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  • CLASSES

    Vinca Alkaloids and Analogs

    BOXED WARNING

    Ensure correct formulation selection

    Vincristine liposomal has different dosage recommendations than vincristine sulfate injection. Ensure correct formulation selection and dose before preparation and administration to avoid overdosage.

    DEA CLASS

    Rx

    DESCRIPTION

    Sphingomyelin/cholesterol liposome-encapsulated formulation of vincristine sulfate, a vinca alkaloid agent
    FDA-approved for the treatment of adult patients with Philadelphia chromosome-negative acute lymphoblastic leukemia in second or greater relapse or whose disease has progressed following 2 or more anti-leukemia therapies
    Intrathecal administration is fatal

    COMMON BRAND NAMES

    Marqibo

    HOW SUPPLIED

    Marqibo Intravenous Inj Lipos
    Marqibo Intravenous Inj Sol

    DOSAGE & INDICATIONS

    For the treatment of Philadelphia chromosome-negative acute lymphocytic leukemia (ALL) in second or greater relapse or that has progressed after 2 or more anti-leukemia therapies.
    NOTE: Vincristine sulfate liposome (Marqibo) has a different dosage than vincristine sulfate; verify drug name and dose prior to administration.
    NOTE: FDA approval of vincristine sulfate liposome was based on response rate.
    Intravenous dosage
    Adults

    2.25 mg/m2 IV over 1 hour once every 7 days. Avoid concomitant use with strong CYP3A4 inducers or inhibitors. Treatment with vincristine sulfate liposome (median of 4 doses; range, 1—18 doses) led to an overall complete remission rate (CR) rate of 20% (CR, 11%; CR with incomplete blood count recovery (CRi), 9%) and an overall response (CR + CRi + partial response + bone marrow blast response) rate of 35% in a multicenter, single-arm, phase II study in 65 patients with Philadelphia chromosome-negative acute lymphocytic leukemia (ALL) in second or greater relapse or that progressed after 2 or more anti-leukemia therapies (median of 9 prior anti-leukemia agents). Most patients had B-cell ALL (85%). Concomitant hydroxyurea use was permitted for the first 14 days and corticosteroid use was allowed for the first 5 days to control leukocytosis. All patients had received prior vincristine sulfate therapy and 77% of patients had residual neuropathy prior to study entry. Additionally, patients in this study were not eligible for immediate hematopoetic stem-cell transplantation (HSCT) and had achieved a CR from at least 1 previous anti-leukemic therapy (defined as a leukemia-free interval for at least 90 days). The median duration of CR or CRi was 23 weeks (95% CI, 5—66 weeks) and the median overall survival (OS) time was 4.6 months (range, < 1 month to < 25 months); the 6-month and 24-month OS rates were 35% and 4%, respectively. Twelve patients (18.5%) in this study subsequently underwent a HSCT; the median OS time in these patients was 9.3 months (range, 4—25.3 months).

    MAXIMUM DOSAGE

    Adults

    2.25 mg/m2 IV q7 days.

    Geriatric

    2.25 mg/m2 IV q7 days.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for initial dosage adjustment in hepatic impairment are not available; however, a pharmacokinetic study indicated that the systemic exposure of vincristine sulfate liposome was comparable in melanoma patients with moderate hepatic impairment (Child-Pugh B) due to liver metastases and in acute lymphocytic leukemia patients with normal hepatic function. Vincristine sulfate liposome has not been studied in patients with baseline severe hepatic dysfunction. Reduce or interrupt therapy in patients who develop hepatic toxicity.

    Renal Impairment

    Specific guidelines for dosage adjustment in renal impairment are not available. Vincristine sulfate liposome has not been studied in patients with baseline renal dysfunction.

    ADMINISTRATION

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

    Injectable Administration
    Intravenous Administration

    Call 1-888-292-9617 with any questions about the preparation of vincristine sulfate liposome. 
    Vincristine sulfate liposome takes approximately 60 to 90 minutes to prepare; the preparer should have uninterrupted time.
    Preparation steps that involve mixing should be done in a biological safety cabinet or by other established pharmacy safety procedures for the preparation of hazardous drugs.
    Preparation steps that involve placement of the vial in the water bath should be done outside of the sterile area.
    The manufacturer will provide the water bath, calibrated thermometer, and calibrated electronic timer to the medical facility at the initial order of vincristine sulfate liposome and will replace them every 2 years.
    Do not use with in-line filters.
    Do not mix with other drugs.
     
    Preparation:
    Required Item List: Marqibo (vincristine sulfate liposome) kit, water bath, calibrated thermometer (0—100 degrees Celsius), calibrated electronic timer, sterile venting needle or other suitable device equipped with a sterile 0.2 micron filter, 1 ml or 3 ml sterile syringe with needle, 5 ml sterile syringe with needle 
    Fill a water bath with water to at least 8 centimeters (3.2 inches) from the bottom and maintain this minimum water level throughout the procedure; the water bath must remain outside of the sterile area.
    Place a calibrated thermometer in the water bath to monitor water temperature; leave thermometer in the water bath until the procedure is complete.
    Preheat the water bath to 63—67 degrees Celsius; maintain this water temperature until the procedure is complete.
    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
    Remove the caps on the vials and swab the vials with sterile alcohol pads.
    Vent the Sodium Phosphate Injection vial with a sterile venting needle equipped with a sterile 0.2 micron filter (or other suitable venting device); position the venting needle point well above liquid level before adding sphingomyelin/cholesterol liposome injection and vincristine sulfate injection.
    Withdraw 1 ml of sphingomyelin/cholesterol liposome injection and inject into the sodium phosphate injection vial.
    Withdraw 5 ml of vincristine sulfate injection and inject into the sodium phosphate injection vial.
    Remove the venting needle and gently invert the sodium phosphate injection vial 5 times to mix; do not shake.
    Fit the flotation ring around the neck of the sodium phosphate injection vial.
    Confirm that the water bath temperature is 63—67 degrees Celsius using the calibrated thermometer; remove the sodium phosphate injection vial containing vincristine sulfate injection, sphingomyelin/cholesterol liposome injection, and sodium phosphate injection from the biological safety cabinet and place into the water bath for 10 minutes using the calibrated electronic timer; monitor the temperature to ensure the temperature is maintained at 63—67 degrees Celsius.
    After placing the sodium phosphate injection vial into the water bath, immediately record the constitution start time and water temperature on the Marqibo overlabel.
    Confirm that the water temperature is 63—67 degrees Celsius using the calibrated thermometer at the end of the 10 minutes; using tongs (to avoid burns), remove the vial from the water bath and remove the flotation ring.
    Record the final constitution time and the water temperature on the Marqibo overlabel.
    After drying the exterior of the sodium phosphate injection vial with a clean paper towel, affix the Marqibo overlabel and gently invert 5 times to mix; do not shake.
    Allow the constituted vial contents to equilibrate for at least 30 minutes at controlled room temperature (15—30 degrees Celsius or 59—86 degrees Fahrenheit); the final Marqibo product contains 5 mg/31 ml (0.16 mg/ml) vincristine sulfate.
    The diluted solution may be stored at room temperature (15—30 degrees Celsius or 59—86 degrees Fahrenheit) for no more than 12 hours.
    Swab the top of the Marqibo vial with a sterile alcohol pad and return the vial back to the biological safety cabinet.
    Calculate the Marqibo dose based on actual body surface area.
    Remove the appropriate volume corresponding to the Marqibo dose from an infusion bag containing 100 ml of 5% dextrose injection or 0.9% sodium chloride injection; inject the dose of Marqibo into the infusion bag for a final volume of 100 mL.
    Complete the information required on the infusion bag label and apply to the infusion bag.
    Deviations in temperature, time, and preparation procedures may fail to ensure proper encapsulation of vincristine sulfate into the liposomes; the components of the kit should be discarded and a new kit should be used to prepare the dose if the preparation deviates from the instructions in the above steps.
    Empty, clean, and dry the water bath after each use.
     
    Intravenous Infusion:
    Administer the diluted solution IV over 1 hour; do not administer by any other route; intrathecal administration may be fatal.
    Finish administration of IV infusion within 12 hours from starting the vincristine sulfate liposome preparation.

    STORAGE

    Marqibo:
    - Do not freeze
    - Refrigerate (between 36 and 46 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Vincristine liposomal is contraindicated for use by patients with hypersensitivity to vincristine sulfate or any of the other product components.

    Intrathecal administration


    Intrathecal administration of vincristine liposomal is contraindicated. Death has occurred with intrathecal use. Vincristine liposomal is only for intravenous use.

    Neurological disease, peripheral neuropathy

    Vincristine liposomal is contraindicated for use by patients with demyelinating conditions including Charcot-Marie-Tooth syndrome. Patients with preexisting severe neurological disease such as peripheral neuropathy should be treated with vincristine liposomal only after careful risk-benefit assessment. Vincristine itself can cause a variety of neurologic problems, and the risk of neurologic toxicity is greater if vincristine liposomal is administered to patients with preexisting neuromuscular disorders or when other drugs with risk of neurologic toxicity are being given. A detailed description of antecedent neurologic problems can aid in monitoring toxicity from vincristine. Monitor patients for symptoms of neuropathy such as hypoesthesia, hyperesthesia, paresthesia, hyporeflexia, areflexia, neuralgia, jaw pain, decreased vibratory sense, cranial neuropathy, ileus, burning sensation, arthralgia, myalgia, muscle spasm, or weakness before and during treatment. Worsening neuropathy requires dose delay, reduction, or discontinuation of vincristine liposomal.

    Hepatic disease

    Cautious use of vincristine liposomal is warranted for patients with hepatic disease; dose reduction or drug interruption may be needed (see Adverse Reactions). Monitor liver function tests, as fatal hepatotoxicity has been noted. Non-liposomal vincristine sulfate is metabolized primarily by the liver, and the influence of severe hepatic impairment on the safety and efficacy of vincristine liposomal has not been evaluated.

    Vaccination

    Persons receiving chemotherapy such as vincristine liposomal are assumed to have altered immunocompetence. Do not administer live, attenuated vaccines for at least 3 months after such immunosuppressive therapy. Except for inactivated influenza vaccine, avoid, if possible, vaccination with inactivated vaccines during chemotherapy because antibody response might be suboptimal. Consider patients vaccinated within 14 days before starting immunosuppressive therapy or while receiving immunosuppressive therapy unimmunized and revaccinate at least 3 months after therapy is discontinued if immune competence has been restored. Administer all indicated vaccines to all persons before initiation of chemotherapy. In general, revaccination of a person after chemotherapy or radiation therapy is considered unnecessary if the previous vaccination occurred before therapy and not during therapy.

    Anemia, neutropenia, thrombocytopenia

    Severe myelosuppression has been reported with vincristine sulfate liposome use (see Adverse Reactions). Monitor complete blood counts before each dose of vincristine sulfate liposome. Consider a dose modification or reduction and institute supportive care measures in patients who develop grade 3 or 4 neutropenia, thrombocytopenia, or anemia.

    Tumor lysis syndrome (TLS)

    Tumor lysis syndrome (TLS) may develop in patients with acute lymphoblastic leukemia who receive vincristine sulfate liposome. Monitor patients for evidence of TLS (e.g., hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia, uremia) during treatment; manage symptoms of TLS promptly.

    Constipation, GI obstruction, ileus

    Ileus, GI obstruction (specifically bowel obstruction and colonic pseudo-obstruction), and constipation have been reported with vincristine sulfate liposome use (see Adverse Reactions). A prophylactic bowel regimen that includes adequate dietary fiber intake, hydration, and routine use of stool softeners (e.g., docusate) should be instituted to help prevent these GI complications. Other laxatives such as senna, bisacodyl, milk of magnesia, magnesium citrate, and lactulose may be considered.

    Ensure correct formulation selection

    Vincristine liposomal has different dosage recommendations than vincristine sulfate injection. Ensure correct formulation selection and dose before preparation and administration to avoid overdosage.

    Pregnancy

    Vincristine liposomal is classified as FDA pregnancy risk category D. Vincristine can cause fetal harm and/or death and should not be administered during pregnancy. In animal studies, vincristine is embryotoxic and teratogenic. Women receiving vincristine should be advised to avoid becoming pregnant. If a women becomes pregnant while receiving this drug, she should be counseled of the potential harm to the fetus and the possibility of loss of pregnancy.

    Breast-feeding

    According to the manufacturer, vincristine liposomal or breast-feeding should be discontinued because of the potential for serious adverse reactions in nursing infants from vincristine liposomal. It is not known if vincristine liposomal is excreted into human milk. Consider the benefits of breast-feeding, the risk of infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    ADVERSE REACTIONS

    Severe

    infection / Delayed / 39.8-39.8
    neutropenia / Delayed / 18.1-18.1
    thrombocytopenia / Delayed / 16.9-16.9
    anemia / Delayed / 16.9-16.9
    peripheral neuropathy / Delayed / 16.7-16.7
    fever / Early / 14.5-14.5
    fatigue / Early / 12.0-12.0
    elevated hepatic enzymes / Delayed / 6.0-11.0
    abdominal pain / Early / 8.4-8.4
    hypotension / Rapid / 6.0-6.0
    ileus / Delayed / 6.0-6.0
    cardiac arrest / Early / 6.0-6.0
    asthenia / Delayed / 4.8-4.8
    constipation / Delayed / 4.8-4.8
    respiratory arrest / Rapid / 4.8-4.8
    weakness / Early / 1.2-1.2
    tumor lysis syndrome (TLS) / Delayed / Incidence not known
    hyperkalemia / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known
    tissue necrosis / Early / Incidence not known

    Moderate

    hyperesthesia / Delayed / Incidence not known
    hypocalcemia / Delayed / Incidence not known
    hyperuricemia / Delayed / Incidence not known
    hyperphosphatemia / Delayed / Incidence not known
    hyperbilirubinemia / Delayed / Incidence not known
    phlebitis / Rapid / Incidence not known
    erythema / Early / Incidence not known

    Mild

    nausea / Early / 52.0-52.0
    diarrhea / Early / 37.0-37.0
    anorexia / Delayed / 33.0-33.0
    insomnia / Early / 32.0-32.0
    hypoesthesia / Delayed / Incidence not known
    arthralgia / Delayed / Incidence not known
    paresthesias / Delayed / Incidence not known
    musculoskeletal pain / Early / Incidence not known
    hyporeflexia / Delayed / Incidence not known
    myalgia / Early / Incidence not known
    skin irritation / Early / Incidence not known
    injection site reaction / Rapid / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.
    Acetaminophen; Butalbital: (Major) Vincristine is a substrate for cytochrome P450 (CYP) 3A4. Agents that induce CYP 3A4 may increase the metabolism of vincristine and decrease the efficacy of drug, including barbiturates. Patients receiving these drugs concurrently should be monitored for possible loss of vincristine efficacy.
    Acetaminophen; Butalbital; Caffeine: (Major) Vincristine is a substrate for cytochrome P450 (CYP) 3A4. Agents that induce CYP 3A4 may increase the metabolism of vincristine and decrease the efficacy of drug, including barbiturates. Patients receiving these drugs concurrently should be monitored for possible loss of vincristine efficacy.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Major) Vincristine is a substrate for cytochrome P450 (CYP) 3A4. Agents that induce CYP 3A4 may increase the metabolism of vincristine and decrease the efficacy of drug, including barbiturates. Patients receiving these drugs concurrently should be monitored for possible loss of vincristine efficacy.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Moderate) Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.
    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.
    Aluminum Hydroxide: (Major) Aluminum hydroxide and magnesium hydroxide (as well as other antacids, i.e. aluminum hydroxide; magnesium carbonate, aluminum hydroxide; magaldrate; magnesium hydroxide, and aluminum hydroxide; magnesium trisilicate) may interact with urinary acidifiers by alkalinizing the urine. Frequent use of these high dose antacids should be avoided in patients receiving urinary acidifiers.
    Aluminum Hydroxide; Magnesium Carbonate: (Major) Aluminum hydroxide and magnesium hydroxide (as well as other antacids, i.e. aluminum hydroxide; magnesium carbonate, aluminum hydroxide; magaldrate; magnesium hydroxide, and aluminum hydroxide; magnesium trisilicate) may interact with urinary acidifiers by alkalinizing the urine. Frequent use of these high dose antacids should be avoided in patients receiving urinary acidifiers.
    Aluminum Hydroxide; Magnesium Hydroxide: (Major) Aluminum hydroxide and magnesium hydroxide (as well as other antacids, i.e. aluminum hydroxide; magnesium carbonate, aluminum hydroxide; magaldrate; magnesium hydroxide, and aluminum hydroxide; magnesium trisilicate) may interact with urinary acidifiers by alkalinizing the urine. Frequent use of these high dose antacids should be avoided in patients receiving urinary acidifiers.
    Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Major) Aluminum hydroxide and magnesium hydroxide (as well as other antacids, i.e. aluminum hydroxide; magnesium carbonate, aluminum hydroxide; magaldrate; magnesium hydroxide, and aluminum hydroxide; magnesium trisilicate) may interact with urinary acidifiers by alkalinizing the urine. Frequent use of these high dose antacids should be avoided in patients receiving urinary acidifiers.
    Aluminum Hydroxide; Magnesium Trisilicate: (Major) Aluminum hydroxide and magnesium hydroxide (as well as other antacids, i.e. aluminum hydroxide; magnesium carbonate, aluminum hydroxide; magaldrate; magnesium hydroxide, and aluminum hydroxide; magnesium trisilicate) may interact with urinary acidifiers by alkalinizing the urine. Frequent use of these high dose antacids should be avoided in patients receiving urinary acidifiers.
    Amiodarone: (Major) Amiodarone inhibits P-glycoprotein (P-gp), and vincristine is a P-gp substrate. Coadministration could increase exposure to vincristine; monitor patients for increased side effects if these drugs are given together.
    Amobarbital: (Major) Vincristine is a substrate for cytochrome P450 (CYP) 3A4. Agents that induce CYP 3A4 may increase the metabolism of vincristine and decrease the efficacy of drug, including barbiturates. Patients receiving these drugs concurrently should be monitored for possible loss of vincristine efficacy.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Increased concentrations of vincristine are likely. Consider if alternative antibiotic therapy is appropriate. Monitor for vincristine-related side effects, including neurotoxicity, if these drugs must be used together. Clarithromycin is a potent inhibitor of CYP3A4 and also inhibits P-gp. Vincristine is a CYP3A4 and P-gp substrate. Postmarketing reports of interactions, including serious toxicity, between clarithromycin or similar macrolides and vinca alkaloids have been noted.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Increased concentrations of vincristine are likely. Consider if alternative antibiotic therapy is appropriate. Monitor for vincristine-related side effects, including neurotoxicity, if these drugs must be used together. Clarithromycin is a potent inhibitor of CYP3A4 and also inhibits P-gp. Vincristine is a CYP3A4 and P-gp substrate. Postmarketing reports of interactions, including serious toxicity, between clarithromycin or similar macrolides and vinca alkaloids have been noted.
    Amprenavir: (Major) The plasma concentrations of vincristine may be significantly elevated when administered concurrently with protease inhibitors. Consideration should be given to temporarily withholding the regimen in patients who develop significant hematological or gastrointestinal toxicity when protease inhibitors are coadministered with vincristine. Vincristine is a CYP3A4 and P-glycoprotein (P-gp) substrate; protease inhibitors are CYP3A4 inhibitors and some also inhibit P-gp. If the antiretroviral regimen needs to be withheld for a prolonged period, consider use of a revised regimen that does not include a CYP3A4 and P-gp inhibitor.
    Antacids: (Major) Aluminum hydroxide and magnesium hydroxide (as well as other antacids, i.e. aluminum hydroxide; magnesium carbonate, aluminum hydroxide; magaldrate; magnesium hydroxide, and aluminum hydroxide; magnesium trisilicate) may interact with urinary acidifiers by alkalinizing the urine. Frequent use of these high dose antacids should be avoided in patients receiving urinary acidifiers.
    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.
    Apalutamide: (Major) Avoid coadministration of vincristine with apalutamide due to decreased plasma concentrations of vincristine. Vincristine is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer.
    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.
    Aprepitant, Fosaprepitant: (Moderate) Aprepitant, fosaprepitant is indicated for the prophylaxis of chemotherapy-induced nausea/vomiting and may be used in combination with vincristine. However, use caution and monitor for a possible increase in non-emetogenic vincristine-related adverse effects for several days after administration of a multi-day aprepitant regimen. Vincristine is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and theoretically could increase plasma concentrations of vincristine. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
    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.
    Armodafinil: (Minor) Vincristine is a substrate for cytochrome P450 (CYP) 3A4. Agents that induce CYP 3A4 may increase the metabolism of vincristine and decrease the efficacy of drug, including armodafinil (in vitro). Patients receiving these drugs concurrently should be monitored for possible loss of vincristine efficacy.
    Asparaginase Erwinia chrysanthemi: (Moderate) Use L-asparaginase and vincristine together with caution; increased vincristine-related toxicity may occur. L-asparaginase administered before or concurrently with vincristine may reduce the hepatic clearance of vincristine. If these drugs are used together, administer vincristine 12 to 24 hours before L-asparaginase to minimize toxicity.
    Aspirin, ASA: (Moderate) Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.
    Aspirin, ASA; Butalbital; Caffeine: (Major) Vincristine is a substrate for cytochrome P450 (CYP) 3A4. Agents that induce CYP 3A4 may increase the metabolism of vincristine and decrease the efficacy of drug, including barbiturates. Patients receiving these drugs concurrently should be monitored for possible loss of vincristine efficacy. (Moderate) Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Vincristine is a substrate for cytochrome P450 (CYP) 3A4. Agents that induce CYP 3A4 may increase the metabolism of vincristine and decrease the efficacy of drug, including barbiturates. Patients receiving these drugs concurrently should be monitored for possible loss of vincristine efficacy. (Moderate) Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.
    Aspirin, ASA; Carisoprodol: (Moderate) Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.
    Aspirin, ASA; Dipyridamole: (Moderate) Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.
    Aspirin, ASA; Omeprazole: (Moderate) Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.
    Aspirin, ASA; Oxycodone: (Moderate) Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.
    Aspirin, ASA; Pravastatin: (Moderate) Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.
    Atazanavir: (Major) The plasma concentrations of vincristine may be significantly elevated when administered concurrently with protease inhibitors. Consideration should be given to temporarily withholding the regimen in patients who develop significant hematological or gastrointestinal toxicity when protease inhibitors are coadministered with vincristine. Vincristine is a CYP3A4 and P-glycoprotein (P-gp) substrate; protease inhibitors are CYP3A4 inhibitors and some also inhibit P-gp. If the antiretroviral regimen needs to be withheld for a prolonged period, consider use of a revised regimen that does not include a CYP3A4 and P-gp inhibitor.
    Atazanavir; Cobicistat: (Major) Avoid coadministration of vincristine with cobicistat due to increased plasma concentrations of vincristine, resulting in an earlier onset and/or increased severity of neuromuscular side effects. Vincristine is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. (Major) The plasma concentrations of vincristine may be significantly elevated when administered concurrently with protease inhibitors. Consideration should be given to temporarily withholding the regimen in patients who develop significant hematological or gastrointestinal toxicity when protease inhibitors are coadministered with vincristine. Vincristine is a CYP3A4 and P-glycoprotein (P-gp) substrate; protease inhibitors are CYP3A4 inhibitors and some also inhibit P-gp. If the antiretroviral regimen needs to be withheld for a prolonged period, consider use of a revised regimen that does not include a CYP3A4 and P-gp inhibitor.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Vincristine is a substrate for cytochrome P450 (CYP) 3A4. Agents that induce CYP 3A4 may increase the metabolism of vincristine and decrease the efficacy of drug, including barbiturates. Patients receiving these drugs concurrently should be monitored for possible loss of vincristine efficacy.
    Azelastine; Fluticasone: (Moderate) Use sodium phosphate cautiously with corticosteroids, especially mineralocorticoids or corticotropin, ACTH, as concurrent use can cause hypernatremia.
    Barbiturates: (Major) Vincristine is a substrate for cytochrome P450 (CYP) 3A4. Agents that induce CYP 3A4 may increase the metabolism of vincristine and decrease the efficacy of drug, including barbiturates. Patients receiving these drugs concurrently should be monitored for possible loss of vincristine efficacy.
    Beclomethasone: (Moderate) Use sodium phosphate cautiously with corticosteroids, especially mineralocorticoids or corticotropin, ACTH, as concurrent use can cause hypernatremia.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Vincristine is a substrate for cytochrome P450 (CYP) 3A4. Agents that induce CYP 3A4 may increase the metabolism of vincristine and decrease the efficacy of drug, including barbiturates. Patients receiving these drugs concurrently should be monitored for possible loss of vincristine efficacy.
    Betamethasone: (Moderate) Use sodium phosphate cautiously with corticosteroids, especially mineralocorticoids or corticotropin, ACTH, as concurrent use can cause hypernatremia.
    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.
    Bexarotene: (Moderate) Vincristine is a substrate for cytochrome P450 (CYP) 3A4. Agents that induce CYP3A4 may increase the metabolism of vincristine and decrease the efficacy of drug, including bexarotene. Patients receiving these drugs concurrently with vincristine should be monitored for possible loss of vincristine efficacy.
    Bismuth Subsalicylate: (Moderate) Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.
    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.
    Boceprevir: (Moderate) Close clinical monitoring is advised when administering vincristine with boceprevir due to an increased potential for vincristine-related adverse events. If vincristine dose adjustments are made, re-adjust the dose upon completion of boceprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of vincristine. Vincristine is a substrate of the drug efflux transporter P-glycoprotein (PGP) and of the hepatic isoenzyme CYP3A4; boceprevir is an inhibitor of both the efflux protein and the isoenzyme. Coadministration may result in elevated vincristine plasma concentrations.
    Bortezomib: (Minor) Monitor patients for the development of peripheral neuropathy when receiving bortezomib in combination with other drugs that can cause peripheral neuropathy like vincristine; the risk of peripheral neuropathy may be additive.
    Bosutinib: (Major) Bosutinib inhibits P-glycoprotein (P-gp), and vincristine is a P-gp substrate. Coadministration could increase exposure to vincristine; monitor patients for increased side effects if these drugs are given together.
    Brigatinib: (Moderate) Monitor for decreased efficacy of vincristine if coadministration with brigatinib is necessary. Vincristine is a CYP3A substrate and brigatinib induces CYP3A in vitro; plasma concentrations of vincristine may decrease.
    Budesonide: (Moderate) Use sodium phosphate cautiously with corticosteroids, especially mineralocorticoids or corticotropin, ACTH, as concurrent use can cause hypernatremia.
    Budesonide; Formoterol: (Moderate) Use sodium phosphate cautiously with corticosteroids, especially mineralocorticoids or corticotropin, ACTH, as concurrent use can cause hypernatremia.
    Butabarbital: (Major) Vincristine is a substrate for cytochrome P450 (CYP) 3A4. Agents that induce CYP 3A4 may increase the metabolism of vincristine and decrease the efficacy of drug, including barbiturates. Patients receiving these drugs concurrently should be monitored for possible loss of vincristine efficacy.
    Cabozantinib: (Moderate) Monitor for an increase in vincristine-related adverse reactions, including neurotoxicity and severe constipation, if coadministration of with cabozantinib is necessary. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and has the potential to increase plasma concentrations of P-gp substrates such as vincristine; however, the clinical relevance of this finding is unknown. The effect of concomitant use of P-gp inhibitors with vincristine has not been investigated, but it is likely that these agents will alter the pharmacokinetics or pharmacodynamics of vincristine.
    Caffeine: (Major) Sodium phosphates should be used with caution in patients using concomitant medications that lower the seizure threshold like psychostimulants.
    Calcium Carbonate; Magnesium Hydroxide: (Major) Aluminum hydroxide and magnesium hydroxide (as well as other antacids, i.e. aluminum hydroxide; magnesium carbonate, aluminum hydroxide; magaldrate; magnesium hydroxide, and aluminum hydroxide; magnesium trisilicate) may interact with urinary acidifiers by alkalinizing the urine. Frequent use of these high dose antacids should be avoided in patients receiving urinary acidifiers.
    Carbamazepine: (Moderate) Vincristine is a substrate for cytochrome P450 (CYP) 3A4. Agents that induce CYP3A4 such as carbamazepine may increase the metabolism of vincristine and decrease the efficacy of drug. In addition, myelosuppressive antineoplastic agents possess hematologic toxicities similar to carbamazepine, and should be used concomitantly with caution.
    Carvedilol: (Moderate) Increased concentrations of vincristine may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and vincristine is a P-gp substrate.
    Ceritinib: (Moderate) Monitor for vincristine-related adverse reactions, including constipation and peripheral neuropathy, in patients receiving concomitant treatment with ceritinib; coadministration may cause an earlier onset and/or increased severity of neuromuscular side effects. Ceritinib is a CYP3A4 inhibitor and vincristine is metabolized by CYP3A4. Formal drug interaction studies have not been conducted with liposomal vincristine (Marqibo), but it is expected to share drug interactions with non-liposomal vincristine.
    Chloramphenicol: (Major) Chloramphenicol inhibits CYP3A4, and vincristine is a CYP3A substrate. Coadministration could increase exposure to vincristine; monitor patients for increased side effects if these drugs are given together.
    Choline Salicylate; Magnesium Salicylate: (Moderate) Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.
    Ciclesonide: (Moderate) Use sodium phosphate cautiously with corticosteroids, especially mineralocorticoids or corticotropin, ACTH, as concurrent use can cause hypernatremia.
    Cimetidine: (Moderate) Cimetidine is a mild CYP3A4 inhibitor, and vincristine is a CYP3A substrate. Coadministration could increase exposure to vincristine; monitor patients for increased side effects if these drugs are given together.
    Clarithromycin: (Major) Increased concentrations of vincristine are likely. Consider if alternative antibiotic therapy is appropriate. Monitor for vincristine-related side effects, including neurotoxicity, if these drugs must be used together. Clarithromycin is a potent inhibitor of CYP3A4 and also inhibits P-gp. Vincristine is a CYP3A4 and P-gp substrate. Postmarketing 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: (Major) Avoid coadministration of vincristine with cobicistat due to increased plasma concentrations of vincristine, resulting in an earlier onset and/or increased severity of neuromuscular side effects. Vincristine is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid coadministration of vincristine with cobicistat due to increased plasma concentrations of vincristine, resulting in an earlier onset and/or increased severity of neuromuscular side effects. Vincristine is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of vincristine with cobicistat due to increased plasma concentrations of vincristine, resulting in an earlier onset and/or increased severity of neuromuscular side effects. Vincristine is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor.
    Colchicine: (Moderate) Colchicine is an alkaloid that is inhibited by acidifying agents. The colchicine dose may need adjustment
    Conivaptan: (Major) Avoid coadministration of vincristine with conivaptan due to increased plasma concentrations of vincristine. Vincristine is a CYP3A4 substrate and conivaptan is a strong CYP3A4 inhibitor. Concomitant administration of vincristine and another strong CYP3A4 inhibitor resulted in an increased incidence of neurotoxicity.
    Corticosteroids: (Moderate) Use sodium phosphate cautiously with corticosteroids, especially mineralocorticoids or corticotropin, ACTH, as concurrent use can cause hypernatremia.
    Corticotropin, ACTH: (Moderate) Use sodium phosphate cautiously with corticosteroids, especially mineralocorticoids or corticotropin, ACTH, as concurrent use can cause hypernatremia.
    Cortisone: (Moderate) Use sodium phosphate cautiously with corticosteroids, especially mineralocorticoids or corticotropin, ACTH, as concurrent use can cause hypernatremia.
    Crizotinib: (Major) Avoid coadministration of vincristine with crizotinib due to increased vincristine exposure resulting in an earlier onset and/or increased severity of vincristine-related adverse reactions, including neuromuscular toxicities. Vincristine is a CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor.
    Cyclosporine: (Moderate) Use cyclosporine and vincristine together with caution; concomitant use may result in increased vincristine plasma concentrations and increased vincristine toxicity. Cyclosporine is a CYP3A4 and P-glycoprotein (P-gp) inhibitor and vincristine is a CYP3A4 and P-gp substrate. Early onset and/or increased severity of neuromuscular adverse events have been reported when vincristine was administered with a strong CYP3A4 and P-gp 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.
    Dabrafenib: (Moderate) Vincristine is a substrate for cytochrome P450 (CYP) 3A4. Agents that induce CYP3A4 may increase the metabolism of vincristine and decrease the efficacy of drug, including dabrafenib. Patients receiving these drugs concurrently with vincristine should be monitored for possible loss of vincristine efficacy.
    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.
    Darunavir: (Major) The plasma concentrations of vincristine may be significantly elevated when administered concurrently with protease inhibitors. Consideration should be given to temporarily withholding the regimen in patients who develop significant hematological or gastrointestinal toxicity when protease inhibitors are coadministered with vincristine. Vincristine is a CYP3A4 and P-glycoprotein (P-gp) substrate; protease inhibitors are CYP3A4 inhibitors and some also inhibit P-gp. If the antiretroviral regimen needs to be withheld for a prolonged period, consider use of a revised regimen that does not include a CYP3A4 and P-gp inhibitor.
    Darunavir; Cobicistat: (Major) Avoid coadministration of vincristine with cobicistat due to increased plasma concentrations of vincristine, resulting in an earlier onset and/or increased severity of neuromuscular side effects. Vincristine is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. (Major) The plasma concentrations of vincristine may be significantly elevated when administered concurrently with protease inhibitors. Consideration should be given to temporarily withholding the regimen in patients who develop significant hematological or gastrointestinal toxicity when protease inhibitors are coadministered with vincristine. Vincristine is a CYP3A4 and P-glycoprotein (P-gp) substrate; protease inhibitors are CYP3A4 inhibitors and some also inhibit P-gp. If the antiretroviral regimen needs to be withheld for a prolonged period, consider use of a revised regimen that does not include a CYP3A4 and P-gp inhibitor.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid coadministration of vincristine with cobicistat due to increased plasma concentrations of vincristine, resulting in an earlier onset and/or increased severity of neuromuscular side effects. Vincristine is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. (Major) The plasma concentrations of vincristine may be significantly elevated when administered concurrently with protease inhibitors. Consideration should be given to temporarily withholding the regimen in patients who develop significant hematological or gastrointestinal toxicity when protease inhibitors are coadministered with vincristine. Vincristine is a CYP3A4 and P-glycoprotein (P-gp) substrate; protease inhibitors are CYP3A4 inhibitors and some also inhibit P-gp. If the antiretroviral regimen needs to be withheld for a prolonged period, consider use of a revised regimen that does not include a CYP3A4 and P-gp inhibitor.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) The plasma concentrations of vincristine may be significantly elevated when administered concurrently with protease inhibitors. Consideration should be given to temporarily withholding the regimen in patients who develop significant hematological or gastrointestinal toxicity when protease inhibitors are coadministered with vincristine. Vincristine is a CYP3A4 and P-glycoprotein (P-gp) substrate; protease inhibitors are CYP3A4 inhibitors and some also inhibit P-gp. If the antiretroviral regimen needs to be withheld for a prolonged period, consider use of a revised regimen that does not include a CYP3A4 and P-gp inhibitor.
    Deflazacort: (Moderate) Use sodium phosphate cautiously with corticosteroids, especially mineralocorticoids or corticotropin, ACTH, as concurrent use can cause hypernatremia.
    Delavirdine: (Major) Delavirdine is a potent inhibitor of CYP3A4, and vincristine is a CYP3A substrate. Coadministration could increase exposure to vincristine; monitor patients for increased side effects if these drugs are given together.
    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.
    Desmopressin: (Major) Additive hyponatremic effects may be seen in patients treated with desmopressin and drugs associated with SIADH including vincristine. Use combination with caution, and monitor patients for signs and symptoms of hyponatremia.
    Dexamethasone: (Moderate) Avoid the concomitant use of dexamethasone and vincristine. Vincristine is a substrate for cytochrome P450 (CYP) 3A4. Agents that induce CYP 3A4 such as dexamethasone may increase the metabolism of vincristine and decrease the efficacy of drug. (Moderate) Use sodium phosphate cautiously with corticosteroids, especially mineralocorticoids or corticotropin, ACTH, as concurrent use can cause hypernatremia.
    Dextromethorphan; Quinidine: (Major) Quinidine inhibits P-glycoprotein (P-gp), and vincristine is a P-gp substrate. Coadministration could increase exposure to vincristine; monitor patients for increased side effects if these drugs are given together.
    Diazoxide: (Moderate) Use sodium phosphates cautiously with diazoxide, as concurrent use can cause hypernatremia.
    Dichlorphenamide: (Moderate) Use dichlorphenamide and sodium phosphate monobasic monohydrate; sodium phosphate dibasic anhydrous together with caution. Dichlorphenamide increases potassium excretion and can cause hypokalemia and should be used cautiously with other drugs that may cause hypokalemia including laxatives. Measure potassium concentrations at baseline and periodically during dichlorphenamide treatment. If hypokalemia occurs or persists, consider reducing the dichlorphenamide dose or discontinuing dichlorphenamide therapy.
    Diclofenac: (Minor) An increased risk of bleeding may occur when NSAIDs, such as diclofenac, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Diclofenac; Misoprostol: (Minor) An increased risk of bleeding may occur when NSAIDs, such as diclofenac, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Diphenhydramine; Ibuprofen: (Major) An increased risk of bleeding may occur when NSAIDs, such as ibuprofen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Diphenhydramine; Naproxen: (Minor) An increased risk of bleeding may occur when NSAIDs, such as naproxen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Dronedarone: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A; dronedarone also inhibits P-gp. Vincristine is a substrate for CYP3A4 and P-gp. The concomitant administration of dronedarone with CYP3A4 and P-gp substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Drospirenone; Ethinyl Estradiol: (Moderate) In vitro, ethinyl estradiol is a mild CYP3A4 inhibitor, and vincristine is a CYP3A substrate. Theoretically, coadministration could increase exposure to vincristine; monitor patients for increased side effects if these drugs are given together.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) In vitro, ethinyl estradiol is a mild CYP3A4 inhibitor, and vincristine is a CYP3A substrate. Theoretically, coadministration could increase exposure to vincristine; monitor patients for increased side effects if these drugs are given together.
    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) Administering vincristine with elbasvir; grazoprevir may result in elevated vincristine plasma concentrations. Vincristine is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
    Eliglustat: (Major) Eliglustat inhibits P-glycoprotein (P-gp), and vincristine is a P-gp substrate. Coadministration could increase exposure to vincristine; monitor patients for increased side effects if these drugs are given together.
    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.
    Enzalutamide: (Major) Avoid coadministration of vincristine with enzalutamide due to decreased plasma concentrations of vincristine. Vincristine is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer.
    Erythromycin: (Major) Increased concentrations of vincristine are likely. Consider if alternative antibiotic therapy is appropriate. Monitor for vincristine-related side effects, including neurotoxicity, if these drugs must be used together. Erythromycin is an inhibitor of CYP3A4 and also inhibits P-gp. Vincristine is a CYP3A4 and P-gp substrate. Reports of interactions between erythromycin and vinca alkaloids have been noted.
    Erythromycin; Sulfisoxazole: (Major) Increased concentrations of vincristine are likely. Consider if alternative antibiotic therapy is appropriate. Monitor for vincristine-related side effects, including neurotoxicity, if these drugs must be used together. Erythromycin is an inhibitor of CYP3A4 and also inhibits P-gp. Vincristine is a CYP3A4 and P-gp substrate. Reports of interactions between erythromycin and vinca alkaloids have been noted.
    Eslicarbazepine: (Major) Vincristine is a substrate for cytochrome P450 (CYP) 3A4. Agents that induce CYP3A4 may increase the metabolism of vincristine and decrease the efficacy of drug, including eslicarbazepines. Patients receiving these drugs concurrently with vincristine should be monitored for possible loss of vincristine efficacy.
    Esomeprazole; Naproxen: (Minor) An increased risk of bleeding may occur when NSAIDs, such as naproxen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Ethinyl Estradiol: (Moderate) In vitro, ethinyl estradiol is a mild CYP3A4 inhibitor, and vincristine is a CYP3A substrate. Theoretically, coadministration could increase exposure to vincristine; monitor patients for increased side effects if these drugs are given together.
    Ethinyl Estradiol; Desogestrel: (Moderate) In vitro, ethinyl estradiol is a mild CYP3A4 inhibitor, and vincristine is a CYP3A substrate. Theoretically, coadministration could increase exposure to vincristine; monitor patients for increased side effects if these drugs are given together.
    Ethinyl Estradiol; Ethynodiol Diacetate: (Moderate) In vitro, ethinyl estradiol is a mild CYP3A4 inhibitor, and vincristine is a CYP3A substrate. Theoretically, coadministration could increase exposure to vincristine; monitor patients for increased side effects if these drugs are given together.
    Ethinyl Estradiol; Etonogestrel: (Moderate) In vitro, ethinyl estradiol is a mild CYP3A4 inhibitor, and vincristine is a CYP3A substrate. Theoretically, coadministration could increase exposure to vincristine; monitor patients for increased side effects if these drugs are given together.
    Ethinyl Estradiol; Levonorgestrel: (Moderate) In vitro, ethinyl estradiol is a mild CYP3A4 inhibitor, and vincristine is a CYP3A substrate. Theoretically, coadministration could increase exposure to vincristine; monitor patients for increased side effects if these drugs are given together.
    Ethinyl Estradiol; Levonorgestrel; Ferrous bisglycinate: (Moderate) In vitro, ethinyl estradiol is a mild CYP3A4 inhibitor, and vincristine is a CYP3A substrate. Theoretically, coadministration could increase exposure to vincristine; monitor patients for increased side effects if these drugs are given together.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Moderate) In vitro, ethinyl estradiol is a mild CYP3A4 inhibitor, and vincristine is a CYP3A substrate. Theoretically, coadministration could increase exposure to vincristine; monitor patients for increased side effects if these drugs are given together.
    Ethinyl Estradiol; Norelgestromin: (Moderate) In vitro, ethinyl estradiol is a mild CYP3A4 inhibitor, and vincristine is a CYP3A substrate. Theoretically, coadministration could increase exposure to vincristine; monitor patients for increased side effects if these drugs are given together.
    Ethinyl Estradiol; Norethindrone Acetate: (Moderate) In vitro, ethinyl estradiol is a mild CYP3A4 inhibitor, and vincristine is a CYP3A substrate. Theoretically, coadministration could increase exposure to vincristine; monitor patients for increased side effects if these drugs are given together.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Moderate) In vitro, ethinyl estradiol is a mild CYP3A4 inhibitor, and vincristine is a CYP3A substrate. Theoretically, coadministration could increase exposure to vincristine; monitor patients for increased side effects if these drugs are given together.
    Ethinyl Estradiol; Norethindrone: (Moderate) In vitro, ethinyl estradiol is a mild CYP3A4 inhibitor, and vincristine is a CYP3A substrate. Theoretically, coadministration could increase exposure to vincristine; monitor patients for increased side effects if these drugs are given together.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Moderate) In vitro, ethinyl estradiol is a mild CYP3A4 inhibitor, and vincristine is a CYP3A substrate. Theoretically, coadministration could increase exposure to vincristine; monitor patients for increased side effects if these drugs are given together.
    Ethinyl Estradiol; Norgestimate: (Moderate) In vitro, ethinyl estradiol is a mild CYP3A4 inhibitor, and vincristine is a CYP3A substrate. Theoretically, coadministration could increase exposure to vincristine; monitor patients for increased side effects if these drugs are given together.
    Ethinyl Estradiol; Norgestrel: (Moderate) In vitro, ethinyl estradiol is a mild CYP3A4 inhibitor, and vincristine is a CYP3A substrate. Theoretically, coadministration could increase exposure to vincristine; monitor patients for increased side effects if these drugs are given together.
    Etodolac: (Minor) An increased risk of bleeding may occur when NSAIDs, such as etodolac, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Etravirine: (Moderate) Etravirine is a CYP3A4 inducer/substrate and a P-glycoprotein (PGP) inhibitor and vincristine is a CYP3A4 and PGP substrate. Caution is warranted if these drugs are coadministered.
    Famotidine; Ibuprofen: (Major) An increased risk of bleeding may occur when NSAIDs, such as ibuprofen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Febuxostat: (Major) Coadministration of febuxostat and cytotoxic antineoplastic agents has not been studied. After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and calculi.
    Felbamate: (Moderate) Vincristine is a substrate for cytochrome P450 (CYP) 3A4. Agents that induce CYP3A4 may increase the metabolism of vincristine and decrease the efficacy of drug, including felbamate. Patients receiving these drugs concurrently with vincristine should be monitored for possible loss of vincristine efficacy.
    Fenoprofen: (Major) An increased risk of bleeding may occur when NSAIDs, such as vincristine, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    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.
    Fludrocortisone: (Moderate) Use sodium phosphate cautiously with corticosteroids, especially mineralocorticoids or corticotropin, ACTH, as concurrent use can cause hypernatremia.
    Flunisolide: (Moderate) Use sodium phosphate cautiously with corticosteroids, especially mineralocorticoids or corticotropin, ACTH, as concurrent use can cause hypernatremia.
    Flurbiprofen: (Minor) An increased risk of bleeding may occur when NSAIDs, such as flurbiprofen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Flutamide: (Moderate) Vincristine is a substrate for cytochrome P450 (CYP) 3A4. Agents that induce CYP3A4 may increase the metabolism of vincristine and decrease the efficacy of drug, including flutamide (in vitro). Patients receiving these drugs concurrently with vincristine should be monitored for possible loss of vincristine efficacy.
    Fluticasone: (Moderate) Use sodium phosphate cautiously with corticosteroids, especially mineralocorticoids or corticotropin, ACTH, as concurrent use can cause hypernatremia.
    Fluticasone; Salmeterol: (Moderate) Use sodium phosphate cautiously with corticosteroids, especially mineralocorticoids or corticotropin, ACTH, as concurrent use can cause hypernatremia.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) Use sodium phosphate cautiously with corticosteroids, especially mineralocorticoids or corticotropin, ACTH, as concurrent use can cause hypernatremia.
    Fluticasone; Vilanterol: (Moderate) Use sodium phosphate cautiously with corticosteroids, especially mineralocorticoids or corticotropin, ACTH, as concurrent use can cause hypernatremia.
    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.
    Formoterol; Mometasone: (Moderate) Use sodium phosphate cautiously with corticosteroids, especially mineralocorticoids or corticotropin, ACTH, as concurrent use can cause hypernatremia.
    Fosamprenavir: (Major) The plasma concentrations of vincristine may be significantly elevated when administered concurrently with protease inhibitors. Consideration should be given to temporarily withholding the regimen in patients who develop significant hematological or gastrointestinal toxicity when protease inhibitors are coadministered with vincristine. Vincristine is a CYP3A4 and P-glycoprotein (P-gp) substrate; protease inhibitors are CYP3A4 inhibitors and some also inhibit P-gp. If the antiretroviral regimen needs to be withheld for a prolonged period, consider use of a revised regimen that does not include a CYP3A4 and P-gp inhibitor.
    Fosphenytoin: (Major) Fosphenytoin is a prodrug of phenytoin, and the concomitant use of phenytoin and vincristine is to be avoided. Vincristine is a substrate for cytochrome P450 (CYP) 3A4. Agents that induce CYP 3A4 such as phenytoin may increase the metabolism of vincristine and decrease the efficacy of drug. Also, simultaneous oral or intravenous administration of phenytoin and antineoplastic chemotherapy combinations that included non-liposomal vincristine sulfate have been reported to reduce blood levels of phenytoin and to increase seizure activity. Concurrent treatment with vinca alkaloids and phenytoin has resulted in 50% decreases in phenytoin concentrations and seizures. Reduced phenytoin concentrations may be noted within 24 hours and continue for up to 10 days.
    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.
    Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with the coadministration of pibrentasvir and vincristine as coadministration may increase serum concentrations of vincristine and increase the risk of adverse effects. Vincristine is a substrate of P-glycoprotein (P-gp); pibrentasvir is an inhibitor of P-gp.
    Grapefruit juice: (Major) Grapefruit juice inhibits CYP3A4 and P-glycoprotein (P-gp); vincristine is both a CYP3A and P-gp substrate. Coadministration could increase exposure to vincristine; monitor patients for increased side effects if these drugs are given together.
    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.
    Hydralazine: (Moderate) Use sodium phosphates cautiously with hydralazine as concurrent use can cause hypernatremia.
    Hydralazine; Hydrochlorothiazide, HCTZ: (Moderate) Use sodium phosphates cautiously with hydralazine as concurrent use can cause hypernatremia.
    Hydralazine; Isosorbide Dinitrate, ISDN: (Moderate) Use sodium phosphates cautiously with hydralazine as concurrent use can cause hypernatremia.
    Hydrochlorothiazide, HCTZ; Methyldopa: (Moderate) Use sodium phosphates cautiously with methyldopa, as concurrent use can cause hypernatremia.
    Hydrocodone; Ibuprofen: (Major) An increased risk of bleeding may occur when NSAIDs, such as ibuprofen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Hydrocortisone: (Moderate) Use sodium phosphate cautiously with corticosteroids, especially mineralocorticoids or corticotropin, ACTH, as concurrent use can cause hypernatremia.
    Ibuprofen: (Major) An increased risk of bleeding may occur when NSAIDs, such as ibuprofen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Ibuprofen; Oxycodone: (Major) An increased risk of bleeding may occur when NSAIDs, such as ibuprofen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Ibuprofen; Pseudoephedrine: (Major) An increased risk of bleeding may occur when NSAIDs, such as ibuprofen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with vincristine, a CYP3A substrate, as vincristine toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
    Imatinib: (Moderate) Imatinib, STI-571, inhibits CYP3A4, and vincristine is a CYP3A substrate. Coadministration could increase exposure to vincristine; monitor patients for increased side effects if these drugs are given together.
    Indinavir: (Major) The plasma concentrations of vincristine may be significantly elevated when administered concurrently with protease inhibitors. Consideration should be given to temporarily withholding the regimen in patients who develop significant hematological or gastrointestinal toxicity when protease inhibitors are coadministered with vincristine. Vincristine is a CYP3A4 and P-glycoprotein (P-gp) substrate; protease inhibitors are CYP3A4 inhibitors and some also inhibit P-gp. If the antiretroviral regimen needs to be withheld for a prolonged period, consider use of a revised regimen that does not include a CYP3A4 and P-gp inhibitor.
    Indomethacin: (Major) An increased risk of bleeding may occur when NSAIDs, such as vincristine, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Interferon Alfa-2a: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Interferon Alfa-2b: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Interferon Alfa-2b; Ribavirin: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Interferon Alfacon-1: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Interferon Alfa-n3: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with vincristine may result in increased serum concentrations of vincristine. Vincristine is a substrate of the hepatic isoenzyme CYP3A4 and drug transporter P-glycoprotein (P-gp); isavuconazole, the active moiety of isavuconazonium, is an inhibitor of CYP3A4 and P-gp. Caution and close monitoring are advised if these drugs are used together.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Vincristine is a substrate for cytochrome P450 (CYP) 3A4. Agents that induce CYP3A4 may increase the metabolism of vincristine and decrease the efficacy of the drug, including rifampin. Patients receiving these drugs concurrently with vincristine should be monitored for possible loss of vincristine efficacy.
    Isoniazid, INH; Rifampin: (Moderate) Vincristine is a substrate for cytochrome P450 (CYP) 3A4. Agents that induce CYP3A4 may increase the metabolism of vincristine and decrease the efficacy of the drug, including rifampin. Patients receiving these drugs concurrently with vincristine should be monitored for possible loss of vincristine efficacy.
    Itraconazole: (Major) Avoid the use of vincristine during and for 2 weeks after discontinuation of itraconazole due to the risk of an earlier onset and/or increased severity of vincristine-related adverse reactions, including constipation and peripheral neuropathy. Vincristine is a CYP3A4 substrate and itraconazole is a strong CYP3A4 inhibitor. Concomitant administration of vincristine and itraconazole has resulted in an increased incidence of neurotoxicity.
    Ixabepilone: (Minor) Ixabepilone is a weak inhibitor of P-glycoprotein (Pgp). Vincristine is a Pgp substrate, and concomitant use of ixabepilone with a Pgp substrate may cause an increase in vincristine concentrations. Use caution if ixabepilone is coadministered with a Pgp substrate.
    Ketoconazole: (Major) Ketoconazole inhibits CYP3A4 and P-glycoprotein (P-gp); vincristine is both a CYP3A and P-gp substrate. Coadministration could increase exposure to vincristine; monitor patients for increased side effects if these drugs are given together.
    Ketoprofen: (Major) An increased risk of bleeding may occur when NSAIDs, such as ketoprofen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Ketorolac: (Major) An increased risk of bleeding may occur when NSAIDs, such as ketorolac, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Lansoprazole; Naproxen: (Minor) An increased risk of bleeding may occur when NSAIDs, such as naproxen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Lapatinib: (Moderate) Vincristine is a substrate of both CYP3A4 and P-glycoprotein. In vitro, lapatinib, at clinically relevant concentrations, inhibits CYP3A4. Also, lapatinib is a substrate and inhibitor of the efflux transporter P-glycoprotein (Pgp, ABCB1). Coadministration of lapatinib and vincristine may lead to increased serum concentrations of vincristine. Cautious coadministration is recommended, and consider a dose reduction of vincristine.
    L-Asparaginase Escherichia coli: (Moderate) Use L-asparaginase and vincristine together with caution; increased vincristine-related toxicity may occur. L-asparaginase administered before or concurrently with vincristine may reduce the hepatic clearance of vincristine. If these drugs are used together, administer vincristine 12 to 24 hours before L-asparaginase to minimize toxicity.
    Ledipasvir; Sofosbuvir: (Moderate) Caution and close monitoring of vincristine-associated adverse reactions is advised with concomitant administration of ledipasvir. Vincristine is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor. Taking these drugs together may increase vincristine plasma concentrations.
    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: (Major) Avoid coadministration of letermovir and vincristine in patients additionally receiving cyclosporine due to increased plasma concentrations of vincristine. Vinorelbine is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor that may be administered with vincristine; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. An increase in plasma concentrations of vincristine may occur during concurrent administration with letermovir; in patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified.
    Live Vaccines: (Severe) Do not administer live vaccines to vincristine recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving vincristine. At least 2 weeks before initiation of vincristine therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Vincristine recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased.
    Lopinavir; Ritonavir: (Major) The plasma concentrations of vincristine may be significantly elevated when administered concurrently with protease inhibitors. Consideration should be given to temporarily withholding the regimen in patients who develop significant hematological or gastrointestinal toxicity when protease inhibitors are coadministered with vincristine. Vincristine is a CYP3A4 and P-glycoprotein (P-gp) substrate; protease inhibitors are CYP3A4 inhibitors and some also inhibit P-gp. If the antiretroviral regimen needs to be withheld for a prolonged period, consider use of a revised regimen that does not include a CYP3A4 and P-gp inhibitor.
    Lumacaftor; Ivacaftor: (Major) Lumacaftor; ivacaftor may alter the exposure of vincristine. If coadministration is necessary, use caution and monitor closely. Vincristine is a substrate of CYP3A and the P-glycoprotein (P-gp) drug transporter. Lumacaftor is a strong CYP3A inducer; in vitro data suggest lumacaftor; ivacaftor may also induce and/or inhibit P-gp. Although induction of vincristine metabolism through the CYP3A pathway may lead to decreased drug efficacy, the net effect of lumacaftor; ivacaftor on P-gp transport is not clear. Monitor the patient for decreased chemotherapeutic efficacy and vincristine-related toxicity.
    Magnesium Hydroxide: (Major) Aluminum hydroxide and magnesium hydroxide (as well as other antacids, i.e. aluminum hydroxide; magnesium carbonate, aluminum hydroxide; magaldrate; magnesium hydroxide, and aluminum hydroxide; magnesium trisilicate) may interact with urinary acidifiers by alkalinizing the urine. Frequent use of these high dose antacids should be avoided in patients receiving urinary acidifiers.
    Magnesium Salicylate: (Moderate) Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.
    Meclofenamate Sodium: (Major) An increased risk of bleeding may occur when NSAIDs, such as meclofenamate sodium, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Mefenamic Acid: (Major) An increased risk of bleeding may occur when NSAIDs, such as mefenamic acid, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Mefloquine: (Major) Mefloquine inhibits P-glycoprotein (P-gp), and vincristine is a P-gp substrate. Coadministration could increase exposure to vincristine; monitor patients for increased side effects if these drugs are given together.
    Meloxicam: (Minor) An increased risk of bleeding may occur when NSAIDs, such as meloxicam, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Mephobarbital: (Major) Vincristine is a substrate for cytochrome P450 (CYP) 3A4. Agents that induce CYP 3A4 may increase the metabolism of vincristine and decrease the efficacy of drug, including barbiturates. Patients receiving these drugs concurrently should be monitored for possible loss of vincristine efficacy.
    Methadone: (Minor) As methadone is a weak base, the renal elimination of methadone is increased by urine acidification. Thus acidifying agents may lower the serum methadone concentration. The limited amounts of circulating methadone that undergo glomerular filtration are partially reabsorbed by the kidney tubules, and this reabsorption is pH-dependent. Several studies have demonstrated that methadone is cleared faster from the body with an acidic urinary pH as compared with a more basic pH.
    Methohexital: (Major) Vincristine is a substrate for cytochrome P450 (CYP) 3A4. Agents that induce CYP 3A4 may increase the metabolism of vincristine and decrease the efficacy of drug, including barbiturates. Patients receiving these drugs concurrently should be monitored for possible loss of vincristine efficacy.
    Methotrexate: (Major) Monitor for increased serum concentrations and toxicities of methotrexate when administered concurrently with vincristine. When given 0 to 1 hour prior to methotrexate, vincristine increases the cellular retention of methotrexate by inhibiting methotrexate efflux from the cell. Since the window of opportunity for a synergistic interaction is short, the effects in vivo are clinically not seen. Therapeutic synergism is noted when methotrexate is given 8 to 48 hours before vincristine. The mechanism for this interaction has not been clearly defined.
    Methyldopa: (Moderate) Use sodium phosphates cautiously with methyldopa, as concurrent use can cause hypernatremia.
    Methylprednisolone: (Moderate) Use sodium phosphate cautiously with corticosteroids, especially mineralocorticoids or corticotropin, ACTH, as concurrent use can cause hypernatremia.
    Mifepristone: (Moderate) Increased concentrations of vincristine are likely if chronic mifepristone therapy is given concurrently; exercise caution and monitor for vincristine-related side effects, including neurotoxicity. Mifepristone is an inhibitor of CYP3A4 and possibly an inhibitor of P-gp. Vincristine 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 vincristine 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.
    Mitotane: (Major) Concomitant use of mitotane with vincristine should be undertaken with caution as it could result in decreased plasma concentrations of vincristine, leading to reduced efficacy. Mitotane is a strong CYP3A4 inducer and vincristine is a CYP3A4 substrate.
    Modafinil: (Moderate) Vincristine is a substrate for cytochrome P450 (CYP) 3A4. Agents that induce CYP3A4 may increase the metabolism of vincristine and decrease the efficacy of drug, including modafinil. Patients receiving these drugs concurrently with vincristine should be monitored for possible loss of vincristine efficacy.
    Mometasone: (Moderate) Use sodium phosphate cautiously with corticosteroids, especially mineralocorticoids or corticotropin, ACTH, as concurrent use can cause hypernatremia.
    Nabumetone: (Minor) An increased risk of bleeding may occur when NSAIDs, such as nabumetone, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Nafcillin: (Moderate) Vincristine is a substrate for cytochrome P450 (CYP) 3A4. Agents that induce CYP3A4 may increase the metabolism of vincristine and decrease the efficacy of drug, including nafcillin (in vitro). Patients receiving these drugs concurrently with vincristine should be monitored for possible loss of vincristine efficacy.
    Naproxen: (Minor) An increased risk of bleeding may occur when NSAIDs, such as naproxen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Naproxen; Pseudoephedrine: (Minor) An increased risk of bleeding may occur when NSAIDs, such as naproxen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Naproxen; Sumatriptan: (Minor) An increased risk of bleeding may occur when NSAIDs, such as naproxen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Nelfinavir: (Major) The plasma concentrations of vincristine may be significantly elevated when administered concurrently with protease inhibitors. Consideration should be given to temporarily withholding the regimen in patients who develop significant hematological or gastrointestinal toxicity when protease inhibitors are coadministered with vincristine. Vincristine is a CYP3A4 and P-glycoprotein (P-gp) substrate; protease inhibitors are CYP3A4 inhibitors and some also inhibit P-gp. If the antiretroviral regimen needs to be withheld for a prolonged period, consider use of a revised regimen that does not include a CYP3A4 and P-gp inhibitor.
    Neratinib: (Major) Avoid coadministration of vincristine with neratinib due to increased vincristine exposure. Vincristine is a P-glycoprotein (P-gp) substrate. Neratinib may inhibit the transport of P-gp substrates. The effect of concomitant use of P-gp inhibitors has not been investigated; it is likely that these agents will alter the pharmacokinetics or pharmacodynamics of vincristine.
    Netupitant, Fosnetupitant; Palonosetron: (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4, such as vincristine. The plasma concentrations of CYP3A4 substrates can increase when co-administered with netupitant. The inhibitory effect on CYP3A4 can last for multiple days. If coadministration is necessary, use caution and monitor for chemotherapeutic related adverse reactions.
    Nifedipine: (Major) Use caution if coadminsitration of nifedipine is necessary with vincristine and monitor for vincristine toxicity. In a pharmacokinetic study of 26 patients with solid tumors and normal renal and hepatic function, vincristine 2 mg IV was administered alone (n = 14) or with nifedipine 10 mg by mouth three times daily for 3 days before and 7 days after (n = 12). Coadministration of nifedipine significantly increased vincristine AUC (10 +/- 2.91 mcg x min/ml vs 2.9 +/- 0.86 mcg x min/ml; p = < 0.001) and terminal half-life (85.56 +/- 23.51 hours vs 21.72 +/- 9.61 hours; p < 0.05) compared with vincristine alone; additionally, the plasma clearance was significantly reduced in patients treated with nifedipine (309.54 +/- 95.46 vs 985.06 +/- 258.6 ml/min/m2; p < 0.01). The mechanism of this interaction is poorly understood.
    Nilotinib: (Moderate) Monitor for increased severity or earlier onset of vincristine-related adverse reactions (e.g., periipheral, autonomic and central neuropathy; low blood counts) if coadministration with nilotinib is necessary. Nilotinib may increase vincristine exposure. Vincristine is a CYP3A4 substrate and nilotinib is a moderate CYP3A4 inhibitor.
    Octreotide: (Major) Octreotide inhibits CYP3A4, and vincristine is a CYP3A substrate. Coadministration could increase exposure to vincristine; monitor patients for increased side effects if these drugs are given together.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) The plasma concentrations of vincristine may be significantly elevated when administered concurrently with protease inhibitors. Consideration should be given to temporarily withholding the regimen in patients who develop significant hematological or gastrointestinal toxicity when protease inhibitors are coadministered with vincristine. Vincristine is a CYP3A4 and P-glycoprotein (P-gp) substrate; protease inhibitors are CYP3A4 inhibitors and some also inhibit P-gp. If the antiretroviral regimen needs to be withheld for a prolonged period, consider use of a revised regimen that does not include a CYP3A4 and P-gp inhibitor.
    Oritavancin: (Minor) Vincristine is metabolized by CYP3A4; oritavancin is a weak CYP3A4 inducer. Plasma concentrations and efficacy of vincristine may be reduced if these drugs are administered concurrently.
    Osimertinib: (Moderate) Monitor for an increase in vincristine-related adverse reactions if coadministration with osimertinib is necessary. Vincristine is a P-glycoprotein (P-gp) substrate and osimertinib is a P-gp inhibitor.
    Oxaprozin: (Minor) An increased risk of bleeding may occur when NSAIDs, such as oxaprozin, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Oxcarbazepine: (Moderate) Vincristine is a substrate for cytochrome P450 (CYP) 3A4. Agents that induce CYP3A4 may increase the metabolism of vincristine and decrease the efficacy of the drug, include oxcarbazepine. Patients receiving these drugs concurrently with vincristine should be monitored for possible loss of vincristine efficacy.
    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) Pazopanib is a weak inhibitor of CYP3A4. Coadministration of pazopanib and vincristine, a CYP3A4 substrate, may cause an increase in systemic concentrations of vincristine. Use caution when administering these drugs concomitantly.
    Pegaspargase: (Major) Administration of pegaspargase concurrently or prior to vincristine may result in decreased hepatic metabolism of vincristine and cause additive neurotoxicity. Administration of L-asparaginase after vincristine may lessen this effect; vincristine should be given 12 to 24 hours prior to L-asparaginase or pegaspargase.
    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.
    Pentobarbital: (Major) Vincristine is a substrate for cytochrome P450 (CYP) 3A4. Agents that induce CYP 3A4 may increase the metabolism of vincristine and decrease the efficacy of drug, including barbiturates. Patients receiving these drugs concurrently should be monitored for possible loss of vincristine efficacy.
    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.
    Perampanel: (Moderate) Vincristine is a substrate for cytochrome P450 (CYP) 3A4. Agents that induce CYP3A4 may increase the metabolism of vincristine and decrease the efficacy of the drug, including perampanel (in vitro). Patients receiving these drugs concurrently with vincristine should be monitored for possible loss of vincristine efficacy.
    Phenobarbital: (Major) Vincristine is a substrate for cytochrome P450 (CYP) 3A4. Agents that induce CYP 3A4 may increase the metabolism of vincristine and decrease the efficacy of drug, including barbiturates. Patients receiving these drugs concurrently should be monitored for possible loss of vincristine efficacy.
    Phenytoin: (Major) Avoid the concomitant use of phenytoin and vincristine. Vincristine is a substrate for cytochrome P450 (CYP) 3A4. Agents that induce CYP 3A4 such as phenytoin may increase the metabolism of vincristine and decrease the efficacy of drug. Also, simultaneous oral or intravenous administration of phenytoin and antineoplastic chemotherapy combinations that included non-liposomal vincristine sulfate have been reported to reduce blood levels of phenytoin and to increase seizure activity. Concurrent treatment with vinca alkaloids and phenytoin has resulted in 50% decreases in phenytoin concentrations and seizures. Reduced phenytoin concentrations may be noted within 24 hours and continue for up to 10 days.
    Piroxicam: (Minor) An increased risk of bleeding may occur when NSAIDs, such as piroxicam, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Posaconazole: (Major) Avoid coadministration of posaconazole with vincristine due to increased plasma concentrations of vincristine. Vincristine 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.
    Prednisolone: (Moderate) Use sodium phosphate cautiously with corticosteroids, especially mineralocorticoids or corticotropin, ACTH, as concurrent use can cause hypernatremia.
    Prednisone: (Moderate) Use sodium phosphate cautiously with corticosteroids, especially mineralocorticoids or corticotropin, ACTH, as concurrent use can cause hypernatremia.
    Primidone: (Major) Vincristine is a substrate for cytochrome P450 (CYP) 3A4. Agents that induce CYP 3A4 may increase the metabolism of vincristine and decrease the efficacy of drug, including barbiturates. Patients receiving these drugs concurrently should be monitored for possible loss of vincristine efficacy.
    Propafenone: (Major) Propafenone inhibits P-glycoprotein (P-gp), and vincristine is a P-gp substrate. Coadministration could increase exposure to vincristine; monitor patients for increased side effects if these drugs are given together.
    Protease inhibitors: (Major) The plasma concentrations of vincristine may be significantly elevated when administered concurrently with protease inhibitors. Consideration should be given to temporarily withholding the regimen in patients who develop significant hematological or gastrointestinal toxicity when protease inhibitors are coadministered with vincristine. Vincristine is a CYP3A4 and P-glycoprotein (P-gp) substrate; protease inhibitors are CYP3A4 inhibitors and some also inhibit P-gp. If the antiretroviral regimen needs to be withheld for a prolonged period, consider use of a revised regimen that does not include a CYP3A4 and P-gp inhibitor.
    Quinidine: (Major) Quinidine inhibits P-glycoprotein (P-gp), and vincristine is a P-gp substrate. Coadministration could increase exposure to vincristine; monitor patients for increased side effects if these drugs are given together.
    Quinine: (Moderate) Quinine inhibits CYP3A4, and vincristine is a CYP3A substrate. Coadministration could increase exposure to vincristine; monitor patients for increased side effects if these drugs are given together.
    Regorafenib: (Moderate) In vitro, Regorafenib is both a mild CYP3A4 and P-glycoprotein (P-gp) inhibitor; vincristine is a substrate of both CYP3A and P-gp. Theoretically, concentrations of vincristine may be affected by coadministration. Monitor patients for vincristine toxicity if these drugs are used together.
    Ribociclib: (Major) Avoid coadministration of vincristine with ribociclib due to increased plasma concentrations of vincristine, resulting in an earlier onset and/or increased severity of neuromuscular side effects. Vincristine is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor.
    Ribociclib; Letrozole: (Major) Avoid coadministration of vincristine with ribociclib due to increased plasma concentrations of vincristine, resulting in an earlier onset and/or increased severity of neuromuscular side effects. Vincristine is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor.
    Rifabutin: (Moderate) Vincristine is a substrate for cytochrome P450 (CYP) 3A4. Agents that induce CYP3A4 may increase the metabolism of vincristine and decrease the efficacy of the drug, including rifabutin. Patients receiving these drugs concurrently with vincristine should be monitored for possible loss of vincristine efficacy.
    Rifampin: (Moderate) Vincristine is a substrate for cytochrome P450 (CYP) 3A4. Agents that induce CYP3A4 may increase the metabolism of vincristine and decrease the efficacy of the drug, including rifampin. Patients receiving these drugs concurrently with vincristine should be monitored for possible loss of vincristine efficacy.
    Rifapentine: (Major) Avoid the concomitant use of rifapentine and vincristine. Vincristine is a substrate for cytochrome P450 (CYP) 3A4. Agents that induce CYP 3A4 such as rifapentine may increase the metabolism of vincristine and decrease the efficacy of drug.
    Rifaximin: (Moderate) In vitro, rifaximin is a CYP3A4 inducer and a mild P-glycoprotein (P-gp) inhibitor, and vincristine is a CYP3A and P-gp substrate. With normal liver function and at normal doses, rifaximin is not expected to induce CYP3A4. Oral rifaximin is largely unabsorbed and should not result in drug interactions. However, theoretically, coadministration may affect vincristine concentrations; monitor patients for changes in vincristine efficacy and toxicity if these drugs are used together.
    Ritonavir: (Major) The plasma concentrations of vincristine may be significantly elevated when administered concurrently with protease inhibitors. Consideration should be given to temporarily withholding the regimen in patients who develop significant hematological or gastrointestinal toxicity when protease inhibitors are coadministered with vincristine. Vincristine is a CYP3A4 and P-glycoprotein (P-gp) substrate; protease inhibitors are CYP3A4 inhibitors and some also inhibit P-gp. If the antiretroviral regimen needs to be withheld for a prolonged period, consider use of a revised regimen that does not include a CYP3A4 and P-gp 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.
    Rolapitant: (Moderate) Use caution if vincristine and rolapitant are used concurrently, and monitor for vincristine-related adverse effects. Vincristine is a P-glycoprotein (P-gp) substrate, where an increase in exposure may significantly increase adverse effects; rolapitant is a P-gp inhibitor. When rolapitant was administered with another P-gp substrate, digoxin, the day 1 Cmax and AUC were increased by 70% and 30%, respectively; the Cmax and AUC on day 8 were not studied.
    Salsalate: (Moderate) Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.
    Saquinavir: (Major) The plasma concentrations of vincristine may be significantly elevated when administered concurrently with protease inhibitors. Consideration should be given to temporarily withholding the regimen in patients who develop significant hematological or gastrointestinal toxicity when protease inhibitors are coadministered with vincristine. Vincristine is a CYP3A4 and P-glycoprotein (P-gp) substrate; protease inhibitors are CYP3A4 inhibitors and some also inhibit P-gp. If the antiretroviral regimen needs to be withheld for a prolonged period, consider use of a revised regimen that does not include a CYP3A4 and P-gp inhibitor.
    Secobarbital: (Major) Vincristine is a substrate for cytochrome P450 (CYP) 3A4. Agents that induce CYP 3A4 may increase the metabolism of vincristine and decrease the efficacy of drug, including barbiturates. Patients receiving these drugs concurrently should be monitored for possible loss of vincristine efficacy.
    Simeprevir: (Minor) Simeprevir, a P-glycoprotein (P-gp) and a mild intestinal CYP3A4 inhibitor, may increase the side effects of vincristine, which is a P-gp and CYP3A4 substrate. Monitor patients for adverse effects of vincristine, such as myelosuppression and neurotoxicity.
    Sorafenib: (Major) Theoretically, coadministration may increase vincristine concentrations; monitor patients for vincristine toxicity if these drugs are used together. Sorafenib is a P-glycoprotein (P-gp) inhibitor, and vincristine is a P-gp substrate.
    St. John's Wort, Hypericum perforatum: (Moderate) St. John's Wort, Hypericum perforatum induces both CYP3A4 and P-glycoprotein (P-gp), and may decrease serum concentrations of drugs metabolized by this enzyme, such as vincristine. If these drugs are used together, monitor for possible decreased efficacy of vincristine.
    Sulindac: (Minor) An increased risk of bleeding may occur when NSAIDs, such as sulindac, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    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.
    Telaprevir: (Moderate) Close clinical monitoring is advised when administering vincristine with telaprevir due to an increased potential for vincristine-related adverse events. If vincristine dose adjustments are made, re-adjust the dose upon completion of telaprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of vincristine. Vincristine is a substrate of the drug efflux transporter P-glycoprotein (PGP) and of the hepatic isoenzyme CYP3A4; telaprevir is an inhibitor of both the efflux protein and the isoenzyme. Coadministration may result in elevated vincristine plasma concentrations.
    Telithromycin: (Major) Telithromycin is a strong inhibitor of CYP3A4, and vincristine is a CYP3A substrate. Coadministration could increase exposure to vincristine; monitor patients for increased side effects if these drugs are given together.
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and vincristine is necessary, as the systemic exposure of vincristine may be decreased resulting in reduced efficacy; avoid coadministration with vincristine liposomal. If telotristat ethyl and vincristine are used together, monitor patients for suboptimal efficacy of vincristine. Vincristine is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate.
    Temsirolimus: (Major) Avoid coadministration of temsirolimus with vincristine due to increased plasma concentrations of vincristine. Vincristine is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. The effect of concomitant use of P-gp inhibitors has not been investigated, but it is likely that these agents will alter the pharmacokinetics or pharmacodynamics of vincristine.
    Teniposide: (Moderate) Use teniposide and vincristine together with caution; neurotoxicity including cases of severe neuropathy have been reported.
    Testosterone: (Major) Testosterone inhibits P-glycoprotein (P-gp), and vincristine is a P-gp substrate. Coadministration could increase exposure to vincristine; monitor patients for increased side effects if these drugs are given together.
    Thalidomide: (Moderate) Thalidomide and other agents that cause peripheral neuropathy such as vincristine should be used cautiously due to the potential for additive effects.
    Thiopental: (Major) Vincristine is a substrate for cytochrome P450 (CYP) 3A4. Agents that induce CYP 3A4 may increase the metabolism of vincristine and decrease the efficacy of drug, including barbiturates. Patients receiving these drugs concurrently should be monitored for possible loss of vincristine efficacy.
    Ticagrelor: (Moderate) Ticagrelor is a mild CYP3A4 and P-glycoprotein (P-gp) inhibitor, and vincristine is a CYP3A and P-gp substrate. Coadministration may increase vincristine concentrations; monitor patients for vincristine toxicity if these drugs are used together.
    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: (Major) The plasma concentrations of vincristine may be significantly elevated when administered concurrently with protease inhibitors. Consideration should be given to temporarily withholding the regimen in patients who develop significant hematological or gastrointestinal toxicity when protease inhibitors are coadministered with vincristine. Vincristine is a CYP3A4 and P-glycoprotein (P-gp) substrate; protease inhibitors are CYP3A4 inhibitors and some also inhibit P-gp. If the antiretroviral regimen needs to be withheld for a prolonged period, consider use of a revised regimen that does not include a CYP3A4 and P-gp inhibitor.
    Tolmetin: (Minor) An increased risk of bleeding may occur when NSAIDs, such as tolmetin, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Trandolapril; Verapamil: (Major) Verapamil inhibits CYP3A4 and P-glycoprotein (P-gp); vincristine is a CYP3A and P-gp substrate. Coadministration could increase exposure to vincristine; however, verapamil must be given in toxic doses to achieve this effect. An in vitro study has shown that verapamil competes with vincristine for protein binding sites, specifically 1-acid glycoprotein. Verapamil reduced the binding of vincristine to various proteins by 27 to 60%. The clinical significance of this interaction is not known. The absorption of verapamil may also be reduced by coadministration with the cyclophosphamide, vincristine, procarbazine, prednisone (COPP) chemotherapeutic drug regimen. Monitor for increased side effects of vincristine and loss of blood pressure control during coadministration.
    Triamcinolone: (Moderate) Use sodium phosphate cautiously with corticosteroids, especially mineralocorticoids or corticotropin, ACTH, as concurrent use can cause hypernatremia.
    Trientine: (Major) In general, oral mineral supplements should not be given since they may block the oral absorption of trientine. However, iron deficiency may develop, especially in children and menstruating or pregnant women, or as a result of the low copper diet recommended for Wilson's disease. If necessary, iron may be given in short courses, but since iron and trientine each inhibit oral absorption of the other, 2 hours should elapse between administration of trientine and iron doses.
    Trifluoperazine: (Major) Trifluoperazine inhibits P-glycoprotein (P-gp), which is a mechanism of resistance to naturally occurring (non-synthetic) chemotherapy agents; vincristine is a P-gp substrate. Coadministration could increase exposure to vincristine; however, trifluoperazine must be given in toxic doses to achieve this effect.
    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.
    Valproic Acid, Divalproex Sodium: (Moderate) In vitro, Valproic Acid, Divalproex Sodium is a mild CYP3A4 inhibitor and inducer, as well as a mild P-glycoprotein (P-gp) inducer; vincristine is a substrate of both CYP3A and P-gp. Theoretically, concentrations of vincristine may be affected by coadministration. Monitor patients for changes in vincristine efficacy and toxicity if these drugs are used together.
    Vemurafenib: (Moderate) Concomitant use of vemurafenib and vincristine may result in altered concentrations of vincristine. Vemurafenib is an inhibitor of P-glycoprotein (PGP) and an inducer of CYP3A4. Vincristine is a substrate of PGP and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
    Verapamil: (Major) Verapamil inhibits CYP3A4 and P-glycoprotein (P-gp); vincristine is a CYP3A and P-gp substrate. Coadministration could increase exposure to vincristine; however, verapamil must be given in toxic doses to achieve this effect. An in vitro study has shown that verapamil competes with vincristine for protein binding sites, specifically 1-acid glycoprotein. Verapamil reduced the binding of vincristine to various proteins by 27 to 60%. The clinical significance of this interaction is not known. The absorption of verapamil may also be reduced by coadministration with the cyclophosphamide, vincristine, procarbazine, prednisone (COPP) chemotherapeutic drug regimen. Monitor for increased side effects of vincristine and loss of blood pressure control during coadministration.
    Voriconazole: (Major) Avoid coadministration of voriconazole with vincristine due to increased plasma concentrations of vinorelbine. Vincristine is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Although no studies have been conducted, vincristine exposure is likely to be increased.
    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: (Major) Zafirlukast inhibits CYP3A4, and vincristine is a CYP3A substrate. Coadministration could increase exposure to vincristine; monitor patients for increased side effects if these drugs are given together.
    Zalcitabine, ddC: (Major) The risk of neurologic toxicity is greater if vincristine is administered to patients taking other drugs with risk of neurologic toxicity such as zalcitabine, DDC. Cautious concomitant use with careful monitoring is advised.

    PREGNANCY AND LACTATION

    Pregnancy

    Vincristine liposomal is classified as FDA pregnancy risk category D. Vincristine can cause fetal harm and/or death and should not be administered during pregnancy. In animal studies, vincristine is embryotoxic and teratogenic. Women receiving vincristine should be advised to avoid becoming pregnant. If a women becomes pregnant while receiving this drug, she should be counseled of the potential harm to the fetus and the possibility of loss of pregnancy.

    According to the manufacturer, vincristine liposomal or breast-feeding should be discontinued because of the potential for serious adverse reactions in nursing infants from vincristine liposomal. It is not known if vincristine liposomal is excreted into human milk. Consider the benefits of breast-feeding, the risk of infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Vincristine sulfate liposome (Marqibo) is a sphingomyelin/cholesterol liposome-encapsulated formulation of vincristine sulfate, a vinca alkaloid agent. Vincristine sulfate was developed from the periwinkle plant in 1959. It is a cell cycle specific agent that exerts its cytotoxic effects on the cell by binding to tubulin, interfering with the structure and function of microtubules. By stabilizing spindle fibers, chromosome segregation is prevented which causes metaphase arrest and mitosis inhibition. The sphingomyelin/cholesterol liposome-encapsulated formulation of vincristine sulfate is less susceptible to acid hydrolysis. Additionally, this encapsulated formulation may better penetrate the tumor vasculature and allow the drug to be released slowly, exposing it to the tumor over a longer time period.

    PHARMACOKINETICS

    Vincristine liposomal is administered by intravenous infusion.
    Vincristine sulfate, the active agent in vincristine liposomal, is a substrate for cytochrome P450 3A isozymes (CYP3A) and for P-glycoprotein (P-gp). As compared with the rapid clearance of non-liposomal vincristine sulfate (11,340 ml/h), the plasma clearance of vincristine liposomal is slow (mean of 345 ml/h after an IV dose of 2.25 mg/m2). In contrast to non-liposomal vincristine sulfate, liposome-encapsulated drug may not be immediately bioavailable. Thus, the calculated pharmacokinetic parameters for total plasma vincristine sulfate after vincristine liposomal receipt may not be directly comparable to plasma levels of vincristine sulfate after administration of non-liposomal vincristine sulfate.
    Urinary excretion is a minor route of elimination for vincristine sulfate and its metabolite. After IV administration of vincristine liposomal, < 8% of the administered dose was eliminated in the urine over 96 hours, which is similar to the urinary excretion of non-liposomal vincristine sulfate. After non-liposomal vincristine sulfate infusion, the main route of vincristine sulfate excretion was the fecal route, which accounted for 69% of the administered dose over 72 hours.
     
    Affected cytochrome P450 (CYP) isoenzymes and drug transporters: CYP3A, P-glycoprotein (P-gp)
    Formal drug interaction studies have not been conducted with vincristine liposome; however, it is expected to have the same interaction profile as non-liposomal vincristine. Vincristine is a substrate of CYP3A and P-gp.

    Intravenous Route

    After IV administration of 2.25 mg/m2 of vincristine liposomal over an hour to patients with acute lymphocytic leukemia, the mean maximum serum concentration of vincristine sulfate was 1220 ng/ml. As compared with the systemic exposure after administration of non-liposomal vincristine sulfate, the systemic exposure of vincristine after vincristine liposomal administration is much higher. The slow clearance of vincristine liposomal contributes to a much higher systemic exposure relative to non-liposomal vincristine sulfate.