combination with trastuzumab and everolimus†.
    Intravenous dosage
    Adults

    25 mg/m2 IV weekly plus trastuzumab 4 mg/kg IV once followed by trastuzumab 2 mg/kg IV weekly and everolimus 5 mg PO once daily until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided with everolimus or everolimus dosage adjustments may be necessary; review drug interactions. Everolimus plus vinorelbine and trastuzumab significantly improved progression-free survival compared with placebo plus vinorelbine and trastuzumab in patients with HER2-positive, trastuzumab-resistant advanced breast cancer in patients who had received prior taxane therapy; objective response rate and overall survival were not significantly improved.

    For the treatment of recurrent ovarian cancer†.
    Intravenous dosage
    Adults

    30 mg/m2 once weekly or on days 1 and 8 of a 21-day cycle has been studied. In a phase II study of 79 patients with recurrent epithelial ovarian cancer (EOC) who had previously received both platinum and taxane therapy, 30 mg/m2 IV push (into the tubing of a free-flowing IV infusion) on days 1 and 8 repeated every 21 days resulted in a 6-month overall survival (OS) rate of 65%, a median OS time of 10.1 months, and an ORR of 3%. The median OS times were 8 months in 52 patients with chemotherapy-resistant disease and 16 months in 27 patients with chemotherapy-sensitive disease. Grade 3 and 4 toxicity included granulocytopenia (56%) and leukopenia (47%). In a multicenter, phase II study in 38 women with persistent or recurrent EOC who had previously received a platinum-based chemotherapy regimen, 30 mg/m2 IV over 20 minutes repeated once weekly until disease progression or unacceptable toxicity led to a time to treatment failure of 12 weeks, median OS time of 60 weeks, and an ORR of 29%. Grade 3 and 4 granulocytopenia was reported in 63% of patients.

    For the treatment of recurrent or metastatic squamous cell head and neck cancer†.
    Intravenous dosage
    Adults

    30 mg/m2 given as an IV infusion once weekly until disease progression or unacceptable toxicity (median number of cycles, 7; range, 1 to 45 cycles) resulted in a median time to progression of 12 weeks, a median overall survival time of 32 weeks, and an overall response rate of 14% in a phase II study in 63 eligible patients with advanced recurrent and/or metastatic squamous cell carcinoma of the head and neck. Grade 3 and 4 toxicity included leukopenia (51%) and neutropenia (53%); additionally, infection occurred in 46% of patients and was the cause of early death in 2 patients.

    For the treatment of desmoid tumor† or aggressive fibromatosis, in combination with methotrexate.
    Intravenous dosage
    Adults

    20 mg/m2 IV plus methotrexate (30 mg/m2 or 50 mg IV) both given weekly has been studied. Vinorelbine plus methotrexate 50 mg IV resulted in a complete or substantial partial remission rate of 60% in 17 patients with symptomatic fibromatosis or desmoid tumor not amenable to curative surgical resection in a small study. Some patients had previously received treatment with vinblastine plus methotrexate but did not tolerate therapy due to neurotoxicity. In this study, neurotoxicity was reported in 16% of patients. In a retrospective analysis of 94 patients up to 21 years of age with aggressive fibromatosis, an objective response was achieved in 11 of 19 patients (58%) who received vinorelbine or vinblastine in combination with methotrexate (30 mg/m2 IV weekly).

    Infants >= 1 month, Children, and Adolescents

    In a retrospective analysis of 94 pediatric patients (age range, 1 month to 21 years) with aggressive fibromatosis, an objective response was achieved in 11 of 19 patients (58%) who received vinorelbine 20 mg/m2 given as an IV bolus weekly or vinblastine (in combination with methotrexate (30 mg/m2 IV weekly).

    For the treatment of relapsed or refractory Hodgkin lymphoma†, in combination with other chemotherapy agents.
    Intravenous dosage
    Adults

    20 mg/m2 IV over 6-10 minutes as a component of the GVD regimen and as a component of the IGEV regimen have been studied. Vinorelbine in combination with gemcitabine (1000 mg/m2 IV over 30 minutes), and pegylated liposomal doxorubicin (15 mg/m2 IV over 30-60 minutes) on days 1 and 8 repeated every 21 days (GVD regimen) for 2 to 6 cycles (or until disease progression or unacceptable toxicity) led to an overall response rate (ORR) of 70% (complete response (CR) rate, 19%) in a phase I/II study in 91 patients. Reduced doses of chemotherapy (gemcitabine 800 mg/m2, vinorelbine 15 mg/m2, and pegylated liposomal doxorubicin 10 mg/m2) were administered to 37 of 40 patients who had previously received a transplant. The 4-year event-free survival and overall survival (OS) rates were 52% and 70%, respectively, in transplant-naive patients and 10% and 34%, respectively, in patients who had previously received a transplant. Thirty-nine transplant-naive patients received an autologous transplant following GVD therapy. One treatment-related death was reported in this study. Treatment with vinorelbine on day 1 plus ifosfamide (2000 mg/m2 IV over 2 hours on days 1 to 4 with 2000 mL of hydration and mesna 2600 mg/m2 IV on days 1 to 4), gemcitabine (800 mg/m2 IV on days 1 and 4), and prednisolone (100 mg on days 1 to 4) repeated every 3 weeks (IGEV regimen) for up to 4 cycles led to an ORR of 81.3% (complete remission (CR) rate, 53.8%) in a multicenter study in 91 patients; additionally, 3-year freedom from progression and OS rates were 52.98% and 70.03%, respectively. Sixty-four patients in complete or partial remission received single or tandem high-dose chemotherapy with peripheral blood stem cell support after 4 IGEV cycles.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    30 mg/m2 IV.

    Elderly

    30 mg/m2 IV.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Total bilirubin 2 mg/dL or less: No dosage adjustment required.
    Total bilirubin 2.1 to 3 mg/dL: Reduce the dose of vinorelbine to 50% of the original dose.
    Total bilirubin greater than 3 mg/dL: Reduce the dose of vinorelbine to 25% of the original dose.
    NOTE: In patients with concomitant hematologic toxicity, administer the lower of the corresponding vinorelbine dose based on hematologic and hepatic laboratory values.

    Renal Impairment

    No dosage adjustment necessary.

    ADMINISTRATION

    CAUTION: Observe and exercise usual precautions for handling, preparing, and administering solutions of cytotoxic drugs. Vinorelbine is a vesicant; skin reactions may occur with accidental exposure.
     

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    Vinorelbine is only given intravenously by persons experienced in administering antineoplastic agents. Because the drug is a vesicant, it should not be given intramuscularly, subcutaneously, or intrathecally. Fatalities have been associated with intrathecal administration vinca alkaloids.
    Syringes containing vinorelbine should be labeled: 'FOR IV USE ONLY. FATAL IF GIVEN INTRATHECALLY.'
    Care should be taken to ensure proper placement of the IV needle or venous access device to prevent leakage of vinorelbine. If evidence of extravasation occurs during administration, the infusion should be stopped and managed in accordance with institutional policies.
     
    Dilution:
    Syringe: Dilute calculated dose to a concentration of 1.5 mg/mL to 3 mg/mL with 5% Dextrose Injection or 0.9% Sodium Chloride Injection.
    IV bag: Dilute calculated dose to a concentration of 0.5 mg/mL to 2 mg/mL with 5% Dextrose Injection, 0.45% Sodium Chloride Injection, 0.9% Sodium Chloride Injection, 5% Dextrose and 0.45% Sodium Chloride Injection, Ringer's Injection, or Lactated Ringer's Injection.
    Diluted injections are stable for up to 24 hours under normal room light if stored in polypropylene syringes or PVC bags at 5 to 30 degrees C.
     
    Intravenous injection:
    Inject diluted injection over 6 to 10 minutes via Y-site into a free-flowing IV infusion closest to the IV bag.
    Following injection, flush with at least 75 to 125 mL of any of the above solutions.

    STORAGE

    Navelbine:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Do not freeze
    - Protect from light
    - Store between 36 to 46 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Anemia, bleeding, bone marrow suppression, infection, neutropenia, thrombocytopenia

    Monitor complete blood counts prior to each dose of vinorelbine, as a dose reduction or delay in treatment may be necessary; do not administer vinorelbine to patients with neutrophil counts < 1000 neutrophils/mm3 on the day of treatment. Advise patients to promptly report any signs of infection such as fever, sore throat, or abnormal pain to their healthcare provider. Bone marrow suppression, including neutropenia, anemia, and thrombocytopenia, have been reported with vinorelbine treatment; this may increase the incidence of fungal, viral, and bacterial infections, bleeding and fatigue. Neutropenia is the major dose-limiting toxicity; use vinorelbine with caution in patients who have had previous myelosuppressive therapy such as chemotherapy or radiotherapy.

    Radiation therapy

    Administration of vinorelbine to patients who have received prior radiation therapy may result in radiation recall reactions.

    Extravasation

    Vinorelbine is considered a vesicant. The intravenous needle or catheter must be properly placed prior to vinorelbine administration. Extravasation of vinorelbine infusions should be avoided. Extravasation may cause local tissue necrosis and/or thrombophlebitis. Patients should be closely monitored for signs and symptoms of extravasation including pain, swelling and poor blood return; if extravasation occurs, manage in accordance with institutional policies.

    Intramuscular administration, intrathecal administration, subcutaneous administration

    Intramuscular administration and subcutaneous administration of vinorelbine should be avoided due to severe skin and tissue necrosis that may occur following these routes of administration. Intrathecal administration of vinca alkaloids is fatal, and this route must not be used. Syringes containing vinorelbine should be labeled 'WARNING - FOR IV USE ONLY. FATAL if given intrathecally.'

    Biliary tract disease, hepatic disease, jaundice

    Drug induced liver injury can occur in patients treated with vinorelbine when used as a single agent or in combination with other chemotherapy. Hepatic function should be assessed before initiation of vinorelbine therapy and periodically during treatment. Because vinorelbine is metabolized and excreted by the liver, dosages may need to be adjusted in cases of increased bilirubin. Use vinorelbine with caution in patients with hepatic disease, or biliary tract disease with obstructive or hepatocellular jaundice.

    Neurological disease

    Vinorelbine treatment has been associated with sensory and motor neuropathies, including severe neuropathies. There may be increased potential for neurotoxicity in patients with pre-existing neurological disease, regardless of etiology. Monitor patients with new or worsening symptoms including paresthesia, hyperesthesia, hyporeflexia, and muscle weakness; discontinue therapy for Grade 2 or higher neuropathy.

    Acute bronchospasm, asthma, chronic obstructive pulmonary disease (COPD), pneumonitis, pulmonary disease

    Patients with pulmonary disease like asthma or chronic obstructive pulmonary disease (COPD) should receive vinorelbine with caution. There have been reports of severe acute bronchospasm, interstitial pneumonitis, and acute respiratory distress syndrome (ARDS), some of which have been fatal, following use of vinca alkaloids; this may be more common when used concomitantly with mitomycin.. The mean time to onset of interstitial pneumonitis and ARDS was 1 week (range, 3—8 days) after vinorelbine administration. Hold vinorelbine therapy and promptly evaluate any patients with alterations in baseline pulmonary symptoms or with new onset dyspnea, cough, hypoxia, or other symptoms. Permanently discontinue vinorelbine for confirmed interstitial pneumonitis or ARDS.

    Autonomic neuropathy, constipation, GI obstruction, GI perforation, ileus

    Vinorelbine has been associated with severe and fatal paralytic ileus, constipation, GI obstruction, necrosis, and GI perforation. Use a prophylactic bowel regimen including adequate dietary fiber, hydration, and stool softeners, to mitigate these adverse effects. Discontinue therapy for Grade 2 or higher autonomic neuropathy causing constipation.

    Children, infants, neonates

    Vinorelbine safety and efficacy have not been established in children and adolescents younger than 18 years of age. In a single-arm study, vinorelbine 33.75 mg/m2 IV (n = 35) or 30 mg/m2 IV (n = 11) was administered weekly for 6 weeks, followed by 2 weeks of rest (8 week cycles) to patients with recurrent solid malignant tumors (rhabdomyosarcoma or undifferentiated sarcoma, n = 21; neuroblastoma, n = 4; CNS tumors, n = 21). The most significant grade 3 or 4 adverse reactions were neutropenia (70%), anemia (33%), motor neuropathy (15%), cranial neuropathy (13%), hypoxia (13%) and dyspnea (11%). Objective tumor response was observed in 2 of 21 sarcoma patients and in no patients with CNS tumors or neuroblastoma. There is no known use of the drug in infants or neonates.

    Pregnancy

    Vinorelbine is classified as FDA pregnancy risk category D and may cause harm to an unborn child if administered to a woman who is pregnant. If vinorelbine is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to the fetus. In animal studies, vinorelbine is embryotoxic and fetotoxic at doses approximately 0.33 and 0.18 times the human therapeutic dose, respectively. At doses that did not cause maternal toxicity, vinorelbine administration resulted in reduced fetal weight and delayed ossification, both in pregnant mice and rabbits.

    Contraception requirements, infertility, male-mediated teratogenicity, pregnancy testing, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during vinorelbine treatment. Vinorelbine can be teratogenic if taken by the mother during pregnancy. Females should avoid pregnancy and should use highly effective contraception during treatment with vinorelbine. Females of reproductive potential should undergo pregnancy testing prior to initiation of vinorelbine. Women who become pregnant while receiving vinorelbine should be apprised of the potential hazard to the fetus. Vinorelbine may also damage spermatozoa (male-mediated teratogenicity); males should use highly effective contraception during treatment and for 3 months after completion of therapy with vinorelbine. Based on animal studies, vinorelbine can cause decreased fertility (infertility) in males. In male rats, administration of vinorelbine twice weekly for 13 or 26 weeks at approximately 0.07 and 0.24 times the recommended human dose, respectively, resulted in decreased spermatogenesis and prostate/seminal vesicle secretion.

    Breast-feeding

    It is not known if vinorelbine is excreted into breast milk. Due to the potential for serious adverse reactions in the nursing infant, the manufacturer recommends discontinuing breast-feeding or discontinuing the drug, taking into account the importance of the drug to the mother.

    Vaccination

    Vaccination with live vaccines should be avoided due to the high risk of neutropenia during vinorelbine therapy.

    ADVERSE REACTIONS

    Severe

    neutropenia / Delayed / 36.0-82.0
    leukopenia / Delayed / 12.0-58.0
    vomiting / Early / 2.0-30.0
    nausea / Early / 2.0-30.0
    anemia / Delayed / 1.0-24.0
    lethargy / Early / 12.0-12.0
    fatigue / Early / 0-12.0
    malaise / Early / 12.0-12.0
    alopecia / Delayed / 0-7.5
    peripheral neuropathy / Delayed / 0-7.0
    hyperbilirubinemia / Delayed / 0-7.0
    elevated hepatic enzymes / Delayed / 0-6.0
    thrombocytopenia / Delayed / 0-5.0
    hearing loss / Delayed / 4.0-4.0
    constipation / Delayed / 3.0-3.0
    phlebitis / Rapid / 0-3.0
    dyspnea / Early / 3.0-3.0
    injection site reaction / Rapid / 0-2.5
    diarrhea / Early / 1.5-2.0
    weakness / Early / 2.0-2.0
    fever / Early / 1.0-1.0
    weight loss / Delayed / 1.0-1.0
    vertigo / Early / 0-1.0
    dizziness / Early / 0-1.0
    paresthesias / Delayed / 0-1.0
    hyperesthesia / Delayed / 0-1.0
    SIADH / Delayed / 0-1.0
    bronchospasm / Rapid / 0-1.0
    acute respiratory distress syndrome (ARDS) / Early / 0-1.0
    hemorrhagic cystitis / Delayed / 0-1.0
    myalgia / Early / 0-1.0
    arthralgia / Delayed / 0-1.0
    myocardial infarction / Delayed / 0-0.1
    GI obstruction / Delayed / Incidence not known
    GI perforation / Delayed / Incidence not known
    ileus / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    angioedema / Rapid / Incidence not known
    tissue necrosis / Early / Incidence not known
    pulmonary embolism / Delayed / Incidence not known
    thromboembolism / Delayed / Incidence not known
    thrombosis / Delayed / Incidence not known
    pulmonary edema / Early / Incidence not known
    pancreatitis / Delayed / Incidence not known

    Moderate

    chest pain (unspecified) / Early / 5.0-5.0
    bone marrow suppression / Delayed / Incidence not known
    dysphagia / Delayed / Incidence not known
    erythema / Early / Incidence not known
    radiation recall reaction / Delayed / Incidence not known
    esophagitis / Delayed / Incidence not known
    palmar-plantar erythrodysesthesia (hand and foot syndrome) / Delayed / Incidence not known
    hypertension / Early / Incidence not known
    hypotension / Rapid / Incidence not known
    sinus tachycardia / Rapid / Incidence not known
    hyponatremia / Delayed / Incidence not known

    Mild

    anorexia / Delayed / 46.0-46.0
    dysgeusia / Early / 17.0-17.0
    rash / Early / 0-5.0
    abdominal pain / Early / Incidence not known
    headache / Early / Incidence not known
    urticaria / Rapid / Incidence not known
    pruritus / Rapid / Incidence not known
    flushing / Rapid / Incidence not known
    back pain / Delayed / Incidence not known

    DRUG INTERACTIONS

    Aliskiren; Amlodipine: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with amlodipine is necessary. Vinorelbine is a CYP3A4 substrate and amlodipine is a weak CYP3A4 inhibitor.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with amlodipine is necessary. Vinorelbine is a CYP3A4 substrate and amlodipine is a weak CYP3A4 inhibitor.
    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.
    Amiodarone: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with amiodarone is necessary. Vinorelbine is a CYP3A4 substrate and amiodarone is a moderate CYP3A4 inhibitor.
    Amlodipine: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with amlodipine is necessary. Vinorelbine is a CYP3A4 substrate and amlodipine is a weak CYP3A4 inhibitor.
    Amlodipine; Atorvastatin: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with amlodipine is necessary. Vinorelbine is a CYP3A4 substrate and amlodipine is a weak CYP3A4 inhibitor.
    Amlodipine; Benazepril: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with amlodipine is necessary. Vinorelbine is a CYP3A4 substrate and amlodipine is a weak CYP3A4 inhibitor.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with amlodipine is necessary. Vinorelbine is a CYP3A4 substrate and amlodipine is a weak CYP3A4 inhibitor.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with amlodipine is necessary. Vinorelbine is a CYP3A4 substrate and amlodipine is a weak CYP3A4 inhibitor.
    Amlodipine; Olmesartan: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with amlodipine is necessary. Vinorelbine is a CYP3A4 substrate and amlodipine is a weak CYP3A4 inhibitor.
    Amlodipine; Telmisartan: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with amlodipine is necessary. Vinorelbine is a CYP3A4 substrate and amlodipine is a weak CYP3A4 inhibitor.
    Amlodipine; Valsartan: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with amlodipine is necessary. Vinorelbine is a CYP3A4 substrate and amlodipine is a weak CYP3A4 inhibitor.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Increased concentrations of vinorelbine are likely. Consider if alternative antibiotic therapy is appropriate. Monitor for vinorelbine-related side effects, including neurotoxicity and neutropenia, if these drugs must be used together. Clarithromycin is a potent inhibitor of CYP3A4 and also inhibits P-gp. Vinorelbine is a CYP3A4 and P-gp substrate. Reports of interactions, including serious toxicity, between clarithromycin or similar macrolides and vinca alkaloids have been noted.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Increased concentrations of vinorelbine are likely. Consider if alternative antibiotic therapy is appropriate. Monitor for vinorelbine-related side effects, including neurotoxicity and neutropenia, if these drugs must be used together. Clarithromycin is a potent inhibitor of CYP3A4 and also inhibits P-gp. Vinorelbine is a CYP3A4 and P-gp substrate. Reports of interactions, including serious toxicity, between clarithromycin or similar macrolides and vinca alkaloids have been noted.
    Anticoagulants: (Moderate) Due to the risk of bleeding with natural antineoplastics, patients should receive other agents that may increase the risk of bleeding, such as anticoagulants.
    Antithrombin III: (Moderate) Due to the risk of bleeding with natural antineoplastics, patients should receive other agents that may increase the risk of bleeding, such as anticoagulants.
    Apixaban: (Moderate) Due to the risk of bleeding with natural antineoplastics, patients should receive other agents that may increase the risk of bleeding, such as anticoagulants.
    Argatroban: (Moderate) Due to the risk of bleeding with natural antineoplastics, patients should receive other agents that may increase the risk of bleeding, such as anticoagulants.
    Atazanavir: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with atazanavir is necessary. Vinorelbine is a CYP3A4 substrate and atazanavir is a strong CYP3A4 inhibitor.
    Atazanavir; Cobicistat: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with atazanavir is necessary. Vinorelbine is a CYP3A4 substrate and atazanavir is a strong CYP3A4 inhibitor. (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with cobicistat is necessary. Vinorelbine is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor.
    Betrixaban: (Moderate) Due to the risk of bleeding with natural antineoplastics, patients should receive other agents that may increase the risk of bleeding, such as anticoagulants.
    Bicalutamide: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with bicalutamide is necessary. Vinorelbine is a CYP3A4 substrate and bicalutamide is a weak CYP3A4 inhibitor.
    Bivalirudin: (Moderate) Due to the risk of bleeding with natural antineoplastics, patients should receive other agents that may increase the risk of bleeding, such as anticoagulants.
    Ceritinib: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with ceritinib is necessary. Vinorelbine is a CYP3A4 substrate and ceritinib is a CYP3A4 inhibitor.
    Chloramphenicol: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with chloramphenicol is necessary. Vinorelbine is a CYP3A4 substrate and chloramphenicol is a strong CYP3A4 inhibitor.
    Cimetidine: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with cimetidine is necessary. Vinorelbine is a CYP3A4 substrate and cimetidine is a weak CYP3A4 inhibitor.
    Ciprofloxacin: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with ciprofloxacin is necessary. Vinorelbine is a CYP3A4 substrate and ciprofloxacin is a moderate CYP3A4 inhibitor.
    Clarithromycin: (Major) Increased concentrations of vinorelbine are likely. Consider if alternative antibiotic therapy is appropriate. Monitor for vinorelbine-related side effects, including neurotoxicity and neutropenia, if these drugs must be used together. Clarithromycin is a potent inhibitor of CYP3A4 and also inhibits P-gp. Vinorelbine is a CYP3A4 and P-gp substrate. Reports of interactions, including serious toxicity, between clarithromycin or similar macrolides and vinca alkaloids have been noted.
    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: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with cobicistat is necessary. Vinorelbine is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with cobicistat is necessary. Vinorelbine is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with cobicistat is necessary. Vinorelbine is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor.
    Conivaptan: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with conivaptan is necessary. Vinorelbine is a CYP3A4 substrate and conivaptan is a strong CYP3A4 inhibitor.
    Crizotinib: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with crizotinib is necessary. Vinorelbine is a CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor.
    Cyclosporine: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with cyclosporine is necessary. Vinorelbine is a CYP3A4 substrate and cyclosporine is a moderate CYP3A4 inhibitor.
    Dabigatran: (Moderate) Due to the risk of bleeding with natural antineoplastics, patients should receive other agents that may increase the risk of bleeding, such as anticoagulants.
    Dalfopristin; Quinupristin: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with dalfopristin; quinupristin is necessary. Vinorelbine is a CYP3A4 substrate and dalfopristin; quinupristin is a weak CYP3A4 inhibitor.
    Dalteparin: (Moderate) Due to the risk of bleeding with natural antineoplastics, patients should receive other agents that may increase the risk of bleeding, such as anticoagulants.
    Danaparoid: (Moderate) Due to the risk of bleeding with natural antineoplastics, patients should receive other agents that may increase the risk of bleeding, such as anticoagulants.
    Danazol: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with danazol is necessary. Vinorelbine is a CYP3A4 substrate and danazol is a moderate CYP3A4 inhibitor.
    Darunavir: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with darunavir is necessary. Vinorelbine is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor.
    Darunavir; Cobicistat: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with cobicistat is necessary. Vinorelbine is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with darunavir is necessary. Vinorelbine is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with cobicistat is necessary. Vinorelbine is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with darunavir is necessary. Vinorelbine is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with ritonavir is necessary. Vinorelbine is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor.
    Delavirdine: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with delavirdine is necessary. Vinorelbine is a CYP3A4 substrate and delavirdine is a strong CYP3A4 inhibitor.
    Desirudin: (Moderate) Due to the risk of bleeding with natural antineoplastics, patients should receive other agents that may increase the risk of bleeding, such as anticoagulants.
    Diltiazem: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with diltiazem is necessary. Vinorelbine is a CYP3A4 substrate and diltiazem is a moderate CYP3A4 inhibitor.
    Dronedarone: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with dronedarone is necessary. Vinorelbine is a CYP3A4 substrate and dronedarone is a moderate CYP3A4 inhibitor.
    Duvelisib: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with duvelisib is necessary. Vinorelbine is a CYP3A4 substrate and duvelisib is a moderate CYP3A4 inhibitor.
    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 risk of bleeding with natural antineoplastics, patients should receive other agents that may increase the risk of bleeding, such as anticoagulants.
    Elbasvir; Grazoprevir: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with grazoprevir is necessary. Vinorelbine is a CYP3A4 substrate and grazoprevir is a weak CYP3A4 inhibitor.
    Enoxaparin: (Moderate) Due to the risk of bleeding with natural antineoplastics, patients should receive other agents that may increase the risk of bleeding, such as anticoagulants.
    Erythromycin: (Major) Increased concentrations of vinorelbine are likely. Consider if alternative antibiotic therapy is appropriate. Monitor for vinorelbine-related side effects, including neurotoxicity and neutropenia, if these drugs must be used together. Erythromycin is an inhibitor of CYP3A4 and also inhibits P-gp. Vinorelbine is a CYP3A4 and P-gp substrate. Reports of interactions, including serious toxicity, between macrolides and vinca alkaloids have been noted.
    Erythromycin; Sulfisoxazole: (Major) Increased concentrations of vinorelbine are likely. Consider if alternative antibiotic therapy is appropriate. Monitor for vinorelbine-related side effects, including neurotoxicity and neutropenia, if these drugs must be used together. Erythromycin is an inhibitor of CYP3A4 and also inhibits P-gp. Vinorelbine is a CYP3A4 and P-gp substrate. Reports of interactions, including serious toxicity, between macrolides and vinca alkaloids have been noted.
    Everolimus: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with everolimus is necessary. Vinorelbine is a CYP3A4 substrate and everolimus is a weak CYP3A4 inhibitor.
    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.
    Filgrastim, G-CSF: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.
    Fluconazole: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with fluconazole is necessary. Vinorelbine is a CYP3A4 substrate and fluconazole is a moderate CYP3A4 inhibitor.
    Fluoxetine: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with fluoxetine is necessary. Vinorelbine is a CYP3A4 substrate. Fluoxetine is a weak CYP3A4 inhibitor, but its active metabolite, norfluoxetine, is a moderate inhibitor of CYP3A4.
    Fluoxetine; Olanzapine: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with fluoxetine is necessary. Vinorelbine is a CYP3A4 substrate. Fluoxetine is a weak CYP3A4 inhibitor, but its active metabolite, norfluoxetine, is a moderate inhibitor of CYP3A4.
    Fluvoxamine: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with fluvoxamine is necessary. Vinorelbine is a CYP3A4 substrate and fluvoxamine is a moderate CYP3A4 inhibitor.
    Fondaparinux: (Moderate) Due to the risk of bleeding with natural antineoplastics, patients should receive other agents that may increase the risk of bleeding, such as anticoagulants.
    Fosamprenavir: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with fosamprenavir is necessary. Vinorelbine is a CYP3A4 substrate and fosamprenavir is a strong CYP3A4 inhibitor.
    Fostamatinib: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with fostamatinib is necessary. Vinorelbine is a CYP3A4 substrate and fostamatinib is a weak CYP3A4 inhibitor.
    Gadobenate Dimeglumine: (Moderate) Gadobenate dimeglumine is a substrate for the canalicular multi-specific organic anion transporter (MOAT). Use with other MOAT substrates, such as vinca alkaloids, may result in prolonged systemic exposure of the coadministered drug. Caution is advised if these drugs are used together.
    Ganciclovir: (Moderate) Use ganciclovir and vinca alkaloids together only if the potential benefits outweigh the risks; bone marrow suppression, spermatogenesis inhibition, skin toxicity, and gastrointestinal toxicity may be additive as both drugs inhibit rapidly dividing cells.
    Grapefruit juice: (Moderate) Instruct patients that consuming grapefruit or grapefruit juice may result in earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy. Vinorelbine is a CYP3A4 substrate and grapefruit juice is a strong CYP3A4 inhibitor.
    Heparin: (Moderate) Due to the risk of bleeding with natural antineoplastics, patients should receive other agents that may increase the risk of bleeding, such as anticoagulants.
    Idelalisib: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with idelalisib is necessary. Vinorelbine is a CYP3A4 substrate and idelalisib is a strong CYP3A4 inhibitor.
    Imatinib: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with imatinib is necessary. Vinorelbine is a CYP3A4 substrate and imatinib is a moderate CYP3A4 inhibitor.
    Indinavir: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with indinavir is necessary. Vinorelbine is a CYP3A4 substrate and indinavir is a strong CYP3A4 inhibitor.
    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.
    Isavuconazonium: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with isavuconazonium is necessary. Vinorelbine is a CYP3A4 substrate and isavuconazonium is a moderate CYP3A4 inhibitor.
    Isoniazid, INH: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with isoniazid is necessary. Vinorelbine is a CYP3A4 substrate and isoniazid is a weak CYP3A4 inhibitor.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with isoniazid is necessary. Vinorelbine is a CYP3A4 substrate and isoniazid is a weak CYP3A4 inhibitor.
    Isoniazid, INH; Rifampin: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with isoniazid is necessary. Vinorelbine is a CYP3A4 substrate and isoniazid is a weak CYP3A4 inhibitor.
    Itraconazole: (Major) Avoid the use of vinorelbine during and for 2 weeks after discontinuation of itraconazole due to the risk of an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy. Vinorelbine is a CYP3A4 substrate and itraconazole is a strong CYP3A4 inhibitor. Concomitant administration of another vinca alkaloid with itraconazole has resulted in an increased incidence of neurotoxicity.
    Ketoconazole: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with ketoconazole is necessary. Vinorelbine is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor.
    Lapatinib: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with lapatinib is necessary. Vinorelbine is a CYP3A4 substrate and lapatinib is a weak CYP3A4 inhibitor.
    Larotrectinib: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with larotrectinib is necessary. Vinorelbine is a CYP3A4 substrate and larotrectinib is a weak CYP3A4 inhibitor.
    Lepirudin: (Moderate) Due to the risk of bleeding with natural antineoplastics, patients should receive other agents that may increase the risk of bleeding, such as anticoagulants.
    Letermovir: (Moderate) An increase in plasma concentrations of vinorelbine may occur during concurrent administration with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Closely monitor for vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if these drugs are given together. Vinorelbine is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
    Live Vaccines: (Severe) Do not administer live vaccines to vinorelbine recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving vinorelbine. Before initiation of vinorelbine therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Vinorelbine recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased.
    Lopinavir; Ritonavir: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with lopinavir; ritonavir is necessary. Vinorelbine is a CYP3A4 substrate and lopinavir; ritonavir is a strong CYP3A4 inhibitor. (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with ritonavir is necessary. Vinorelbine is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor.
    Mifepristone: (Moderate) Increased concentrations of vinorelbine are likely if chronic mifepristone therapy is given concurrently; exercise caution and monitor for vinorelbine-related side effects, including neurotoxicity and myelosuppression. Mifepristone is an inhibitor of CYP3A4 and possibly an inhibitor of P-gp. Vinorelbine is a CYP3A4 and P-gp substrate. Due to the slow elimination of mifepristone from the body, such interactions may be observed for a prolonged period after mifepristone administration. Use the lowest dose of vinorelbine necessary, with appropriate monitoring and follow-up
    Mitomycin: (Moderate) Monitor for pulmonary toxicity if coadministration of mitomycin and vinca alkaloids is necessary. Acute shortness of breath and severe bronchospasm have been reported following the administration of vinca alkaloids in patients who had previously or simultaneously received mitomycin. The onset of acute respiratory distress occurred within minutes to hours after vinca alkaloid administration. Treatment with bronchodilators, steroids, and/or oxygen may provide symptomatic relief.
    Nefazodone: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with nefazodone is necessary. Vinorelbine is a CYP3A4 substrate and nefazodone is a strong CYP3A4 inhibitor.
    Nelfinavir: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with nelfinavir is necessary. Vinorelbine is a CYP3A4 substrate and nelfinavir is a strong CYP3A4 inhibitor.
    Netupitant, Fosnetupitant; Palonosetron: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with netupitant is necessary. Vinorelbine is a CYP3A4 substrate and netupitant is a moderate CYP3A4 inhibitor.
    Nicardipine: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with nicardipine is necessary. Vinorelbine is a CYP3A4 substrate and nicardipine is a weak CYP3A4 inhibitor.
    Nilotinib: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including (e.g. myelosuppression, peripheral neuropathy) if coadministration with nilotinib is necessary. Nilotinib may increase vinorelbine exposure. Vinorelbine is a CYP3A4 substrate and nilotinib is a moderate CYP3A4 inhibitor.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with ritonavir is necessary. Vinorelbine is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor.
    Palbociclib: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with palbociclib is necessary. Vinorelbine is a CYP3A4 substrate and palbociclib is a weak CYP3A4 inhibitor.
    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) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with pazopanib is necessary. Vinorelbine is a CYP3A4 substrate and pazopanib is a weak CYP3A4 inhibitor.
    Pegfilgrastim: (Major) Pegfilgrastim induces the proliferation of neutrophil-progenitor cells, and because antineoplastic agents exert 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 risk of bleeding with natural antineoplastics, patients should receive other agents that may increase the risk of bleeding, such as anticoagulants.
    Perindopril; Amlodipine: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with amlodipine is necessary. Vinorelbine is a CYP3A4 substrate and amlodipine is a weak CYP3A4 inhibitor.
    Posaconazole: (Major) Avoid coadministration of posaconazole with vinorelbine if possible due to increased plasma concentrations of vinorelbine. If concomitant use is unavoidable and alternative antifungal options are not available, frequently monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including ileus and neurotoxicity. Vinorelbine is a CYP3A4 substrate and posaconazole is a strong CYP3A4 inhibitor. Concomitant administration of azole antifungals, including posaconazole, with another vinca alkaloid has been associated with neurotoxicity and other serious adverse reactions, including seizures, peripheral neuropathy, syndrome of inappropriate antidiuretic hormone secretion, and paralytic ileus.
    Quinine: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with quinine is necessary. Vinorelbine is a CYP3A4 substrate and quinine is a moderate CYP3A4 inhibitor.
    Ranolazine: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with ranolazine is necessary. Vinorelbine is a CYP3A4 substrate and ranolazine is a weak CYP3A4 inhibitor.
    Ribociclib: (Moderate) Monitor for increased severity or earlier onset of vinorelbine-related adverse reactions if coadministration with ribociclib is necessary. Vinorelbine is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor.
    Ribociclib; Letrozole: (Moderate) Monitor for increased severity or earlier onset of vinorelbine-related adverse reactions if coadministration with ribociclib is necessary. Vinorelbine is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor.
    Ritonavir: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with ritonavir is necessary. Vinorelbine is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor.
    Rivaroxaban: (Moderate) Due to the risk of bleeding with natural antineoplastics, patients should receive other agents that may increase the risk of bleeding, such as anticoagulants.
    Rucaparib: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with rucaparib is necessary. Vinorelbine is a CYP3A4 substrate and rucaparib is a weak CYP3A4 inhibitor.
    Saquinavir: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with saquinavir is necessary. Vinorelbine is a CYP3A4 substrate and saquinavir is a strong CYP3A4 inhibitor.
    Simeprevir: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with simeprevir is necessary. Vinorelbine is a CYP3A4 substrate and simeprevir is a weak CYP3A4 inhibitor.
    Streptogramins: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with dalfopristin; quinupristin is necessary. Vinorelbine is a CYP3A4 substrate and dalfopristin; quinupristin is a weak CYP3A4 inhibitor.
    Tbo-Filgrastim: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.
    Telithromycin: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with telithromycin is necessary. Vinorelbine is a CYP3A4 substrate and telithromycin is a strong CYP3A4 inhibitor.
    Ticagrelor: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with ticagrelor is necessary. Vinorelbine is a CYP3A4 substrate and ticagrelor is a weak CYP3A4 inhibitor.
    Tinzaparin: (Moderate) Due to the risk of bleeding with natural antineoplastics, patients should receive other agents that may increase the risk of bleeding, such as anticoagulants.
    Tipranavir: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with tipranavir is necessary. Vinorelbine is a CYP3A4 substrate and tipranavir is a strong CYP3A4 inhibitor.
    Trandolapril; Verapamil: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with verapamil is necessary. Vinorelbine is a CYP3A4 substrate and verapamil is a moderate CYP3A4 inhibitor.
    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.
    Valganciclovir: (Moderate) Use valganciclovir and vinca alkaloids together only if the potential benefits outweigh the risks; bone marrow suppression, spermatogenesis inhibition, skin toxicity, and gastrointestinal toxicity may be additive as both drugs inhibit rapidly dividing cells.
    Verapamil: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with verapamil is necessary. Vinorelbine is a CYP3A4 substrate and verapamil is a moderate CYP3A4 inhibitor.
    Voriconazole: (Major) Avoid coadministration of voriconazole with vinorelbine if possible due to increased plasma concentrations of vinorelbine. If concomitant use is unavoidable and alternative antifungal options are not available, frequently monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including ileus and neurotoxicity. Vinorelbine is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Concomitant administration of azole antifungals, including posaconazole, with another vinca alkaloid has been associated with neurotoxicity and other serious adverse reactions, including seizures, peripheral neuropathy, syndrome of inappropriate antidiuretic hormone secretion, and paralytic ileus.
    Warfarin: (Moderate) Due to the risk of bleeding with natural antineoplastics, patients should receive other agents that may increase the risk of bleeding, such as anticoagulants.
    Zafirlukast: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with zafirlukast is necessary. Vinorelbine is a CYP3A4 substrate and zafirlukast is a weak CYP3A4 inhibitor.

    PREGNANCY AND LACTATION

    Pregnancy

    Vinorelbine is classified as FDA pregnancy risk category D and may cause harm to an unborn child if administered to a woman who is pregnant. If vinorelbine is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to the fetus. In animal studies, vinorelbine is embryotoxic and fetotoxic at doses approximately 0.33 and 0.18 times the human therapeutic dose, respectively. At doses that did not cause maternal toxicity, vinorelbine administration resulted in reduced fetal weight and delayed ossification, both in pregnant mice and rabbits.

    Counsel patients about the reproductive risk and contraception requirements during vinorelbine treatment. Vinorelbine can be teratogenic if taken by the mother during pregnancy. Females should avoid pregnancy and should use highly effective contraception during treatment with vinorelbine. Females of reproductive potential should undergo pregnancy testing prior to initiation of vinorelbine. Women who become pregnant while receiving vinorelbine should be apprised of the potential hazard to the fetus. Vinorelbine may also damage spermatozoa (male-mediated teratogenicity); males should use highly effective contraception during treatment and for 3 months after completion of therapy with vinorelbine. Based on animal studies, vinorelbine can cause decreased fertility (infertility) in males. In male rats, administration of vinorelbine twice weekly for 13 or 26 weeks at approximately 0.07 and 0.24 times the recommended human dose, respectively, resulted in decreased spermatogenesis and prostate/seminal vesicle secretion.

    MECHANISM OF ACTION

    Vinorelbine, as with all vinca alkaloids, primarily exerts its cytotoxic effects on the cell by interfering with microtubules, which compose mitotic spindle fibers leading to cell cycle arrest in the metaphase. Vinca alkaloids bind to a common pair of sites on each subunit of tubulin (alpha, beta) during the M-phase of the cell cycle. There are at least 2 types of tubulin binding sites for vinca alkaloids. The high-affinity sites, which are found in small numbers, are responsible for the disruption of microtubule assembly. Vinca alkaloid binding to the low-affinity binding sites results in the splitting of the microtubules into spiral aggregates or spiral protofilaments, which leads to the disintegration of the microtubule. Binding to the low-affinity sites occurs at high drug concentrations. The concentration of vinca alkaloids that induces metaphase arrest in 50% of cells results in inhibition of cell proliferation. At their lowest effective concentration, vinca alkaloids cause metaphase arrest by inhibition of mitotic spindle function. At higher concentrations, the organization of the microtubules and chromosomes deteriorates. After exposure to vinca alkaloids, some cells undergo a cell cycle block, or stathmokinesis, which is only temporary. If the drug concentration falls beneath a certain level, these cells may avoid the cytotoxic effects and divide normally. Vinca alkaloids also affect microtubules involved in chemotaxis, migration, intracellular transport, movement of organelles such as mitochondria, secretory processes, membrane trafficking, transmission of receptor signals and cell structural integrity. Vinorelbine has a lower affinity for neuronal microtubules than mitotic tubules, which may explain vinorelbine's decreased incidence of neurotoxicity as compared to vincristine. Vinca alkaloids have other effects that may or may not be related to their effects on tubulin. These activities include competition for transport of amino acids into cells, inhibition of purine synthesis, inhibition of RNA, DNA and protein synthesis, disruption of lipid metabolism, inhibition of glycolysis, changes in antidiuretic hormone release and disruption of cell membrane integrity and membrane function. Differences in the cytotoxic effects of different vinca alkaloids may be due to differences in cellular retention, intracellular concentrations of guanosine triphosphate (GTP), and pharmacokinetics.
     
    Resistance to vinca alkaloids is thought to occur through several mechanisms. Multidrug resistance (MDR) results in decreased intracellular drug accumulation and retention. MDR is due to overexpression of the mdr-1 gene, which codes 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. P-gp is expressed in many malignancies including renal and large bowel cancers, and in post-treatment lymphomas, leukemias and multiple myeloma. The second mechanism of resistance to vinca alkaloids is due to alterations in the alpha- and beta-tubulin subunits. These changes result in either decreased drug binding or increased resistance to microtubule disassembly. This type of resistance to vinca alkaloids may confer sensitivity to taxanes, which inhibit microtubule disassembly. Due to structural differences of vinorelbine, resistance to other vinca alkaloids may not confer resistance to vinorelbine.

    PHARMACOKINETICS

    Vinorelbine is administered intravenously or orally. The oral formulation is not available in the United States. Vinorelbine concentrations are highest in liver, spleen, kidneys, lungs, thymus, heart, and muscle. Minimal distribution occurs to fat, bone marrow, and brain tissue. Vinorelbine achieves higher lung concentrations than vincristine. There is considerable binding of vinorelbine to platelets and lymphocytes. Binding to albumin or alpha-1-acid-glycoprotein also occurs so that total bound drug in the plasma is 79.6% to 91.2%; the free fraction in human plasma was approximately 0.11 over a concentration range of 234 to 1,169 ng/mL. Steady state volume of distribution was 25.4 to 40.1 L/kg. Metabolism of vinorelbine occurs in the liver via cytochrome P450 CYP3A subfamily. Metabolites include deacetylvinorelbine, which is the primary metabolite and possesses antitumor activity similar to vinorelbine, and vinorelbine N-oxide; very small, if any, quantifiable levels of either metabolite are present in blood or urine after therapeutic doses of vinorelbine (30 mg/m2). After administration of radioactive vinorelbine, approximately 18% of the radioactivity was recovered in urine and 46% in feces; in a separate study, 10.9% +/- 0.7% of a 30 mg/m2 IV dose was excreted as parent drug in the urine. Two-thirds of renal elimination happens in the first 24 hours. In a pharmacokinetic study of vinorelbine 30 mg/m2 IV over 15 to 20 minutes (n = 49), the terminal half-life of vinorelbine was 27.7 to 43.6 hours and the mean plasma clearance was 0.97 to 1.25 L/h/kg. Within the therapeutic dosing range, dose dependent pharmacokinetics are not observed.
     
    Affected cytochrome P450 (CYP) isoenzymes and drug transporters: CYP3A and P-glycoprotein (P-gp)
    Vinorelbine is a substrate of the CYP3A isoenzyme subfamily and P-gp.

    Oral Route

    NOTE: The oral formulation of vinorelbine is not available in the United States.
     
    Following oral administration of powder-filled capsules or liquid-filled gelatin capsules, the bioavailability of vinorelbine is 43% and 27%, respectively. Peak plasma concentrations are noted within 1 to 2 hours. The pharmacokinetics of oral vinorelbine are similar the intravenous formulation.