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    Vinca Alkaloids and Analogs

    BOXED WARNING

    Anemia, bone marrow suppression, infection, neutropenia, thrombocytopenia

    Severe bone marrow suppression including neutropenia, anemia, and thrombocytopenia occurs in patients treated with vinorelbine and can lead to infection, septic shock, hospitalization, and death. Neutropenia is the major dose-limiting toxicity, with the nadir between days 7 and 10, and recovery typically within the following 7 to 14 days. Monitor complete blood counts prior to each dose of vinorelbine; a dose adjustment may be necessary based on day-of-treatment neutrophil counts. Do not administer vinorelbine to patients with neutrophil counts less than 1,000 cells/mm3.

    DEA CLASS

    Rx

    DESCRIPTION

    Semi-synthetic vinca alkaloid; microtubule inhibitor
    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).
    For the treatment of metastatic non-small cell lung cancer (NSCLC), as monotherapy.
    Intravenous dosage
    Adults

    30 mg/m2 IV over 6 to 10 minutes, once weekly. Coadministration of certain drugs may require special caution; review drug interactions. Treatment with vinorelbine monotherapy improved the median survival time in patients with previously untreated stage IV NSCLC compared with fluorouracil/leucovorin in a multicenter, randomized, open-label clinical trial (30 weeks vs. 22 weeks). Partial objective responses were observed 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 22, in combination with cisplatin (100 mg/m2 IV on day 1) every 28 days. Coadministration of certain drugs may require special caution; review drug interactions. Treatment with vinorelbine and every-4-week cisplatin significantly improved the overall response rate (19% vs. 8%) and median overall survival (7.8 months vs. 6.2 months) in patients with previously untreated stage IIIb or IV NSCLC compared with cisplatin alone in a randomized, open-label clinical trial.

    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 [34316] [34317] has been evaluated in randomized, phase 3 studies. Coadministration of certain drugs may require special caution; review drug interactions. 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.[34316] 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.[34317] [45478]

    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. Coadministration of certain drugs may require special caution; review drug interactions. In a phase 3 trial of 1,125 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%).[35499] 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.[30549] [30550] [34184] [34185] [43302]

    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). Coadministration of certain drugs may require special caution; review drug interactions. Treatment with vinorelbine plus every-6-week cisplatin significantly improved the response rate (28% vs. 14%) and median overall survival (9.2 months vs. 7.2 months) in patients with previously untreated stage III or IV NSCLC compared with vinorelbine monotherapy in a randomized, open-label clinical trial.

    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: For patients with concurrent hematologic toxicity and hepatic impairment/hepatotoxicity, administer the lower of the recommended dose adjustments based on the corresponding starting dose of vinorelbine.

    Renal Impairment

    No dosage adjustment necessary.

    ADMINISTRATION

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

    Injectable Administration

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

    Intravenous Administration

    Vinorelbine is for intravenous (IV) use only; fatalities have been associated with intrathecal administration of vinca alkaloids.[56871] [64256]
    The Institute for Safe Medication Practices (ISMP) recommend dispensing vinca alkaloids in a minibag of a compatible solution to prevent accidental intrathecal administration; this best practice is supported by other accrediting and professional organizations.[64256] [64348] [64349] [64350] [64351]
    Ensure the IV needle or catheter is properly positioned before administration; monitor the infusion site and immediately discontinue and administer appropriate treatment (e.g., hyaluronidase, application of heat) if extravasation occurs.[56871]
     
    Intermittent IV Infusion
    In a flexible plastic container (i.e., minibag), dilute the calculated dose/volume of vinorelbine in a compatible IV fluid (e.g., 0.9% Sodium Chloride injection, 0.45% Sodium Chloride injection, 5% Dextrose injection, 5% Dextrose and 0.45% Sodium Chloride injection, Ringer's injection, or Lactated Ringer's injection) to a final concentration between 0.5 and 2 mg/mL.[56871]
    ISMP recommends a diluent volume of 25 mL for pediatric patients and 50 mL for adults.[64256]
    Storage of admixture (in polyvinyl chloride bags): Store for up to 24 hours under normal light conditions at 5 to 30 degrees C (41 to 86 degrees F).
    Administer IV over 6 to 10 minutes into the side port of a free-flowing IV line; flush with at least 75 to 125 mL of a compatible solution.[56871]
     
    IV Injection
    NOTE: Several accrediting and professional organizations advise against the administration of vinca alkaloids in a syringe due to the risk of accidental intrathecal administration.[64256] [64348] [64349] [64350] [64351]
    According to the manufacturer, dilute the calculated dose/volume of vinorelbine in 0.9% Sodium Chloride injection or 5% Dextrose injection in a syringe to a final concentration between 1.5 and 3 mg/mL.
    Storage of syringe: Store for up to 24 hours under normal light conditions at 5 to 30 degrees C (41 to 86 degrees F).
    Administer IV over 6 to 10 minutes into the side port of a free-flowing IV line; flush with at least 75 to 125 mL of a compatible solution.[56871]

    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, bone marrow suppression, infection, neutropenia, thrombocytopenia

    Severe bone marrow suppression including neutropenia, anemia, and thrombocytopenia occurs in patients treated with vinorelbine and can lead to infection, septic shock, hospitalization, and death. Neutropenia is the major dose-limiting toxicity, with the nadir between days 7 and 10, and recovery typically within the following 7 to 14 days. Monitor complete blood counts prior to each dose of vinorelbine; a dose adjustment may be necessary based on day-of-treatment neutrophil counts. Do not administer vinorelbine to patients with neutrophil counts less than 1,000 cells/mm3.

    Extravasation, ocular exposure

    Vinorelbine is a moderate vesicant; avoid extravasation of vinorelbine, ocular exposure, and contact with the skin or mucosa.[64253] The intravenous needle or catheter must be properly placed prior to vinorelbine administration.[56871] Vinorelbine commonly causes venous irritation and burning sensations during administration, which can be prevented by proper dilution, short infusion time, and use of an adequately large vein.[64253] If signs or symptoms of extravasation occur, immediately stop administration of vinorelbine and begin recommended management procedures per institutional policies. If vinorelbine contacts the skin or mucosa, immediately wash with soap and water. If ocular exposure occurs, flush the eyes with water immediately and thoroughly.[56871]

    Intrathecal administration

    Fatal neurological effects (e.g., destruction of the central nervous system) have occurred following intrathecal administration of vinca alkaloids; therefore, this route must not be used for vinorelbine. The Institute for Safe Medication Practices (ISMP) recommend dispensing vinca alkaloids in a minibag of a compatible solution to prevent accidental intrathecal administration; this best practice is supported by other accrediting and professional organizations.[64256] [64348] [64349] [64350] [64351]

    Hepatic disease

    Use vinorelbine with caution in patients with a history of hepatic disease; drug-induced liver injury manifested by increased AST and hyperbilirubinemia can occur during treatment. Assess hepatic function prior to initiation of vinorelbine therapy and periodically during treatment. A dose reduction may be necessary for patients with hyperbilirubinemia.[56871]

    Neurotoxicity, peripheral neuropathy

    Use vinorelbine with caution in patients with a history of peripheral neuropathy. Neurotoxicity including sensory and motor neuropathy, in some cases severe, has occurred with vinorelbine treatment. Monitor for new or worsening signs and symptoms of neuropathy, such as paresthesia, hyperesthesia, hyporeflexia, and muscle weakness. Discontinue vinorelbine for grade 2 or higher neuropathy.

    Pneumonitis, pulmonary disease, pulmonary toxicity

    Pulmonary toxicity including severe acute bronchospasm, interstitial pneumonitis, and acute respiratory distress syndrome (ARDS) has occurred with vinorelbine treatment. Use vinorelbine with caution in patients with a history of pulmonary disease. The mean time to onset of interstitial pneumonitis and ARDS was 1 week after administration (range, 3 to 8 days). Interrupt vinorelbine therapy for unexplained dyspnea; permanently discontinue therapy 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

    The safety and efficacy of vinorelbine have not been established in children or infants. In a single-arm trial in pediatric patients (median, 11 years; range, 1 to 25 years) with recurrent solid malignant tumors (n = 46), monotherapy with vinorelbine resulted in an objective tumor response in 2 of 21 patients with rhabdomyosarcoma or undifferentiated sarcoma; no objective tumor response was observed in patients with central nervous system tumors or neuroblastoma. 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%).

    Pregnancy

    Pregnancy should be avoided by females of reproductive potential during vinorelbine treatment and for at least 6 months after the last dose. Although there are no adequately controlled studies in pregnant women, vinorelbine can cause fetal harm or death when administered during pregnancy based on its mechanism of action and animal studies. Women who are pregnant or who become pregnant while receiving vinorelbine should be apprised of the potential hazard to the fetus. Administration of a single dose of vinorelbine in a mouse embryo-fetal development study at a dose approximating 0.33 times the recommended human dose based on BSA was both embryotoxic and fetotoxic. Vinorelbine was also embryotoxic and fetotoxic to pregnant rabbits when administered every 6 days during organogenesis at approximately 0.18 times or more the recommended human dose based on BSA. At doses that did not cause maternal toxicity in either species, vinorelbine administration caused reduced fetal weight and delayed ossification.

    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 and for at least 6 months after 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. Due to the risk of male-mediated teratogenicity, males with female partners of reproductive potential should use highly effective contraception during treatment and for 3 months after completion of therapy with vinorelbine. Although there are no data regarding the effect of vinorelbine on human fertility, male infertility has been observed in animal studies.

    Breast-feeding

    Due to the potential for serious adverse reactions in nursing infants from vinorelbine, advise women to discontinue breast-feeding during treatment and for 9 days after the final dose. It is not known whether vinorelbine is present in human milk, although many drugs are excreted in human milk.

    ADVERSE REACTIONS

    Severe

    neutropenia / Delayed / 29.0-69.0
    leukopenia / Delayed / 12.0-32.0
    anemia / Delayed / 1.0-9.0
    hyperbilirubinemia / Delayed / 5.0-9.0
    neurotoxicity / Early / 7.0-8.5
    asthenia / Delayed / 5.0-7.0
    elevated hepatic enzymes / Delayed / 3.0-6.0
    injection site reaction / Rapid / 0-5.0
    constipation / Delayed / 2.0-3.0
    dyspnea / Early / 2.0-3.0
    weakness / Early / 0-3.0
    vomiting / Early / 1.0-2.0
    nausea / Early / 1.0-2.0
    alopecia / Delayed / 1.0-2.0
    thrombocytopenia / Delayed / 0-1.0
    diarrhea / Early / 0.5-1.0
    phlebitis / Rapid / 0-1.0
    SIADH / Delayed / 0-1.0
    ototoxicity / Delayed / 0-1.0
    hemorrhagic cystitis / Delayed / 0-1.0
    myocardial infarction / Delayed / 0-0.1
    GI perforation / Delayed / Incidence not known
    ileus / Delayed / Incidence not known
    GI obstruction / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    tissue necrosis / Early / Incidence not known
    pulmonary embolism / Delayed / Incidence not known
    thrombosis / Delayed / Incidence not known
    bronchospasm / Rapid / Incidence not known
    pulmonary toxicity / Early / Incidence not known
    acute respiratory distress syndrome (ARDS) / Early / 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
    palmar-plantar erythrodysesthesia (hand and foot syndrome) / Delayed / Incidence not known
    radiation recall reaction / Delayed / Incidence not known
    sinus tachycardia / Rapid / Incidence not known
    hypertension / Early / Incidence not known
    hypotension / Rapid / Incidence not known
    peripheral vasodilation / Rapid / Incidence not known
    hyponatremia / Delayed / Incidence not known
    pneumonitis / Delayed / Incidence not known
    myasthenia / Delayed / Incidence not known
    esophagitis / Delayed / Incidence not known

    Mild

    infection / Delayed / Incidence not known
    fever / Early / Incidence not known
    abdominal pain / Early / Incidence not known
    anorexia / Delayed / Incidence not known
    weight loss / Delayed / Incidence not known
    dysgeusia / Early / Incidence not known
    hyporeflexia / Delayed / Incidence not known
    urticaria / Rapid / Incidence not known
    pruritus / Rapid / Incidence not known
    rash / Early / Incidence not known
    flushing / Rapid / Incidence not known
    back pain / Delayed / Incidence not known
    headache / Early / 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: (Moderate) Consider if an alternative to clarithromycin is appropriate in patients who will undergo vinorelbine therapy. Monitor for vinorelbine-related side effects, including neurotoxicity and neutropenia, if these drugs must be used together. Increased concentrations of vinorelbine are likely. 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 and vinca alkaloids have been noted.
    Amoxicillin; Clarithromycin; Omeprazole: (Moderate) Consider if an alternative to clarithromycin is appropriate in patients who will undergo vinorelbine therapy. Monitor for vinorelbine-related side effects, including neurotoxicity and neutropenia, if these drugs must be used together. Increased concentrations of vinorelbine are likely. 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 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 strong 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: (Moderate) Consider if an alternative to clarithromycin is appropriate in patients who will undergo vinorelbine therapy. Monitor for vinorelbine-related side effects, including neurotoxicity and neutropenia, if these drugs must be used together. Increased concentrations of vinorelbine are likely. 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 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.
    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.
    Elvitegravir; 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.
    Elvitegravir; Cobicistat; 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.
    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: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with erythromycin is necessary. Vinorelbine is a CYP3A4 substrate and erythromycin is a moderate CYP3A4 inhibitor.
    Erythromycin; Sulfisoxazole: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with erythromycin is necessary. Vinorelbine is a CYP3A4 substrate and erythromycin is a moderate CYP3A4 inhibitor.
    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.
    Fedratinib: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with fedratinib is necessary. Vinorelbine is a CYP3A4 substrate and fedratinib is a moderate CYP3A4 inhibitor.
    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.
    Istradefylline: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with istradefylline 40 mg daily is necessary. Vinorelbine is a CYP3A4 and P-gp substrate; istradefylline administered as 40 mg daily is a weak CYP3A4 inhibitor and P-gp inhibitor. There was no effect on drug exposure when istradefylline 20 mg daily was coadministered with a sensitive CYP3A4 substrate.
    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.
    Lefamulin: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with oral lefamulin is necessary. Vinorelbine is a CYP3A4 substrate and oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin.
    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) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with letermovir is necessary; in patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. 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) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with chronic mifepristone therapy is necessary. Vinorelbine is a CYP3A4 substrate and mifepristone is a strong CYP3A4 inhibitor. Due to the slow elimination of mifepristone from the body, such interactions may be observed for a prolonged period after mifepristone administration.
    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 constipation and peripheral neuropathy. 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 constipation and peripheral neuropathy. Vinorelbine is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Concomitant administration of azole antifungals 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

    Pregnancy should be avoided by females of reproductive potential during vinorelbine treatment and for at least 6 months after the last dose. Although there are no adequately controlled studies in pregnant women, vinorelbine can cause fetal harm or death when administered during pregnancy based on its mechanism of action and animal studies. Women who are pregnant or who become pregnant while receiving vinorelbine should be apprised of the potential hazard to the fetus. Administration of a single dose of vinorelbine in a mouse embryo-fetal development study at a dose approximating 0.33 times the recommended human dose based on BSA was both embryotoxic and fetotoxic. Vinorelbine was also embryotoxic and fetotoxic to pregnant rabbits when administered every 6 days during organogenesis at approximately 0.18 times or more the recommended human dose based on BSA. At doses that did not cause maternal toxicity in either species, vinorelbine administration caused reduced fetal weight and delayed ossification.

    Due to the potential for serious adverse reactions in nursing infants from vinorelbine, advise women to discontinue breast-feeding during treatment and for 9 days after the final dose. It is not known whether vinorelbine is present in human milk, although many drugs are excreted in human milk.

    MECHANISM OF ACTION

    Vinorelbine is a semi-synthetic vinca alkaloid. It acts as a microtubule inhibitor, causing cellular instability and preventing mitosis at metaphase. Microtubules are responsible for intracellular transport, maintenance of cell shape, polarity, cell signaling, and mitosis. During mitosis, microtubules form the mitotic spindle that transports daughter chromosomes to separate poles of the dividing cell. Vinorelbine may also interfere with amino acid, cyclic AMP, and glutathione metabolism; calmodulin-dependent calcium-transport ATPase activity; cellular respiration; and nucleic acid and lipid biosynthesis. Vinorelbine inhibited mitotic microtubule formation in intact mouse embryo tectal plates at a concentration of 2 micromolar, inducing a blockade of cells at metaphase; however, it produced depolymerization of axonal microtubules at a concentration of 40 micromolar. This suggests a modest selectivity of vinorelbine for mitotic microtubules.

    PHARMACOKINETICS

    Vinorelbine is administered intravenously. It demonstrates high binding to human platelets and lymphocytes. The free fraction was approximately 0.11 in human plasma over a concentration range of 234 ng/mL to 1,169 ng/mL. The binding to plasma constituents in cancer patients ranged from 79.6% to 91.2%. The steady-state volume of distribution (Vss) of vinorelbine ranged from 25.4 L/kg to 40.1 L/kg. Vinorelbine plasma concentrations decay in a triphasic manner. The terminal phase half-life averaged 27.7 to 43.6 hours and the mean plasma clearance ranged from 0.97 to 1.26 L/hour/kg. Vinorelbine undergoes substantial hepatic elimination to 2 metabolites: vinorelbine N-oxide and deacetylvinorelbine. Deacetylvinorelbine is the primary metabolite in humans and has antitumor activity similar to vinorelbine; however, therapeutic doses of vinorelbine (30 mg/m2) yield very small, if any, quantifiable levels of either metabolite in blood or urine. After IV administration, approximately 46% of a radioactive dose was recovered in the feces and 18% in the urine. In a different study, 10.9% (+/- 0.7%) of a single IV dose was excreted as parent drug in the urine.[56871]
     
    Affected cytochrome P450 (CYP) isoenzymes and drug transporters: CYP3A and P-glycoprotein (P-gp)
    Vinorelbine is a CYP3A and a P-gp substrate.[59581] [59600]