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VINCRISTINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) VinCRIStine is the salt of an alkaloid isolated from Vinca rosea Linn (periwinkle plant). VinCRIStine is structurally similar to vinBLAStine, which is another alkaloid from the same plant. VinCRIStine has a broad spectrum of antitumor activity. Vinca alkaloids are cell-cycle specific agents, arresting cell division at the metaphase stage.

Specific Substances

    1) 22-Oxovincaleukoblastine
    2) Leurocristine
    3) LCR
    4) NCI-C04864
    5) NSC 67574
    6) Vincaleukoblastine, 22-oxo-
    7) Vincrystine
    8) Vinkristin
    9) Molecular Formula: C46-H56-N4-O10 (vincristine)
    10) Molecular Formula: C46-H56-N4-O10.H2-SO4 (vincristine sulfate)
    11) CAS 57-22-7 (vincristine)
    12) CAS 2068-78-2 (vincristine sulfate)
    13) NIOSH/RTECS OH 6340000
    14) VCR (Vincristine)
    15) Vincristine sulfate
    1.2.1) MOLECULAR FORMULA
    1) VinCRIStine: C46H56N4O10
    2) VinCRIStine Sulfate: C46H56N4O10.H2SO4

Available Forms Sources

    A) FORMS
    1) VinCRIStine sulfate is available as a preservative-free single use only product for intravenous use in 1 mg (1 mg/1 mL) and 2 mg (2 mg/2 mL) vials. Each mL contains vinCRIStine sulfate 1 mg; mannitol 100 mg; and water for injection (Prod Info vincristine sulfate IV Injection, 2007; Prod Info vincristine sulfate injection, 2004).
    B) SOURCES
    1) VinCRIStine sulfate is the salt of an alkaloid derived from the periwinkle plant (Vinca rosea Linn. family Apocynaceae) (Nelson et al, 2007).
    2) Periwinkle is a potted plant, 40 to 80 cm high, and woody at the base (Wu et al, 2004).
    3) Leaves: Opposite, 4 to 7 cm long, oblong to lance-shaped, glossy, with smooth edges, deciduous (Wu et al, 2004).
    4) Flowers: Colored rose-pink or violet, but may be white, yellow, or white with a red eye (Wu et al, 2004).
    5) Fruits: A divergent follicle filled with 15 to 30 seeds (Wu et al, 2004).
    6) The plant is probably indigenous to Madagascar, but is now widely distributed throughout warm regions(Wu et al, 2004).
    C) USES
    1) VinCRIStine is indicated for the treatment of acute leukemia in adults and children. It has also been used in combination with other antineoplastic agents for the treatment of Hodgkin's and non-Hodgkin's malignant lymphomas, rhabdomyosarcoma, neuroblastoma, and Wilms' tumor (Prod Info vincristine sulfate IV Injection, 2007; Prod Info vincristine sulfate injection, 2004).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: VinCRIStine, a vinca alkaloid derived from the periwinkle plant, is used in the treatment of acute leukemia, and may be used in combination with other chemotherapeutic agents in the treatment of Hodgkin's disease, non-Hodgkin's malignant lymphomas, rhabdomyosarcoma, neuroblastoma, and Wilms' tumor. In addition, vinCRIStine has been used to treat a variety of other malignancies (ie, small cell lung cancer, bladder cancer, gynecologic cancer) and nonmalignant conditions (ie, thrombocytopenia purpura).
    B) PHARMACOLOGY: The mechanism of vinCRIStine is not completely understood. VinCRIStine appears to bind to the microtubules and induces mitotic arrest of dividing cells in the metaphase stage. In therapeutic use, vinCRIStine does not appear to easily cross the blood brain barrier.
    C) TOXICOLOGY: VinCRIStine inhibits mitotic cellular function, causing cell death. Overdose effects are primarily neurologic, gastrointestinal, and hematologic (ie, bone marrow suppression). Following intrathecal administration, toxicity is related to acute necrotizing myeloencephalopathy.
    D) EPIDEMIOLOGY: Intravenous overdose is rare, but can be fatal. Inadvertent intrathecal administration is rare, but causes severe neurotoxicity and is most often fatal.
    E) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: Neurotoxicity is the primary dose-limiting toxicity of therapeutic or supratherapeutic therapy. Peripheral neuropathies (ie, paresthesia, sensory loss, and loss of deep tendon reflexes) are likely to occur and usually resolve with the discontinuation of therapy. An early sign of peripheral neuropathy is the loss of the Achilles tendon reflexes. Other effects may include: autonomic dysfunction (ie, gastrointestinal symptoms including abdominal pain, nausea, vomiting, constipation, abdominal distension, and paralytic ileus), hypertension, hypotension, muscle wasting, fever, bone marrow suppression, pain and SIADH following long-term vinCRIStine therapy. Ocular findings include ptosis and ophthalmoplegia. EXTRAVASATION: VinCRIStine is a vesicant. Extravasation can lead to severe tissue injury that may require surgical intervention.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Early signs and symptoms may include: fever, abdominal pain, nausea, and vomiting. Toxic effects can progress over a few hours to a week and include: peripheral neuropathies, bone marrow toxicity, bleeding, cerebral dysfunction, constipation, abdominal distension, paralytic ileus, oral mucositis, hypertension (may be followed by hypotension), myalgias, and bone and jaw pain. Other effects reported less frequently include: urinary retention, hyponatremia, hypokalemia, syndrome of inappropriate antidiuretic hormone (SIADH), bladder atony, and diarrhea.
    2) SEVERE TOXICITY: The severity of toxic effects are usually dose-related. In some cases, deaths have occurred within a few days of exposure. Following a large overdose, significant neurotoxicity including: peripheral neuropathy (sensory loss, paresthesia, loss of deep tendon reflexes) and cerebral dysfunction (ie, agitation, insomnia, seizures, delirium, hallucinations, depression), that can progress to coma and death should be anticipated. Myelosuppression can also develop after a severe overdose. INTRATHECAL: Inadvertent intrathecal administration produces ascending paralysis and severe neurotoxicity that can progress to respiratory failure and coma. It is usually fatal. Immediate treatment is necessary.
    0.2.3) VITAL SIGNS
    A) Fever may occur following therapeutic use or overdose.
    0.2.5) CARDIOVASCULAR
    A) WITH THERAPEUTIC USE
    1) Both hypertension and hypotension have occurred with vinCRIStine therapy. Cardiac toxicity has been reported.
    B) WITH POISONING/EXPOSURE
    1) Hypertension has been reported.
    0.2.7) NEUROLOGIC
    A) WITH THERAPEUTIC USE
    1) Neurotoxicity is the dose-limiting toxicity associated with vinCRIStine therapy. Sensory impairment and paresthesia are the early events observed. Neuritic pain and motor difficulties may occur as therapy is continued. Loss of deep tendon reflexes, foot drop, ataxia, and paralysis can develop with ongoing administration.
    B) WITH POISONING/EXPOSURE
    1) Peripheral neuropathies, progressive weakness, loss of deep tendon reflexes, headache, confusion, hallucinations, delirium, insomnia, generalized facial, jaw or neck pain, coma, seizures, optic neuropathy, and death have been reported.
    2) Inadvertent intrathecal administration has produced ascending paralysis, neurotoxicity, coma, and is often fatal.
    0.2.12) FLUID-ELECTROLYTE
    A) Hyponatremia, hypokalemia, and SIADH have been reported rarely with therapeutic use or overdose of vinCRIStine.
    0.2.13) HEMATOLOGIC
    A) Severe bone marrow depression usually is not a dose-limiting event of vinCRIStine therapy. However, myelosuppression can develop in overdose.
    0.2.16) ENDOCRINE
    A) Syndrome of inappropriate antidiuretic hormone (SIADH) has been reported in association with overdose of vinCRIStine. It has developed rarely following therapeutic use.
    0.2.20) REPRODUCTIVE
    A) VinCRIStine and vincristine sulfate liposome are both classified as FDA pregnancy category D. There are no adequate and well-controlled studies of vincristine and vincristine sulfate liposome use during pregnancy; however, vincristine has produced azoospermia and amenorrhea in postpubertal patients. In animal studies, increased resorptions, embryo deaths, and malformations were reported with vincristine and vincristine sulfate liposome exposure. In addition, gross malformations developed in monkeys exposed to single doses of vincristine sulfate in utero.
    0.2.21) CARCINOGENICITY
    A) VinCRIStine combined with other chemotherapeutic agents has produced second malignancies; the role of vinCRIStine has not been determined. No studies conclusively demonstrate mutagenicity with vinCRIStine, but carcinogenicity is possible based on the mechanism of action and limited genotoxic data.

Laboratory Monitoring

    A) Monitor neurologic function closely following exposure. Neurotoxicity can present as peripheral, autonomic or cranial nerve dysfunction.
    B) Monitor CBC with differential and platelet count daily until patient recovery. Based on several cases of overdose, myelotoxicity is likely to occur within a week or less of exposure (WBC nadir occurred at day 4 to 10; platelet nadir often occurred at day 4).
    C) Monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract. Evaluate patients for signs and symptoms of mucositis.
    D) Monitor electrolytes, renal function, and liver enzymes as indicated. Monitor serum and urine osmolality in patients with hyponatremia.
    E) Monitor vital signs. Obtain baseline ECG.
    F) Monitor fluid intake and output.
    G) Monitor uric acid concentration.
    H) Evaluate patients for signs and symptoms of mucositis.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) VinCRIStine is absorbed poorly from the gastrointestinal tract and it is usually administered intravenously. Treatment of vinCRIStine poisoning is symptomatic and supportive. There is no specific antidote. Please see the PARENTERAL EXPOSURE OVERVIEW section for further treatment recommendations.
    0.4.3) INHALATION EXPOSURE
    A) INHALATION: Move patient to fresh air. Monitor for respiratory distress. If cough or difficulty breathing develops, evaluate for respiratory tract irritation, bronchitis, or pneumonitis. Administer oxygen and assist ventilation as required. Treat bronchospasm with an inhaled beta2-adrenergic agonist. Consider systemic corticosteroids in patients with significant bronchospasm.
    0.4.4) EYE EXPOSURE
    A) DECONTAMINATION: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, the patient should be seen in a healthcare facility.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).
    0.4.6) PARENTERAL EXPOSURE
    A) TREATMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. There is no antidote. Early events may include abdominal pain, nausea, vomiting and fever. Neurotoxicity is the dose-limiting event with vinCRIStine. Early symptoms are likely to include peripheral neuropathy (ie, sensory impairment and paresthesia). Monitor neuro status closely. Glutamic acid may be effective in reducing neurotoxicity, the usual adult dose is 10 g IV over 24 hours followed by 500 mg IV every 8 hours. Gastrointestinal events may progress to include: abdominal distension, constipation and paralytic ileus. Enemas may be indicated. Myelosuppression may develop; treat severe neutropenia with colony stimulating factors. Platelets and red cell transfusions may also be necessary.
    B) TREATMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. NEUROTOXICITY: Central neurotoxicity (ie, seizures, ascending paralysis, respiratory compromise and coma) can develop following a significant IV overdose. Monitor airway and neuro status closely. Glutamic acid may be effective in reducing neurotoxicity, the usual adult dose is 10 g IV over 24 hours followed by 500 mg IV every 8 hours. Treat seizures with benzodiazepines, add propofol or barbiturate if seizures persist. MYELOSUPPRESSION may develop. Colony stimulating factor (filgrastim or sargramostim) should be administered if severe neutropenia develops. Patients with severe neutropenia should be in protective isolation. Platelet and red cell transfusions may be necessary. GASTROINTESTINAL: Severe abdominal distension and paralytic ileus may develop. Abdominal decompression with nasogastric suction, and administration of enemas may be needed. VOMITING: Aggressively treat with antiemetics and fluid and electrolyte replacement as indicated. OTHER: Closely monitor vital signs; hypertension followed by hypotension can develop. Treat infections with antibiotics as needed. Monitor electrolytes for evidence of syndrome of inappropriate antidiuretic hormone (SIADH); fluid restriction may be necessary. Consider plasmapheresis or exchange transfusion if they can be performed within a few hours after a potentially fatal overdose.
    C) INTRATHECAL INJECTION
    1) IMMEDIATE TREATMENT IS REQUIRED: Inadvertent intrathecal injection has been reported with vinCRIStine, and is usually fatal. Immediate, aggressive treatment is critical. Keep the patient upright if possible. Immediately drain AT LEAST 20 mL CSF; drainage of up to 70 mL has been tolerated in adults. Follow with CSF exchange (remove serial 20 mL aliquots CSF and replace with equivalent volumes of warmed, preservative free normal saline or lactated ringers). Consult a neurosurgeon immediately for placement of a ventricular catheter and begin ventriculolumbar perfusion (infuse warmed preservative free normal saline or LR through ventricular catheter, drain fluid from lumbar catheter; typical volumes are 80 to 150 mL/hr for at least 24 hours). Fresh frozen plasma (25 mL FFP/liter NS or LR) or albumin 5% should be added to the fluid used for perfusion to increase protein binding. Intravenous or oral therapy with folinic acid (leucovorin), glutamic acid, and pyridoxine have also been used in combination to minimize the neuropathy that can develop with vinCRIStine. Administer dexamethasone 4 mg intravenously every 6 hours to prevent arachnoiditis.
    D) DECONTAMINATION
    1) VinCRIStine is administered IV; GI decontamination is not indicated.
    E) AIRWAY MANAGEMENT
    1) Intubate if patient is unable to protect airway or if unstable neurotoxicity (ie, seizures, ascending paralysis) or respiratory depression develops following a severe overdose.
    F) ANTIDOTE
    1) There is no known antidote for vinCRIStine.
    G) NEUROTOXICITY
    1) Neurotoxicity is the dose-limiting event with vinCRIStine. Treatment is symptomatic and supportive. The degree of peripheral neuropathy (ie, paraesthesia, loss of deep tendon reflexes, foot drop and muscle weakness) is usually dose-related and reversible. Central neurotoxicity can develop following a significant IV exposure and will occur following an intrathecal administration (ie ascending paralysis, respiratory compromise, coma); fatalities have occurred (see INTRATHECAL INJECTION). Monitor neurologic function closely. Glutamic acid may be effective in reducing neurotoxicity. The usual adult dose is 10 g IV over 24 hours followed by 500 mg IV every 8 hours. Folinic acid and pyridoxine have also been used but their efficacy is not established. Prophylactic splinting during periods of muscle weakness may help to prevent deformities associated with contractures.
    H) SEIZURES
    1) Administer IV benzodiazepines, add propofol or barbiturates if seizures persist or recur.
    I) NAUSEA AND VOMITING
    1) Nausea and vomiting are early findings of vinCRIStine toxicity. Treat severe nausea and vomiting with agents from several different classes. Agents to consider: dopamine (D2) receptor antagonists (eg, metoclopramide), phenothiazines (eg, prochlorperazine, promethazine), 5-HT3 serotonin antagonists (eg, dolasetron, granisetron, ondansetron), benzodiazepines (eg, lorazepam), corticosteroids (eg, dexamethasone), and antipsychotics (eg, haloperidol). AVOID: Aprepitant may cause a possible drug interaction (ie, CYP3A4 inhibition).
    J) PARALYTIC ILEUS
    1) Autonomic nervous system events can produce gastrointestinal symptoms including abdominal pain, constipation and paralytic ileus. Bowel stimulants may be beneficial in preventing constipation. Enemas may be needed to prevent an ileus. Abdominal decompression via nasogastric suction may be indicated in severe cases.
    K) MUCOSITIS
    1) Mucositis has been reported with vinCRIStine overdose. Treat mild mucositis with bland oral rinses with 0.9% saline, sodium bicarbonate, and water. For moderate cases with pain, consider adding a topical anesthetic (eg, lidocaine, benzocaine, dyclonine, diphenhydramine, or doxepin). Treat moderate to severe mucositis with topical anesthetics and systemic analgesics. Patients with mucositis and moderate xerostomia may receive sialagogues (eg, sugarless candy/mints, pilocarpine/cevimeline, or bethanechol) and topical fluorides to stimulate salivary gland function. Consider prophylactic antiviral and antifungal agents to prevent infections. Topical oral antimicrobial mouthwashes, rinses, pastilles, or lozenges may be used to decrease the risk of infection. Palifermin is indicated to reduce the incidence and duration of severe oral mucositis in patients with hematologic malignancies receiving myelotoxic therapy requiring hematopoietic stem cell support. In patients with a vinCRIStine overdose, administer palifermin 60 mcg/kg/day IV bolus injection starting 24 hours after the overdose for 3 consecutive days.
    L) MYELOSUPPRESSION
    1) Severe myelosuppression is NOT the primary dose-limiting toxicity of vinCRIStine. However, leukopenia, anemia, and thrombocytopenia have occurred following therapeutic use and overdose. Most reports of myelosuppression following overdose with vinCRIStine have occurred as a result of receiving multiple chemotherapeutic agents. Administer colony stimulating factors to patients who develop severe neutropenia. Filgrastim: 5 mcg/kg/day IV or subQ. Sargramostim: 250 mcg/m(2)/day IV over 4 hours. Monitor CBC with differential for evidence of bone marrow suppression. If fever or infection develop, cultures should be obtained and appropriate antibiotics started. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia or hemorrhage. Patients with severe neutropenia should be in protective isolation.
    M) SIADH
    1) Supportive measures and fluid restriction are usually adequate. Administration of 3% NaCl solution (hypertonic saline) may be considered in severe cases. Monitor fluid and electrolytes (serum sodium) closely.
    N) EXTRAVASATION INJURY
    1) VinCRIStine, a vesicant, can produce pain and necrosis following extravasation. If extravasation occurs, stop the infusion. Disconnect the IV tubing, but leave the cannula or needle in place. Attempt to aspirate the extravasated drug from the needle or cannula. If possible, withdraw 3 to 5 mL of blood and/or fluids through the needle/cannula. Administer hyaluronidase (see below for dosing). Elevate the affected area. Apply warm packs for 15 to 20 minutes at least 4 times daily for 1 to 2 days. Administer analgesia for severe pain. If pain persists, there is concern for compartment syndrome, or injury is apparent, an early surgical consult should be considered. Close observation of the extravasated area is suggested. If tissue sloughing, necrosis or blistering occurs, treat as a chemical burn (ie, antiseptic dressings, silver sulfadiazine, antibiotics when applicable). Surgical or enzymatic debridement may be required. Risk of infection is increased in chemotherapy patients with reduced neutrophil count following extravasation. Consider culturing any open wounds. Monitor the site for the development of cellulitis, which may require antibiotic therapy. HYALURONIDASE: DOSE: Inject 1 to 6 mL of 150 Units/mL through the existing IV line; if IV device was removed, inject by subQ route in a clockwise manner. Usual dose: 1 mL of solution for 1 mL of extravasated drug. Another source recommended the following dose: 150 Units (1 mL) given as five 0.2 mL injections into the extravasation site at the leading edge; use solution 150 Units/1 mL vial and do not dilute further. Use a 25-gauge needle or smaller to inject subQ or intradermally into the extravasation site.
    O) ENHANCED ELIMINATION
    1) Consider plasmapheresis or exchange transfusion if they can be performed within a few hours after a potentially fatal overdose. Hemodialysis is unlikely to be beneficial following overdose. Plasmapheresis of 1.5 times the plasma volume reduced vinCRIStine concentration by 23% in an adult with vinCRIStine overdose. In two children with vinCRIStine overdose, double volume exchange transfusion decreased vinCRIStine concentration by more than 50%, in a third child virtually no vinCRIStine was removed. Treatment was started within 6 hours of exposure.
    P) PATIENT DISPOSITION
    1) HOME CRITERIA: There is no data to support home management. Patients with a vinCRIStine overdose need to be admitted.
    2) OBSERVATION CRITERIA: Patients should be closely monitored in an inpatient setting, with frequent monitoring of vital signs and neurologic function (hourly for the first 24 hours), CBC with differential until bone marrow suppression is resolved, along with monitoring of gastrointestinal function, serum electrolytes, and hepatic enzymes.
    3) ADMISSION CRITERIA: Patients should be closely monitored in a health care facility for a minimum of 72 hours after overdose. If neurologic effects are pronounced the patient should remain in a health care facility longer, based on clinical judgement, due to delayed onset of coma and seizures following large overdoses. Patients with myelosuppression should remain hospitalized until counts are recovering.
    4) CONSULT CRITERIA: IMMEDIATELY consult a neurosurgeon if intrathecal exposure has occurred or is suspected. Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with a vinCRIStine overdose.
    5) TRANSFER CRITERIA: Patients with an intrathecal exposure or profound neurotoxicity should be transferred to an intensive care setting.
    Q) PHARMACOKINETICS
    1) Over 90% of vinCRIStine is distributed from the blood into the tissue. It is tightly bound to protein, but binding is not irreversible. It exhibits a large and variable volume of distribution, and is metabolized and excreted by the liver. Approximately, 80% of an intravenous dose is excreted in the feces and 10% to 20% is excreted in the urine. Toxicity risk can be increased in hepatic dysfunction. The cytochrome P450 3A4 (CYP3A4) enzyme is responsible for the metabolism of vinCRIStine. Potent inhibitors of CYP3A4 such as itraconazole and posaconazole have been associated with a risk of increased toxicity. Cerebral spinal fluid concentrations following an intravenous dose have been minimal (20 to 30 times lower than the serum concentration).
    R) TOXICOKINETICS
    1) INTRATHECAL INJECTION produces ascending radioculomyeloencephalopathy. VinCRIStine binds to the tubulin and forms neurofilament aggregates that destroy the neuronal cytoskeleton of the neurons.
    S) PITFALLS
    1) Symptoms may be delayed (particularly myelosuppression), so ongoing monitoring may be indicated. A patient receiving vinCRIStine may have significant co-morbidities and be receiving other chemotherapeutic agents that can also produce significant toxicity. Failure to recognize that an inadvertent exposure has occurred. In the event of an intrathecal exposure, failure to start treatment immediately, need for specialized care and consultation, and stopping treatment too soon.
    T) DIFFERENTIAL DIAGNOSIS
    1) Differential diagnosis includes toxicities from other concomitant chemotherapeutic agents.

Range Of Toxicity

    A) TOXICITY: A minimum lethal or maximum tolerated dose is not well established. Severe symptoms should be anticipated in patients after single intravenous doses of 3 mg/m(2) or more in adults and 3 to 4 mg/m(2) in patients under 13 years of age. Fatalities have been reported in children after an IV vinCRIStine overdose of: 13.5 mg in a 7-year-old (intended dose 1.35 mg), 7.5 mg (7.5 mg/m(2)) in a 5-year-old, and 32 mg in a 13-year-old.
    B) INTRAVENOUS INFUSION: Mild to moderate toxicity (ie, neurologic {paraesthesia, diminished reflexes} and hematologic {decrease WBC and platelets} developed following a continuous intravenous infusion of 0.5 and 0.75 mg/m(2) daily for 5 days; severe toxicity (ie, myelosuppression {leukopenia}, autonomic neuropathy {ileus, urinary retention}, hyponatremia, marked muscle weakness) occurred in patients receiving 1 mg/m(2) daily for 5 days.
    C) ADULT: An adult survived a vinCRIStine dose of 25 mg IV; paresthesia remained 6 months after exposure. Another adult recovered completely after receiving cumulative doses of cyclophosphamide 6000 mg, doxorubicin 420 mg, and vinCRIStine 12 mg over 5 consecutive days. PEDIATRIC: One child survived an overdose of 8.75 mg as a single dose and another survived a dose of 9 mg/m(2) over 6 days with supportive care.
    D) INTRATHECAL EXPOSURE: VinCRIStine is usually FATAL if given intrathecally. Fatal intrathecal doses have ranged from 0.3 to 3 mg vinCRIStine. Of the patients who survived, all sustained some degree of permanent neurologic injury.
    E) THERAPEUTIC DOSE: GENERAL: Varies with disease state. Dose limit is dependent on the patient and protocol being used. Maximum dose should not exceed 2 mg/wk IV due to vinCRIStine-related neurotoxicities. ADULT: USUAL DOSE: 1.4 mg/m(2)/wk IV. PEDIATRIC: USUAL DOSE: 1.5 to 2 mg/m(2)/wk IV. For patients weighing 10 kg or less: 0.05 mg/kg/wk IV. HIGH DOSE THERAPY: In one study, a total dose of 3.5 mg/m(2) administered over 4 days was well tolerated in select patients prior to autologous marrow rescue.

Clinical Effects

Summary Of Exposure

    A) USES: VinCRIStine, a vinca alkaloid derived from the periwinkle plant, is used in the treatment of acute leukemia, and may be used in combination with other chemotherapeutic agents in the treatment of Hodgkin's disease, non-Hodgkin's malignant lymphomas, rhabdomyosarcoma, neuroblastoma, and Wilms' tumor. In addition, vinCRIStine has been used to treat a variety of other malignancies (ie, small cell lung cancer, bladder cancer, gynecologic cancer) and nonmalignant conditions (ie, thrombocytopenia purpura).
    B) PHARMACOLOGY: The mechanism of vinCRIStine is not completely understood. VinCRIStine appears to bind to the microtubules and induces mitotic arrest of dividing cells in the metaphase stage. In therapeutic use, vinCRIStine does not appear to easily cross the blood brain barrier.
    C) TOXICOLOGY: VinCRIStine inhibits mitotic cellular function, causing cell death. Overdose effects are primarily neurologic, gastrointestinal, and hematologic (ie, bone marrow suppression). Following intrathecal administration, toxicity is related to acute necrotizing myeloencephalopathy.
    D) EPIDEMIOLOGY: Intravenous overdose is rare, but can be fatal. Inadvertent intrathecal administration is rare, but causes severe neurotoxicity and is most often fatal.
    E) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: Neurotoxicity is the primary dose-limiting toxicity of therapeutic or supratherapeutic therapy. Peripheral neuropathies (ie, paresthesia, sensory loss, and loss of deep tendon reflexes) are likely to occur and usually resolve with the discontinuation of therapy. An early sign of peripheral neuropathy is the loss of the Achilles tendon reflexes. Other effects may include: autonomic dysfunction (ie, gastrointestinal symptoms including abdominal pain, nausea, vomiting, constipation, abdominal distension, and paralytic ileus), hypertension, hypotension, muscle wasting, fever, bone marrow suppression, pain and SIADH following long-term vinCRIStine therapy. Ocular findings include ptosis and ophthalmoplegia. EXTRAVASATION: VinCRIStine is a vesicant. Extravasation can lead to severe tissue injury that may require surgical intervention.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Early signs and symptoms may include: fever, abdominal pain, nausea, and vomiting. Toxic effects can progress over a few hours to a week and include: peripheral neuropathies, bone marrow toxicity, bleeding, cerebral dysfunction, constipation, abdominal distension, paralytic ileus, oral mucositis, hypertension (may be followed by hypotension), myalgias, and bone and jaw pain. Other effects reported less frequently include: urinary retention, hyponatremia, hypokalemia, syndrome of inappropriate antidiuretic hormone (SIADH), bladder atony, and diarrhea.
    2) SEVERE TOXICITY: The severity of toxic effects are usually dose-related. In some cases, deaths have occurred within a few days of exposure. Following a large overdose, significant neurotoxicity including: peripheral neuropathy (sensory loss, paresthesia, loss of deep tendon reflexes) and cerebral dysfunction (ie, agitation, insomnia, seizures, delirium, hallucinations, depression), that can progress to coma and death should be anticipated. Myelosuppression can also develop after a severe overdose. INTRATHECAL: Inadvertent intrathecal administration produces ascending paralysis and severe neurotoxicity that can progress to respiratory failure and coma. It is usually fatal. Immediate treatment is necessary.

Vital Signs

    3.3.1) SUMMARY
    A) Fever may occur following therapeutic use or overdose.
    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) Fever has been reported with therapeutic use of vinCRIStine (Prod Info vincristine sulfate injection, 2004).
    B) WITH POISONING/EXPOSURE
    1) Fever may develop within 24 hours of overdose (Chae et al, 1998; Kaufman et al, 1976a).
    2) CASE REPORT: Shaking chills and an oral temperature of 102.2 degrees F occurred in a 55-year-old man after receiving 10 mg of vinCRIStine (Berenson, 1971).

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) CASE SERIES: In a series of 50 patients, ptosis and diplopia were reported in 32% of patients (Sandler et al, 1969). Ocular muscle complications have occurred. Night blindness occurred in one patient following treatment with vinCRIStine.
    2) BLINDNESS
    a) Permanent loss of vision following a single dose of vinCRIStine has been reported (Teichmann & Dabbagh, 1988). Transient cortical blindness has occurred in 3 children (Grant, 1986).
    b) CASE REPORT: A 77-year-old man with stage III diffuse large B-cell lymphoma was started on rituximab (375 mg/m(2) day 1), cyclophosphamide (750 mg/m(2) day 1), doxorubicin (50 mg/m(2) day 1) and vinCRIStine 1.4 mg/m(2) and oral prednisone. He had a positive history of chronic diplopia and previous cataract surgery. Following his first cycle of chemotherapy, the patient developed transient ametropia of the left eye. An ophthalmology and neurologic examinations were normal. Other diagnostic studies were within normal limits. However, the patient developed bilateral blindness prior to the fourth cycle of chemotherapy. The patient had a second visual examination showing ischemic optic neuropathy. Although vinCRIStine was discontinued, the patient's vision did not return (Adhikari et al, 2014).
    3) OPTIC ATROPHY
    a) Bilateral optic atrophy developed in a 15-year-old girl following posterior craniectomy, whole neuraxis radiation therapy, and weekly vinCRIStine. Following discontinuation of vinCRIStine therapy, recovery of visual function occurred (Shurin et al, 1982).
    3.4.6) THROAT
    A) WITH THERAPEUTIC USE
    1) HOARSENESS has been reported and may be associated with the neurotoxic effects of vinCRIStine on the recurrent laryngeal nerve (Legha, 1986).

Cardiovascular

    3.5.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Both hypertension and hypotension have occurred with vinCRIStine therapy. Cardiac toxicity has been reported.
    B) WITH POISONING/EXPOSURE
    1) Hypertension has been reported.
    3.5.2) CLINICAL EFFECTS
    A) HYPERTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Both hypertension and hypotension have occurred with vinCRIStine therapy (Prod Info vincristine sulfate IV Injection, 2007; Prod Info vincristine sulfate injection, 2004).
    2) WITH POISONING/EXPOSURE
    a) Hypertension has been observed in adults and children following overdose (Chae et al, 1998; Kaufman et al, 1976a)
    b) CASE REPORT: Hypertension has been reported in a pediatric patient after receiving an overdose of vinCRIStine (9 mg/m(2) over 6 days). The patient recovered with supportive care (Stones, 1998).
    c) CASE REPORT: Hypertension was observed in an adult after receiving 14 mg of vinCRIStine (Chae et al, 1998).
    B) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Both hypertension and hypotension have occurred with vinCRIStine therapy (Prod Info vincristine sulfate injection, 2004).
    2) WITH POISONING/EXPOSURE
    a) In overdose, hypertension followed by hypotension has been observed in some cases (Kaufman et al, 1976a).
    C) CARDIOVASCULAR FINDING
    1) WITH THERAPEUTIC USE
    a) Cardiac toxicity (coronary artery disease and myocardial infarction) has been reported with vinCRIStine therapy when combined with other chemotherapeutic agents in patients previously treated with mediastinal radiation (Prod Info vincristine sulfate injection, 2004).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) RESPIRATORY INSUFFICIENCY
    1) WITH POISONING/EXPOSURE
    a) Respiratory failure has been observed following intrathecal vinCRIStine injection due to progression of ascending myeloencephalopathy (Kwack et al, 1999; Fernandez et al, 1998; Lau, 1996; Bleck & Jacobsen, 1991).
    B) HICCOUGHS
    1) WITH POISONING/EXPOSURE
    a) Hiccoughs may occur following inadvertent intrathecal administration due to the progression of ascending myeloencephalopathy (Alcaraz et al, 2002).

Neurologic

    3.7.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Neurotoxicity is the dose-limiting toxicity associated with vinCRIStine therapy. Sensory impairment and paresthesia are the early events observed. Neuritic pain and motor difficulties may occur as therapy is continued. Loss of deep tendon reflexes, foot drop, ataxia, and paralysis can develop with ongoing administration.
    B) WITH POISONING/EXPOSURE
    1) Peripheral neuropathies, progressive weakness, loss of deep tendon reflexes, headache, confusion, hallucinations, delirium, insomnia, generalized facial, jaw or neck pain, coma, seizures, optic neuropathy, and death have been reported.
    2) Inadvertent intrathecal administration has produced ascending paralysis, neurotoxicity, coma, and is often fatal.
    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH THERAPEUTIC USE
    a) Neurotoxicity is the dose-limiting toxicity associated with vinCRIStine therapy. Sensory impairment and paresthesia are the early events observed. Neuritic pain and motor difficulties may occur as therapy is continued. Loss of deep tendon reflexes, foot drop, ataxia, and paralysis can develop with ongoing administration (Prod Info vincristine sulfate injection, 2004). The effects appear to be cumulative. Therapy with vinCRIStine usually cannot exceed 30 to 50 mg total dose over the entire treatment period.
    2) WITH POISONING/EXPOSURE
    a) SUMMARY
    1) More severe central nervous system toxic effects including delirium progressing to unconsciousness, seizures, and death have been reported in patients who received accidental overdoses of vinCRIStine (Legha, 1986; Kaufman et al, 1976a). Sensory involvement (initially, peripheral neuropathy) is likely following IV overdose to vinCRIStine (Chae et al, 1998; Jackson et al, 1981; Kaufman et al, 1976a).
    2) Neurotoxicity is usually reversible with discontinuation of vinCRIStine, but recovery is usually slow (Legha, 1986; Kaufman et al, 1976a). There are no specific agents that can reverse the neuromuscular events that occur with vinCRIStine (Prod Info vincristine sulfate injection, 2004).
    b) INTRATHECAL ROUTE
    1) SUMMARY: There have been numerous reports in the literature of inadvertent intrathecal administration of vinCRIStine resulting in ascending paralysis, neurotoxicity, coma, and death (Qweider et al, 2007; Alcaraz et al, 2002; Kwack et al, 1999; Legha, 1986; Williams et al, 1983a; Manelis et al, 1982; Shepherd et al, 1978).
    2) INCIDENCE: In the United Kingdom, it is estimated that 3 out of 100,000 administrations of vinCRIStine resulted in inadvertent intrathecal administration (Seger, 2010),
    3) SYMPTOMS: VinCRIStine is extremely neurotoxic. Intrathecal injection is commonly fatal. Manifestations include: headache, sensory loss, bladder and bowel paresis, loss of deep tendon reflexes, ascending sensorimotor impairment, paralysis, fever, opisthotonus, encephalopathy, coma and respiratory failure. Signs and symptoms progress over days to weeks (more rapid progression occurs in patients with more severe toxicity) (Alcaraz et al, 2002; Dettmeyer et al, 2001a; Kwack et al, 1999; Zaragoza et al, 1995; Manelis et al, 1982; Shepherd et al, 1978). A few patients have survived with immediate, aggressive therapy. Patients who have survived had permanent neurologic impairment (Walter, 2010; Zaragoza et al, 1995; Michelagnoli et al, 1997).
    4) CASE REPORTS
    a) ADULT
    1) CASE REPORT: A 32-year-old man with Burkitt lymphoma inadvertently received 1 mg vinCRIStine intrathecally. Immediately afterward 6 mL of cerebrospinal fluid was aspirated, and the patient was placed in a sitting position. External ventricular and lumbar drains were placed and the intrathecal compartment was irrigated with lactated ringers with fresh frozen plasma at 50 to 80 mL/hr for 6 days. Intrathecal irrigation was stopped on day 6 due to severe respiratory alkalosis, and resumed from day 7 to day 10. He was also treated with intravenous folic acid, glutamic acid and pyridoxine. On the second day, urinary retention and fecal incontinence developed. On the 8th day, lower extremity paraparesis developed, which then ascended and became more severe. On day 14, dysesthesia of the feet and perianal hypesthesia occurred. By day 60, the patient had incomplete sensorimotor deficit below T-9 (Qweider et al, 2007).
    2) CASE REPORT/FATALITY: A 59-year-old woman with ALL inadvertently received 2 mg of vinCRIStine intraventricularly into her Ommaya reservoir, instead of cytarabine. Ten minutes later 50 mL of CSF was aspirated, and another 75 mL CSF was aspirated 30 min later. Lactated ringers solution with 25 mL fresh frozen plasma/L was infused at 150 mL/hr into the Ommaya reservoir with CSF removal via a lumbar drain for 24 hr. Intravenous glutamic acid was also given. Initial symptoms included nausea and vomiting, followed by tremor, chills and shivering. On day 3, the patient became disoriented followed by stupor and weakness. Coma was observed by day 11. Death occurred 40 days after the event with no improvement in neurologic function (Meggs & Hoffman, 1998).
    3) CASE REPORT/FATALITY: A 27-year-old woman received vinCRIStine 2 mg intraventricularly into an Ommaya reservoir. The following day CNS washout with diluted fresh frozen plasma was performed, but she developed ascending paralysis, respiratory failure and coma, and died 10 days after the event (Lau, 1996).
    4) CASE REPORT/FATALITY: A 23-year-old man received 2 mg of vinCRIStine intrathecally. The error was noted within 10 minutes and a repeat lumbar puncture was performed with removal of 110 mL cerebrospinal fluid (CSF); with additional large volume lumbar punctures performed on day 2 and 3. Leg weakness and loss of reflexes occurred by day 3, with progressive weakness, nystagmus, urinary retention, and hiccups by day 5. He developed respiratory failure on day 8, and was unresponsive with intermittent seizures by day 10. The patient never regained consciousness and died 348 days after the event (Bleck & Jacobsen, 1991).
    5) CASE REPORT: An adult received 2 mg vinCRIStine intrathecally and was treated immediately with cerebrospinal fluid (CSF) drainage and replacement with lactated ringers (LR). A catheter was placed in the lateral ventricle and LR was infused (25 mL fresh frozen plasma was added per liter of LR for some of the infusion) at 75 to 150 mL/hr. Intravenous glutamic acid followed by oral dosing was also given. The patient had residual leg neuropathy and died of his primary disease 3 months later. Analysis showed that 95% of the administered vinCRIStine was removed by the various therapies (Dyke, 1989).
    b) PEDIATRIC
    1) CASE REPORT/FATALITY: A 12-year-old girl received 2 mg vinCRIStine intrathecally. About 30 minutes later 35 mL of cerebrospinal fluid (CSF) was drained, 15 mL lactated ringers (LR) was instilled, and another 15 mL CSF was withdrawn. She was kept in a sitting position, and a right frontal Ommaya reservoir was implanted and a lumbar subarachnoid catheter inserted. Three hours after the event, CSF lavage was commenced. LR to which 15 mL/L of fresh frozen plasma was added and infused into the Ommaya reservoir and drained through the lumbar drain; 615 mL of fluid was infused and drained over the next 10 hours. Oral glutamic acid and pyridoxine were also given. On day 3, hyporeflexia of the legs, followed by flaccid paraparesis and distal paresthesias developed. Paralysis progressed, with bilateral paresis of cranial nerve VI, nystagmus, hiccups, urinary retention, decreased rectal tone, and intermittent drowsiness and confusion. Her neurologic condition worsened over several weeks to tetraparesis, absent reflexes and coma; death occurred 83 days after the event (Alcaraz et al, 2002).
    2) CASE REPORT: A 7-year-old girl received 0.5 mg vinCRIStine intrathecally. Immediately afterwards 75 mL of cerebrospinal fluid (CSF) was withdrawn and replaced with ringers lactate. A catheter was placed in the right lateral ventricle and a lumbar subarachnoid drain was placed. CSF lavage was commenced at 100 mL/hr. After the first liter, 15 mL of fresh frozen plasma was added to subsequent liters and the lavage rate reduced to 55 mL/hr; CSF lavage was continued for 24 hours. She also received oral glutamic acid. On day 7, urinary retention and loss of strength and sensation in the legs developed, which progressed to complete sensorimotor paraplegia. After several weeks, partial recovery occurred, but the patient was left with predominant motor paraparesis (AlFerayan et al, 1999).
    3) CASE REPORT/FATALITY: Inadvertent intrathecal vinCRIStine administration produced irreversible neuronal damage in a 3-year-old boy. He experienced leg pain and motor weakness followed by meningism (ie, fever and neck stiffness), urinary dysfunction, opisthotonus, increased heart rates, progressive sensory loss, coma, respiratory failure, and death (Kwack et al, 1999).
    4) CASE REPORT/FATALITY: A 4-year-old girl inadvertently received 1.5 mg intrathecal vinCRIStine. She was treated immediately with cerebrospinal fluid (CSF) exchange with normal saline (48 to 58 mL total) over 40 minutes, followed by CSF lavage using a ventricular and 2 lumbar drains for a total volume of 200 mL CSF, followed by ventriculolumbar perfusion at 50 mL/hr for 12 hours. She became encephalopathic and developed flaccid paralysis by 12 hours and treatment was stopped. About 24 hours after the event, she improved (able to communicate, able to move her right leg), but deteriorated again about 4 to 5 days after the event, and died of respiratory failure 13 days after vinCRIStine administration (Fernandez et al, 1998).
    5) CASE REPORT/FATALITY: A 16-year-old boy received 2 mg vinCRIStine intrathecally. Two hours later he developed severe leg pain. Over the next 36 hours somnolence, leg weakness, urinary retention, fever and meningismus developed. By 48 hours, the patient was obtunded with frequent apneic episodes, flaccid lower extremities, and a T10 sensory level. By day 7, there was no evidence of brain stem function; ventilatory support was stopped and death occurred 36 days after the injection (Williams et al, 1983a).
    6) CASE REPORT/FATALITY: A 5-year-old girl received 0.9 mg vinCRIStine intrathecally. She developed headache, vomiting and neck stiffness within 12 hours, by 24 hours had opisthotonos, urinary retention with loss of reflexes in the legs. Confusion and drowsiness occurred over the next several days, by day 4 the patient was febrile with nystagmus, and by day 6 had paraplegia. She was barely responsive by day 6 and required intubation on day 7. By day 15, the patient became unresponsive and flaccid with unequal pupils, and had a flat EEG. Death occurred 17 days after the event (Manelis et al, 1982).
    7) CASE REPORT/FATALITY: A 5-year-old girl received 1.2 mg vinCRIStine intrathecally. Within 30 minutes, 20 mL cerebrospinal fluid (CSF) was removed, with another 20 mL removed the following day. Within 48 hours she had generalized weakness and absent deep tendon reflexes in the legs. She progressively developed nystagmus, paraplegia, coma, hiccups, intermittent apnea, and fixed pupils over the next 6 days, and died 12 days after the event (Shepherd et al, 1978).
    B) PARESTHESIA
    1) WITH THERAPEUTIC USE
    a) EARLY FINDING: Neurotoxicity is the dose-limiting toxicity associated with vinCRIStine therapy. Sensory impairment and paresthesia are the early events observed with ongoing therapy (Prod Info vincristine sulfate injection, 2004).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 55-year-old man developed paresthesias, numbness, and weakness of the lower extremities 12 days after receiving 10 mg of vinCRIStine. The maximum neurologic deficit occurred 30 days after the overdose (Berenson, 1971).
    C) NEUROPATHY
    1) WITH THERAPEUTIC USE
    a) Neuromuscular impairment with ongoing vinCRIStine therapy can include loss of deep tendon reflexes, foot drop, ataxia, and paralysis (Tazi et al, 2013; Prod Info vincristine sulfate injection, 2004).
    b) CASE REPORT: A 55-year-old man with large B-cell lymphoma began treatments with vinCRIStine (2 mg day 1), cyclophosphamide (400 mg/m(2), day 1) and prednisolone (100 mg, days 1-5) and by day 8 of therapy he developed severe progressive weakness of the lower extremities (ie, total areflexia); upper extremities were normal. Physical examinations showed no evidence of cranial nerve involvement and a MRI of the brain and spine were normal. Serology testing showed no signs of infection. Nerve conduction studies showed signs of axonal motor sensory neuropathy. Symptoms appeared to mimic Guillan-Barre syndrome. Immunoglobulin was started (0.4 g/kg/day for 5 days) along with intensive supportive care. However, the patient continued to deteriorate and developed ascending paralysis and died of respiratory failure (Tazi et al, 2013).
    2) WITH POISONING/EXPOSURE
    a) INTRATHECAL
    1) VinCRIStine is extremely neurotoxic. Symptoms can include: sensory loss, bladder and bowel paresis, loss of deep tendon reflexes, ascending sensorimotor impairment, and paralysis. Signs and symptoms progress over days to weeks (more rapid progression occurs in patients with more severe toxicity) (Alcaraz et al, 2002; Zaragoza et al, 1995; Manelis et al, 1982; Shepherd et al, 1978; Dettmeyer et al, 2001a; Kwack et al, 1999).
    b) INTRAVENOUS
    1) SUMMARY: Peripheral neuropathy is likely following IV overdose of vinCRIStine (Kaufman et al, 1976a).
    2) CASE REPORT: Diffusely depressed deep tendon reflexes were reported in a 35-year-old woman who was inadvertently administered 10 mg of vinCRIStine (Yoffe et al, 1986).
    3) CASE REPORT: Central and peripheral neuropathy with muscle atrophy was reported in an adult following an overdose of 24 mg of vinCRIStine (Maeda et al, 1987).
    c) INTRAMUSCULAR
    1) CASE REPORT/INTRAMUSCULAR EXPOSURE: A 6-year-old girl with history of a Wilm's tumor inadvertently received 4 doses of vinCRIStine by the IM route on 4 consecutive days (instead of 1 mg/day once weekly IV) as an outpatient and was admitted 3 weeks later with complains of back pain, constipation and mild lower extremity paresthesia. Following symptomatic care her symptoms resolved with 5 days. Her chemotherapy was restarted approximately 4 weeks later (Patiroglu et al, 2012).
    D) DELIRIUM
    1) WITH POISONING/EXPOSURE
    a) Agitation, hallucinations, and delirium can occur following overdose (Casteels-Van Daele et al, 1977).
    E) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache has been reported with therapeutic use of vinCRIStine (Prod Info vincristine sulfate injection, 2004).
    2) WITH POISONING/EXPOSURE
    a) Headache has been observed following intrathecal and intravenous overdose of vinCRIStine (Alcaraz et al, 2002; Zaragoza et al, 1995; Manelis et al, 1982; Shepherd et al, 1978; Dettmeyer et al, 2001a; Kwack et al, 1999; Yoffe et al, 1986).
    F) SEIZURE
    1) WITH THERAPEUTIC USE
    a) Seizures have occurred infrequently in patients treated with vinCRIStine. The development of seizures followed by coma has occurred in some pediatric patients (Prod Info vincristine sulfate injection, 2004).
    b) CASE SERIES: Four children, ranging in age from 3 to 12 years, developed seizures 5 to 6 days after receiving IV vinCRIStine therapy (Johnson et al, 1973).
    2) WITH POISONING/EXPOSURE
    a) SUMMARY: Seizures have developed in pediatric patients following inadvertent intravenous overdose of vinCRIStine (Kaufman et al, 1976a). They may be due to vinCRIStine neurotoxicity or secondary to hyponatremia from SIADH.
    b) CASE REPORT: A 4.5-year-old child was mistakenly administered 8.75 mg vinCRIStine and experienced grand mal seizures 9 days after overdose. Twenty-two months later, the patient continued to suffer from petit mal seizures several times a day, aggressive and hyperkinetic behavior, and uncontrolled movements (Casteels-Van Daele et al, 1977).
    c) CASE REPORT: Generalized seizures along with hyponatremia and hypokalemia have been reported in a pediatric patient after receiving an overdose of vinCRIStine (9 mg/m(2) over 6 days). He recovered following supportive care (Stones, 1998).
    G) COMA
    1) WITH POISONING/EXPOSURE
    a) INTRATHECAL EXPOSURE: Coma has been observed following intrathecal events in both adults and children (Alcaraz et al, 2002; Meggs & Hoffman, 1998; Lau, 1996; Manelis et al, 1982; Shepherd et al, 1978).
    b) INTRAVENOUS OVERDOSE: Coma may develop following significant intravenous overdose of vinCRIStine (Casteels-Van Daele et al, 1977; Kaufman et al, 1976a).
    c) CASE REPORT: Coma developed soon after a massive overdose (32 mg) in a child. Supportive efforts were ineffective and the patient died 33 hours after exposure (Kaufman et al, 1976a).
    d) CASE REPORT: Decreasing level of consciousness with labored respirations occurred 10 days after an overdose of vinCRIStine (8.75 mg) in a 4.5-year-old child. Assisted ventilation was required for 24 hr (Casteels-Van Daele et al, 1977).
    H) CLOUDED CONSCIOUSNESS
    1) WITH POISONING/EXPOSURE
    a) Other central nervous system effects associated with vinCRIStine toxicity include: confusion, hallucinations, and insomnia (Legha, 1986; Casteels-Van Daele et al, 1977).
    I) PAIN
    1) WITH THERAPEUTIC USE
    a) Neuritic pain has been reported with single weekly doses of vinCRIStine; symptoms usually resolve within 7 days (Prod Info vincristine sulfate injection, 2004).
    2) WITH POISONING/EXPOSURE
    a) Generalized pain in the face, jaw, and neck have been reported to occur 7 to 10 days after an overdose of vinCRIStine. The pain is not responsive to analgesics or carbamazepine (Beer et al, 1983; Thomas et al, 1982a).
    J) PARALYTIC SYNDROME
    1) WITH THERAPEUTIC USE
    a) INTRATHECAL
    1) Ascending paralysis, neuromuscular weakness, and paraplegia have been reported with inadvertent intrathecal vinCRIStine administration (Alcaraz et al, 2002; AlFerayan et al, 1999)
    b) INTRAVENOUS
    1) CASE REPORT: A 61-year-old developed quadriplegia, with flaccid-type weakness in both proximal and distal muscles following a single IV dose of cyclophosphamide 1000 mg and vinCRIStine 2 mg (Mubashir & Bart, 1972).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea and vomiting may develop with therapeutic use (Prod Info vincristine sulfate injection, 2004).
    2) WITH POISONING/EXPOSURE
    a) VinCRIStine is reported to cause mild nausea and vomiting following overdose (Legha, 1986). It may be an early symptom of toxicity following overdose (Chae et al, 1998; Berenson, 1971).
    b) CASE REPORT: Nausea and vomiting occurred 4 to 5 hours after administration of 10 mg of vinCRIStine in a 55-year-old man (Berenson, 1971).
    c) CASE REPORT: Nausea and vomiting were early findings of overdose in an adult after receiving 14 mg of vinCRIStine (Chae et al, 1998).
    B) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) Constipation has been reported with single, weekly doses of vinCRIStine; symptoms usually resolve within 7 days (Prod Info vincristine sulfate injection, 2004).
    b) Upper-colon impaction, with an empty rectum, has been observed upon physical exam in some patients. High enemas and laxatives have been used to treat this condition (Prod Info vincristine sulfate injection, 2004).
    2) WITH POISONING/EXPOSURE
    a) A significant reduction in gut motility and constipation may occur in association with vinCRIStine's neurotoxic effects (Legha, 1986; Kaufman et al, 1976a).
    b) PATHOLOGY: Autonomic dysfunction, a feature of vinCRIStine-induced neurotoxicity, can produce severe abdominal pain and constipation (Kaufman et al, 1976a).
    c) CASE REPORT: Severe constipation with abdominal pain occurred 9 to 13 days after administration of 10 mg of vinCRIStine in a 55-year-old man (Berenson, 1971).
    d) CASE REPORT/INTRAMUSCULAR EXPOSURE: A 6-year-old girl with history of a Wilm's tumor inadvertently received 4 doses of vinCRIStine by the intramuscular route on 4 consecutive days (instead of 1 mg/day once weekly IV) as an outpatient and was readmitted 3 weeks later with complains of back pain, constipation and mild lower extremity paresthesia. Following symptomatic care her symptoms resolved with 5 days. Her chemotherapy was restarted approximately 4 weeks later (Patiroglu et al, 2012).
    C) DRUG-INDUCED ILEUS
    1) WITH THERAPEUTIC USE
    a) Paralytic ileus (it may mimic a "surgical abdomen") may develop in patients, particularly young children, treated with vinCRIStine. Symptoms usually resolve with discontinuation of therapy and symptomatic care (Prod Info vincristine sulfate injection, 2004).
    2) WITH POISONING/EXPOSURE
    a) Abdominal distension (early finding) and paralytic ileus have been observed following overdose of vinCRIStine (Chae et al, 1998; Maeda et al, 1987a; Kaufman et al, 1976a). Paralytic ileus appears to be dose-related (Jackson et al, 1981). Onset may be as short as 24 hours after overdose (especially in children) (Kaufman et al, 1976a) or days after overdose (Takada et al, 1989).
    b) Paralytic ileus occurred in a pediatric patient who received an overdose of vinCRIStine (9 mg/m(2) over 6 days) (Stones, 1998).
    D) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) Severe colicky abdominal pain may occur after vinCRIStine administration (Prod Info vincristine sulfate injection, 2004). Symptoms may be most profound 3 to 10 days later, and require several days to resolve.
    1) Abdominal pain does not appear to be cumulative with repeated doses, but is more common at doses larger than 2 mg (Legha, 1986).
    2) WITH POISONING/EXPOSURE
    a) Abdominal pain has been reported in overdose and may be severe (Kaufman et al, 1976a).
    b) PATHOLOGY: Autonomic dysfunction, a feature of vinCRIStine-induced neurotoxicity, can produce severe abdominal pain and constipation (Kaufman et al, 1976a).
    E) GASTROINTESTINAL TRACT FINDING
    1) WITH THERAPEUTIC USE
    a) Oral ulceration, intestinal necrosis and/or perforation have been reported with vinCRIStine therapy (Prod Info vincristine sulfate injection, 2004). Grade 3 and 4 oral mucositis has been observed in patients receiving combination therapy that included vinCRIStine.
    2) WITH POISONING/EXPOSURE
    a) Oral mucositis has been reported in some patients following vinCRIStine overdose (Chae et al, 1998; Maeda et al, 1987a)
    b) CASE REPORT: An adult developed oral mucositis 4 days after receiving 14 mg (4 mg m(2)/day for 2 days) of vinCRIStine (Chae et al, 1998).
    F) PANCREATITIS
    1) WITH THERAPEUTIC USE
    a) Acute pancreatitis was reported in a 24-year-old woman after receiving combination chemotherapy with cyclophosphamide, doxorubicin, and vinCRIStine. The authors speculated that the combination of these agents, rather than any single agent, was responsible (Puckett et al, 1982).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) VENO-OCCLUSIVE DISEASE OF THE LIVER
    1) WITH THERAPEUTIC USE
    a) CASE REPORTS: Two cases of hepatic VOD have been reported in pediatric patients with Wilms' tumor and clear cell sarcoma of the kidney who received vinCRIStine, actinomycin D, and epirubicin. Recovery occurred after 1 to 2 weeks with supportive care (Hazar & Kutluk, 1998).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) ACONTRACTILE DETRUSOR
    1) WITH THERAPEUTIC USE
    a) Atony of the bladder can develop with therapy. Symptoms include polyuria, dysuria, and urinary retention (Prod Info vincristine sulfate injection, 2004) .
    2) WITH POISONING/EXPOSURE
    a) Autonomic neuropathy may produce atony of the urinary bladder, urinary retention, postural hypotension, and on rare occasions, impotence (Kwack et al, 1999; Legha, 1986; Manelis et al, 1982; Casteels-Van Daele et al, 1977).
    B) DISORDER OF OVARY
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Ovarian dysfunction has been reported in a woman treated with vinCRIStine chemotherapy. She was later able to become pregnant and deliver a healthy baby (Shalet et al, 1985).
    C) AZOOSPERMIA
    1) WITH THERAPEUTIC USE
    a) VinCRIStine use was found to be independently correlated with azoospermia in 28 (51%) of 55 male survivors of childhood cancer who had received various combinations of surgery, radiation therapy, and cytotoxic agents. On multivariate analysis, vinCRIStine dose was determined to have an inverse relationship to sperm count, and was found to be 5 times as likely as the other cytotoxic agents to produce azoospermia (Rautonen et al, 1992).

Hematologic

    3.13.1) SUMMARY
    A) Severe bone marrow depression usually is not a dose-limiting event of vinCRIStine therapy. However, myelosuppression can develop in overdose.
    3.13.2) CLINICAL EFFECTS
    A) MYELOSUPPRESSION
    1) WITH THERAPEUTIC USE
    a) Severe bone marrow depression is usually not a dose-limiting event of vinCRIStine therapy; however, anemia, leukopenia, and thrombocytopenia have been observed (Prod Info vincristine sulfate injection, 2004).
    2) WITH POISONING/EXPOSURE
    a) Severe bone marrow depression may occur following an overdose of vinCRIStine (Prod Info vincristine sulfate injection, 2004; Maeda et al, 1987a).
    b) CASE REPORT: A 4.5-year-old child was to receive 1.75 mg vinCRIStine for acute lymphocytic leukemia, but was incorrectly administered 8.75 mg. The leukocyte count 4 days after the dose of vinCRIStine was 600/mm(3) (Casteels-Van Daele et al, 1977).
    B) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) Leukopenia has been reported with single weekly doses of vinCRIStine; symptoms usually resolve within 7 days (Prod Info vincristine sulfate injection, 2004).
    C) NEUTROPENIA
    1) WITH POISONING/EXPOSURE
    a) Neutropenia has been reported in a pediatric patient who received an overdose of vinCRIStine (9 mg/m(2) over 6 days). White cell count normalized 5 days after starting granulated colony stimulating factor (Stones, 1998).
    D) THROMBOCYTOPENIC DISORDER
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: An adult developed significant myelosuppression after inadvertently receiving 24 mg of vinCRIStine. His platelet count reached nadir (25,000) on day 4; multiple platelet transfusions were required (Maeda et al, 1987a).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ALOPECIA
    1) WITH THERAPEUTIC USE
    a) Alopecia is likely to develop with therapy (Prod Info vincristine sulfate injection, 2004).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: Total alopecia developed in a 4.5 year old given 8.75 mg vinCRIStine (Casteels-Van Daele et al, 1977).
    b) CASE REPORT: Near total alopecia occurred in a 5-year-old boy following a 10 mg dose of vinCRIStine (Berenson, 1971).
    B) EXTRAVASATION
    1) WITH THERAPEUTIC USE
    a) VinCRIStine has been classified as a vesicant (Gippsland Oncology Nurses Group, 2010; Goolsby & Lombardo, 2006).
    b) Significant irritation can develop, if extravasation occurs (Prod Info vincristine sulfate injection, 2004).
    C) ERUPTION
    1) WITH THERAPEUTIC USE
    a) Rash has developed with therapy (Prod Info vincristine sulfate injection, 2004).
    2) WITH POISONING/EXPOSURE
    a) Skin rash has been reported in a pediatric patient after receiving an overdose of vinCRIStine (9 mg/m(2) over 6 days) (Stones, 1998).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) MUSCLE PAIN
    1) WITH THERAPEUTIC USE
    a) Muscle and bone pain (including jaw pain) have occurred at therapeutic doses (Moore & Pinkerton, 2009).
    2) WITH POISONING/EXPOSURE
    a) Myalgia and bone pain can develop in adults and children following IV overdose of vinCRIStine (Chae et al, 1998; Kaufman et al, 1976a).

Endocrine

    3.16.1) SUMMARY
    A) Syndrome of inappropriate antidiuretic hormone (SIADH) has been reported in association with overdose of vinCRIStine. It has developed rarely following therapeutic use.
    3.16.2) CLINICAL EFFECTS
    A) ABNORMAL ANTI-DIURETIC HORMONE
    1) WITH THERAPEUTIC USE
    a) There have been rare reports of a syndrome attributable to inappropriate antidiuretic hormone secretion (SIADH) in patients receiving vinCRIStine. High urinary sodium excretion in the presence of hyponatremia is often present with this syndrome (Prod Info vincristine sulfate injection, 2004).
    b) It has been described in some cases after long-term therapy (Fine et al, 1966; Slater et al, 1969; Cutting, 1971).
    c) Onset of SIADH has been reported to occur as late as 10 days after the first dose (Slater et al, 1969).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: Syndrome of inappropriate antidiuretic hormone (SIADH) was reported in a 3.5-year-old and a 14-year-old who each received 10 times the recommended dose of vinCRIStine (Suskind & Brusilow, 1972; Waken & Bennett, 1975; Stones, 1998).
    b) CASE REPORT: A 14-year-old boy with acute lymphocytic leukemia developed evidence of SIADH 12 days after receiving a 15 mg (IV) overdose of vinCRIStine. He was readmitted after having a grand mal seizure with a serum sodium concentration of 118 mEq/L. The patient recovered with supportive care (Wakem & Bennett, 1975).

Reproductive

    3.20.1) SUMMARY
    A) VinCRIStine and vincristine sulfate liposome are both classified as FDA pregnancy category D. There are no adequate and well-controlled studies of vincristine and vincristine sulfate liposome use during pregnancy; however, vincristine has produced azoospermia and amenorrhea in postpubertal patients. In animal studies, increased resorptions, embryo deaths, and malformations were reported with vincristine and vincristine sulfate liposome exposure. In addition, gross malformations developed in monkeys exposed to single doses of vincristine sulfate in utero.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the teratogenic potential of these agents (Prod Info Marqibo(R) intravenous injection, 2012; Prod Info vincristine sulfate IV Injection, 2007).
    B) ANIMAL STUDIES
    1) RATS: Skeletal and visceral malformations occurred with vincristine sulfate liposome exposure during organogenesis at doses 20% to 40% of the reported human exposure at the recommended dose. Increased resorptions, post-implantation losses, and reduced fetal weights also occurred (Prod Info Marqibo(R) intravenous injection, 2012)
    2) MICE, HAMSTERS: Resorptions occurred in 23% to 85% of mice and hamsters dosed with vincristine sulfate during pregnancy; malformations were observed in surviving offspring (Prod Info vincristine sulfate IV Injection, 2007).
    3) MONKEYS: Gross malformations developed in monkeys exposed to single doses of vincristine sulfate in utero between day 27 and 34 of gestation (Prod Info vincristine sulfate IV Injection, 2007).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) VinCRIStine and vinCRIStine sulfate liposome are both classified as FDA Pregnancy Category D (Prod Info Marqibo(R) intravenous injection, 2012; Prod Info vincristine sulfate IV Injection, 2007).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) It is not known whether vinCRIStine or vinCRIStine sulfate liposome are excreted in human milk, and the potential for adverse effects in the nursing infant from exposure to these drugs is unknown. Due to the lack of human safety information, a decision should be made to discontinue nursing or to discontinue these drugs. The importance of the drugs to the mother should be taken into consideration (Prod Info Marqibo(R) intravenous injection, 2012; Prod Info vincristine sulfate IV Injection, 2007).
    3.20.5) FERTILITY
    A) LACK OF INFORMATION
    1) There are no human studies to assess the possible fertility effects of vinCRIStine therapy (Prod Info vincristine sulfate IV Injection, 2007).
    B) POSTPUBERTAL EFFECTS
    1) Based on clinical reports, gonadal dysfunction, including azoospermia and amenorrhea, occurred in post-purbertal patients treated with multi-dose chemotherapy, including non-liposomal vinCRIStine sulfate, to a degree that was age-, dose-, and agent-dependent. Symptoms were reversible many months after the conclusion of chemotherapy in some patients. Prepubertal patients were much less likely to experience azoospermia and amenorrhea with the same treatment regimen (Prod Info Marqibo(R) intravenous injection, 2012; Prod Info vincristine sulfate IV Injection, 2007).
    C) ANIMAL STUDIES
    1) RATS: Testicular degeneration and atrophy and epididymal aspermia developed in male rats administered both single and multiple doses of vinCRIStine sulfate liposome (Prod Info Marqibo(R) intravenous injection, 2012).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) VinCRIStine combined with other chemotherapeutic agents has produced second malignancies; the role of vinCRIStine has not been determined. No studies conclusively demonstrate mutagenicity with vinCRIStine, but carcinogenicity is possible based on the mechanism of action and limited genotoxic data.
    3.21.3) HUMAN STUDIES
    A) LACK OF INFORMATION
    1) No carcinogenicity studies have been conducted, but vinCRIStine sulfate liposome may be carcinogenic based on the mechanism of action and positive genotoxicity findings with vinCRIStine sulfate in nonclinical trials (Prod Info Marqibo(R) intravenous injection, 2012).
    B) CARCINOMA
    1) Patients who have received treatment with vinCRIStine in combination with other chemotherapeutic agents known to be carcinogenic have developed second malignancies. The role of vinCRIStine in the development of these malignancies has not been evaluated (Prod Info vincristine sulfate IV Injection, 2007; Prod Info vincristine sulfate injection, 2004).
    3.21.4) ANIMAL STUDIES
    A) LACK OF EFFECT
    1) RATS, MICE: In a limited study, there was no evidence of carcinogenicity following intraperitoneal administration of vinCRIStine in mice and rats (Prod Info vincristine sulfate IV Injection, 2007; Prod Info vincristine sulfate injection, 2004).

Genotoxicity

    A) There have been no conclusive studies (in vivo or in vitro) that demonstrate mutagenicity (Prod Info vincristine sulfate IV Injection, 2007; Prod Info vincristine sulfate injection, 2004); however, some in vitro and in vivo studies demonstrated non-liposomal vinCRIStine sulfate was genotoxic (Prod Info Marqibo(R) intravenous injection, 2012).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor neurologic function closely following exposure. Neurotoxicity can present as peripheral, autonomic or cranial nerve dysfunction.
    B) Monitor CBC with differential and platelet count daily until patient recovery. Based on several cases of overdose, myelotoxicity is likely to occur within a week or less of exposure (WBC nadir occurred at day 4 to 10; platelet nadir often occurred at day 4).
    C) Monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract. Evaluate patients for signs and symptoms of mucositis.
    D) Monitor electrolytes, renal function, and liver enzymes as indicated. Monitor serum and urine osmolality in patients with hyponatremia.
    E) Monitor vital signs. Obtain baseline ECG.
    F) Monitor fluid intake and output.
    G) Monitor uric acid concentration.
    H) Evaluate patients for signs and symptoms of mucositis.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Serum electrolytes, particularly serum sodium, should be monitored following overdose. Hyponatremia, hypokalemia, and syndrome of inappropriate antidiuretic hormone (SIADH) have been reported following overdose of vinCRIStine (Stones, 1998). Following overdose, the development of SIADH may be highly variable. In one child, hyponatremia did not occur until 12 days after a 15 mg vinCRIStine overdose (Wakem & Bennett, 1975).
    2) Monitor uric acid concentrations; uric acid nephropathy may develop.
    B) HEMATOLOGIC
    1) Monitor CBC and platelet count for evidence of bone marrow suppression (Prod Info vincristine sulfate injection, 2004).
    2) Anemia, leukopenia, and thrombocytopenia may develop, but it is usually NOT the major dose-limiting effect with therapeutic use (Prod Info vincristine sulfate injection, 2004).
    3) Based on several cases of overdose, myelotoxicity is likely to occur within a week or less of exposure (WBC nadir occurred at day 4 to 10; platelet nadir often occurred on day 4) (Takada et al, 1989; Maeda et al, 1987a; Beer et al, 1983; Thomas et al, 1982a; Casteels-Vann Daele et al, 1977; Kaufman et al, 1976a).
    4.1.3) URINE
    A) URINE OSMOLALITY
    1) Obtain urine osmolality in patients with SIADH to evaluate for SIADH.
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) Monitor neurologic function closely. Neurotoxicity is the major dose-limiting event with vinCRIStine therapy (Prod Info vincristine sulfate injection, 2004).
    b) Monitor ECG and vital signs.

Methods

    A) IMMUNOASSAY
    1) VinCRIStine in plasma can be measured by radioimmunoassay (Teale et al, 1977; Pinkerton et al, 1988).
    a) These levels are generally not readily available; nor are they clinically useful to guide management of overdose.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.1) ADMISSION CRITERIA/PARENTERAL
    A) Patients should be closely monitored in a health care facility for a minimum of 72 hours after overdose. If neurologic effects are pronounced the patient should remain in a health care facility longer, based on clinical judgement, due to delayed onset of coma and seizures following large overdoses. Patients with myelosuppression should remain hospitalized until counts are recovering.
    6.3.2.2) HOME CRITERIA/PARENTERAL
    A) There is no data to support home management. Patients with a vinCRIStine overdose need to be admitted.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) IMMEDIATELY consult a neurosurgeon if intrathecal exposure has occurred or is suspected. Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with a vinCRIStine overdose.
    6.3.2.4) PATIENT TRANSFER/PARENTERAL
    A) Patients with an intrathecal exposure or profound neurotoxicity should be transferred to an intensive care setting.
    6.3.2.5) OBSERVATION CRITERIA/PARENTERAL
    A) Patients should be closely monitored in an inpatient setting, with frequent monitoring of vital signs and neurologic function (hourly for the first 24 hours), CBC with differential until bone marrow suppression is resolved, along with monitoring of gastrointestinal function, serum electrolytes, and hepatic enzymes.

Monitoring

    A) Monitor neurologic function closely following exposure. Neurotoxicity can present as peripheral, autonomic or cranial nerve dysfunction.
    B) Monitor CBC with differential and platelet count daily until patient recovery. Based on several cases of overdose, myelotoxicity is likely to occur within a week or less of exposure (WBC nadir occurred at day 4 to 10; platelet nadir often occurred at day 4).
    C) Monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract. Evaluate patients for signs and symptoms of mucositis.
    D) Monitor electrolytes, renal function, and liver enzymes as indicated. Monitor serum and urine osmolality in patients with hyponatremia.
    E) Monitor vital signs. Obtain baseline ECG.
    F) Monitor fluid intake and output.
    G) Monitor uric acid concentration.
    H) Evaluate patients for signs and symptoms of mucositis.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) GI decontamination is not necessary as vinCRIStine is administered IV.
    6.5.3) TREATMENT
    A) SUPPORT
    1) VinCRIStine is absorbed poorly from the gastrointestinal tract and is usually administered intravenously. There is no specific antidote. Treatment of vinCRIStine poisoning is symptomatic and supportive. Please see the PARENTERAL EXPOSURE section for further treatment recommendations.

Inhalation Exposure

    6.7.1) DECONTAMINATION
    A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
    B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.

Eye Exposure

    6.8.1) DECONTAMINATION
    A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) INITIAL DECONTAMINATION
    1) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Enhanced Elimination

    A) SUMMARY
    1) Hemodialysis is unlikely to be beneficial following overdose (Prod Info vincristine sulfate injection, 2004). Exchange transfusion and plasmapheresis appeared to be beneficial in a limited number of vinCRIStine overdoses (Kosmidis et al, 1991; Pierga et al, 1992).
    B) EXCHANGE TRANSFUSION
    1) In one case series, three children with acute lymphoblastic leukemia inadvertently received 7.5 mg/m(2) of vinCRIStine and were treated with double-volume exchange transfusion performed 6 hours after exposure along with supportive measures (ie, IV folinic acid rescue, prophylactic phenobarbital). Exchange transfusion reduced vinCRIStine concentrations by 57.7%, 71.5% and 7.6%, respectively. The first 2 children survived and went on to complete their course of chemotherapy and became disease free. The last child died 9 days after exposure, and had the least amount of drug removed (an estimated 90% of the vinCRIStine was likely bound in the tissues), along with an increase in liver enzymes that was thought to contribute to his death (Kosmidis et al, 1991).
    C) PLASMAPHERESIS
    1) In another case, an 18-year-old man with osteosarcoma received an estimated 10-fold overdose of vinCRIStine (total 16 mg; two 8 mg injections given 12 hours apart) and plasmapheresis of 1.5 times the plasma volume was performed 6 hours after the second injection. The vinCRIStine concentration prior to therapy was 7.1 ng/mL, and decreased to 5.5 ng/mL immediately following treatment (23% reduction) . The plasma concentrations at 24 and 48 hours were 2.3 and 2.1 ng/mL, respectively. By day 4, evidence of clinical toxicity was limited to grade IV neutropenia and drowsiness with a slowed electroencephalogram, and mild peripheral neurologic toxicity. Chemotherapy was continued as scheduled, with the exception of vinca alkaloids, 5 weeks after exposure (Pierga et al, 1992).

Abstracts

Case Reports

    A) ADULT
    1) A 35-year-old woman with myeloblastic leukemia in complete remission was receiving maintenance therapy with vinCRIStine and prednisone. She was mistakenly given 10 mg vinCRIStine. Two days later she was found to be severely depressed, and crying uncontrollably with an occipital headache. The only neurologic finding that had changed from admission was diffusely decreased deep tendon reflexes. The patient's symptoms resolved over 3 weeks (Yoffe et al, 1986).
    2) An adult with esophageal cancer and bilateral lung and lymph node metastases received 24 mg of vinCRIStine and developed severe central and peripheral neuropathy with muscle atrophy, gastrointestinal symptoms, bone marrow suppression, and stomatitis. Cardiotoxicity was also suggested, but no details were provided. The majority of the symptoms subsided clinically within a month, except for residual paresthesias in the peripheral extremities (Maeda et al, 1987).
    B) PEDIATRIC
    1) A 14-year-old boy with a diagnosis of embryonal rhabdomyosarcoma was to receive chemotherapy with actinomycin-D, cyclophosphamide, and vinCRIStine. VinCRIStine 2 mg was administered intravenously at weekly intervals without complications. On the fourth week of chemotherapy, 10 mg of vinCRIStine was administered. Supportive care was administered and 15 mg folinic acid was administered every 3 hours for 24 doses beginning 48 hours after the overdose. The authors suggest that folinic acid shortened the course of side effects and produced a more rapid recovery compared to previous case reports without folinic acid treatment (Grush & Morgan, 1979).

Range Of Toxicity

Summary

    A) TOXICITY: A minimum lethal or maximum tolerated dose is not well established. Severe symptoms should be anticipated in patients after single intravenous doses of 3 mg/m(2) or more in adults and 3 to 4 mg/m(2) in patients under 13 years of age. Fatalities have been reported in children after an IV vinCRIStine overdose of: 13.5 mg in a 7-year-old (intended dose 1.35 mg), 7.5 mg (7.5 mg/m(2)) in a 5-year-old, and 32 mg in a 13-year-old.
    B) INTRAVENOUS INFUSION: Mild to moderate toxicity (ie, neurologic {paraesthesia, diminished reflexes} and hematologic {decrease WBC and platelets} developed following a continuous intravenous infusion of 0.5 and 0.75 mg/m(2) daily for 5 days; severe toxicity (ie, myelosuppression {leukopenia}, autonomic neuropathy {ileus, urinary retention}, hyponatremia, marked muscle weakness) occurred in patients receiving 1 mg/m(2) daily for 5 days.
    C) ADULT: An adult survived a vinCRIStine dose of 25 mg IV; paresthesia remained 6 months after exposure. Another adult recovered completely after receiving cumulative doses of cyclophosphamide 6000 mg, doxorubicin 420 mg, and vinCRIStine 12 mg over 5 consecutive days. PEDIATRIC: One child survived an overdose of 8.75 mg as a single dose and another survived a dose of 9 mg/m(2) over 6 days with supportive care.
    D) INTRATHECAL EXPOSURE: VinCRIStine is usually FATAL if given intrathecally. Fatal intrathecal doses have ranged from 0.3 to 3 mg vinCRIStine. Of the patients who survived, all sustained some degree of permanent neurologic injury.
    E) THERAPEUTIC DOSE: GENERAL: Varies with disease state. Dose limit is dependent on the patient and protocol being used. Maximum dose should not exceed 2 mg/wk IV due to vinCRIStine-related neurotoxicities. ADULT: USUAL DOSE: 1.4 mg/m(2)/wk IV. PEDIATRIC: USUAL DOSE: 1.5 to 2 mg/m(2)/wk IV. For patients weighing 10 kg or less: 0.05 mg/kg/wk IV. HIGH DOSE THERAPY: In one study, a total dose of 3.5 mg/m(2) administered over 4 days was well tolerated in select patients prior to autologous marrow rescue.

Therapeutic Dose

    7.2.1) ADULT
    A) INTRAVENOUS USE ONLY
    1) VINCRISTINE SULFATE
    a) 1.4 mg/m(2) IV once a week; injection should be completed within 1 minute (Prod Info Vincasar PFS(R) intravenous injection solution, 2014; Uner et al, 2005)
    b) FATAL if given intrathecally. For IV use only (Prod Info Vincasar PFS(R) intravenous injection solution, 2014).
    2) VINCRISTINE SULFATE LIPOSOME
    a) DOSE: Administer 2.25 mg/m(2) as an IV infusion over 1 hour once every 7 days (Prod Info Marqibo(R) intravenous injection, 2012).
    b) FATAL if given intrathecally. For IV use only (Prod Info Marqibo(R) intravenous injection, 2012).
    7.2.2) PEDIATRIC
    A) INTRAVENOUS USE ONLY
    1) VINCRISTINE SULFATE
    a) OVER 10 KG: 1.5 to 2 mg/m(2) IV once a week; injection should be completed within 1 minute (Prod Info Vincasar PFS(R) intravenous injection solution, 2014)
    b) 10 KG OR LESS: Starting Dose: 0.05 mg/kg, administered once a week (Prod Info Vincasar PFS(R) intravenous injection solution, 2014)
    c) FATAL if given intrathecally. For IV use only (Prod Info Vincasar PFS(R) intravenous injection solution, 2014).
    2) VINCRISTINE SULFATE LIPOSOME
    a) Safety and effectiveness have not been established in pediatric patients (Prod Info Marqibo(R) intravenous injection, 2012).

Minimum Lethal Exposure

    A) INTRAVENOUS EXPOSURE
    1) CASE REPORT/ADOLESCENT: A 13-year-old girl was inadvertently administered 32 mg of vinCRIStine (IV). The overdose was discovered the following day when the patient developed severe leg pain and bleeding from venipuncture sites. Signs and symptoms rapidly progressed to include: irritability, abdominal distension, fever (103 degrees F), and hypertension following by hypotension. Despite treatment measures, she continued to decline and died 33 hours after exposure (Kaufman et al, 1976).
    2) CASE REPORT/CHILD A 7-year-old girl received 13.5 mg vinCRIStine IV (intended dose 1.35 mg). She developed hypotension, ileus, urinary retention, myelosuppression, hyponatremia and respiratory distress and died 68 hours after the overdose (Kaufman et al, 1976).
    3) CASE REPORT/CHILD: A 5-year-old boy received 7.5 mg IV vinCRIStine (7.5 mg/m(2)). He developed fever, elevated liver enzymes, areflexia, bloody diarrhea, neutropenia and hallucinations. He died 9 days after overdose (Kosmidis et al, 1991).
    4) CASE REPORT/ADULT: A 52-year-old patient with multiple myeloma and multiple courses of irradiation and chemotherapy developed myelosuppression, SIADH, obtundation and an ileus after receiving a single 1 mg/m(2) vinCRIStine infusion. Assisted ventilation was required due to respiratory insufficiency secondary to severe abdominal distension. No improvement was observed, and the patient died 19 days later (Jackson et al, 1981).
    B) INTRATHECAL EXPOSURE
    1) Following inadvertent intrathecal vinCRIStine administration, clinical symptoms usually begin with opisthotonos, sensory and motor dysfunction and ascending paralysis. Based on individuals case reports, fatalities have occurred within days to weeks of exposure and in rare cases up to one year (Qweider et al, 2007; Alcaraz et al, 2002; Dettmeyer et al, 2001; Meggs & Hoffman, 1998; Williams et al, 1983).
    2) CASE REPORTS
    a) PEDIATRIC: Young children (ages 15 months to 5 years) have died following intrathecal vinCRIStine doses ranging from 0.68 mg to 3 mg (Michelagnoli et al, 1997; Manelis et al, 1982; Shepherd et al, 1978).
    b) TODDLER: Fatalities have been reported with small amounts of vinCRIStine administered intrathecally. In a review, a 2 year-old female died 3 days after receiving 3 mg of intrathecal vinCRIStine, despite the placement of a lumbar drain inserted with 2400 mL of CSF exchanged with 0.9% saline for 24 hours (Qweider et al, 2007).
    c) ADOLESCENT: A 16-year-old developed ascending myeloencephalopathy and was in a deep coma 4 days after receiving 2 mg of vinCRIStine intrathecally. Supportive care only was provided. Brain stem function was absent by day 7 and the patient died 36 days later. At autopsy, the spinal cord and regions of the brain that had come in contact with CSF were necrotic (Williams et al, 1983). In another case, a 12-year-old died 83 days after an inadvertent 2 mg intrathecal dose of vinCRIStine. The patient was treated within 3 hours of exposure with an infusion of lactated Ringer's solution plus 15 mL/L of fresh frozen plasma for approximately 10 hours. Despite treatment, progressive neurologic deterioration occurred. Upon autopsy, massive necrosis was found in the spinal cord, along with total destruction of both grey and white matter (Alcaraz et al, 2002).
    d) ADULT: A 56-year-old man died 30 days after receiving 0.3 mg of intrathecal vinCRIStine. The CSF was immediately aspirated and the patient was asymptomatic and felt well. No further treatment was provided, and the patient was sent home. Approximately 11 hours after exposure, the patient was readmitted with urinary frequency, lumbar pain and weakness in the lower limbs. Progressive neurologic deterioration occurred which included ascending radiculomyeloencephalopathy. The patient died with no signs of CNS activity (Bain et al, 1991).
    e) ADULT: Another adult died 40 days after receiving an inadvertent 2 mg intraventricular (ie, Ommaya reservoir) dose of vinCRIStine. Aggressive therapy included immediate CSF aspiration and a CSF infusion with lactated ringer's solution with 25 mL fresh frozen plasma/L at 150 mL/hr for 24 hours with continuous lumbar drain removal and the administration of glutamic acid (10 g IV over 24 hours, then 500 mg every 8 hr) IV. However, neurologic function continued to decline with no return of neurologic function (Meggs & Hoffman, 1998).

Maximum Tolerated Exposure

    A) SUMMARY
    1) The maximum tolerated exposure is unknown. Severe symptoms should be anticipated in patients after receiving single doses of 3 mg/m(2) or more (Prod Info vincristine sulfate IV Injection, 2007).
    2) HIGH DOSE THERAPY: In one study, a total dose of 3.5 mg/m(2) administered over 4 days was well tolerated in select patients prior to autologous marrow rescue. Grade 1 or 2 neurotoxicity was observed in 61% of treatment courses; only one patient developed grade 3 neurotoxicity (Moore & Pinkerton, 2009).
    B) INTRAVENOUS
    1) MULTIPLE AGENTS: A 23-year-old woman with non-Hodgkin's lymphomas was inadvertently administered her total course of chemotherapy over 5 consecutive days and received cumulative doses of cyclophosphamide 6000 mg, doxorubicin 420 mg, and vinCRIStine 12 mg. Following intensive supportive care the patient was discharged on day 31. The patient remained free of disease and treatment-induced toxicities (ie, severe myelosuppression, peripheral and autonomic neuropathy with SIADH) 56 months after exposure (Uner et al, 2005).
    2) CASE SERIES
    a) In a Phase I trial, 30 patients with advanced malignancies refractory to conventional chemotherapy were administered a 0.5 mg IV bolus followed by a continuous intravenous infusion of vinCRIStine (3 dose levels, 0.5, 0.75 and 1 mg/m(2) for 5 days. Mild to moderate toxicity (ie, neurologic {paraesthesia, diminished reflexes} and hematologic {decrease WBC and platelets}) developed following a continuous intravenous infusion of 0.5 and 0.75 mg/m(2) daily for 5 days. Severe toxicity (ie, myelosuppression {leukopenia}, autonomic neuropathy {ileus, urinary retention}, hyponatremia, marked muscle weakness) occurred in patients receiving 1.0 mg/m(2) daily for 5 days (Jackson et al, 1981).
    3) ADULTS
    a) A 35-year-old patient who was accidentally administered 10 mg of vinCRIStine survived with reversible neurotoxic effects (ie, depression and occipital headaches) (Yoffe et al, 1986).
    b) A 24-year-old man with the nodular sclerosing form of Hodgkin's disease survived an inadvertent 25 mg intravenous dose of vinCRIStine. No other chemotherapeutic drugs were given. Supportive care was initiated the following day (when the error was found), including leucovorin rescue. Six months after exposure, the patient continued to have some neurologic deficits (ie, slight paresis of both feet, muscle atrophy of the hands, and loss of deep tendon reflexes) (Thomas et al, 1982).
    c) An adult with esophageal cancer developed neurotoxicity, gastrointestinal symptoms, bone marrow suppression, and stomatitis after inadvertently receiving 24 mg of vinCRIStine instead of vinblastine (the intended therapy). Myocardial toxicity was also suspected. Paresthesia was still evident 11 months after exposure, but muscle weakness had resolved (Maeda et al, 1987).
    4) PEDIATRIC
    a) A 4.5-year-old child was administered 8.75 mg (0.43 mg/kg) of vinCRIStine and survived, but suffers from grand mal seizures, petit mal seizures, aggressive and hyperkinetic behavior, and was uncontrollable (Casteels-Van Daele et al, 1977). In another case, a 4-year-old child was administered 4 mg (0.25 mg/kg instead of the intended 0.025 mg/kg) of vinCRIStine and survived (Wegelius, 1987).
    b) A pediatric patient who received an overdosage of vinCRIStine (9 mg/m(2) over 6 days) survived with supportive treatment (Stones, 1998).
    c) Children have survived overdoses of 3.5 mg to 7.5 mg/m(2) with aggressive supportive care (Kosmidis et al, 1991; Kaufman et al, 1976).
    C) INTRATHECAL
    1) A 7-year-old girl survived an inadvertent intrathecal vinCRIStine injection of 0.5 mg, but developed persistent motor paraparesis with some recovery of bladder function. Electrodiagnostic studies were consistent with severe sensorimotor neuropathy of the axonal type (AlFerayan et al, 1999).
    2) PEDIATRIC: A 5-year-old boy survived an inadvertent intrathecal vinCRIStine injection of 1.2 mg (100 mcg/kg) after receiving immediate aggressive care. Initially, he developed severe neurotoxicity that included quadriplegia and respiratory insufficiency requiring mechanical ventilation. Over several months, he was successfully extubated with normal developmental function, normal upper extremity strength, but persistent paraplegia (Walter, 2010).
    D) INTRAMUSCULAR
    1) SUMMARY: Based on limited experience, inadvertent intramuscular injection of vinCRIStine (1 mg) resulted in only minor complaints of pain and tenderness. Tissue injury (ie, erythema, swelling, necrosis) was not observed. All cases were treated with alternating cold and warm compresses and local injection of sodium bicarbonate 8.4% (Clark et al, 1997).
    2) CASE REPORT: A 6-year-old girl with history of a Wilm's tumor inadvertently received 4 doses of vinCRIStine by the IM route on 4 consecutive days (instead of 1 mg once weekly IV) as an outpatient and was admitted 3 weeks later with complains of back pain, constipation and mild lower extremity paresthesia. Following symptomatic care her symptoms resolved with 5 days. Her chemotherapy was restarted approximately 4 weeks later (Patiroglu et al, 2012).

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) PEDIATRIC: In a pharmacokinetic study, wide variability in area under the curve was seen in children with acute lymphoblastic leukemia or non- Hodgkin's lymphoma or Wilms' tumor receiving vinCRIStine. Area under the curve ranged from 1.5 to 45.1 mg/L/min (mean: 5 mg/L/min) (Gidding et al, 1999).
    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) GENERAL
    a) Use of a 5-day continuous infusion of vinCRIStine (total dose 4 mg/m(2)) produced plasma concentration of 1.8 to 10.9 ng/mL at 1 hour, a mean steady state concentration of 1.7 ng/mL, and less than 0.25 ng/mL within 24 hr of discontinuation of the infusion (Pinkerton et al, 1988).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ANIMAL DATA
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 1300 mcg/kg ((RTECS, 2000))
    2) LD50- (INTRAPERITONEAL)RAT:
    a) 1250 mcg/kg ((RTECS, 2000))

Pharmacology Toxicology

Pharmacologic Mechanism

    A) The exact mechanism remains unknown. Vincristine appears to inhibit microtubule formation in mitotic spindle, causing cell division arrest in metaphase(Prod Info vincristine sulfate injection, 2004). Vincristine is an M-phase dependent, cell-cycle phase specific antitumor agent (Legha, 1986).

Toxicologic Mechanism

    A) Neurotoxicity, the dose-limiting toxicity, might be explained by disruption of axoplasmic transport and a variety of secretory functions in which microtubules are involved.
    B) Vinca alkaloids, like vinCRIStine inhibit microtubule formation in mitotic spindle causing cell division arrest in metaphase (Prod Info vincristine sulfate injection, 2004). (Legha, 1986).
    C) HUMAN
    1) INTRATHECAL INJECTION of vinCRIStine produces ascending radioculomyeloencephalopathy; death occurs within days to weeks of exposure. The apparent mechanism is the binding of vinCRIStine to the tubulin and forming neurofilament aggregates that destroy the neuronal cytoskeleton of the neurons (Reddy et al, 2010).

Physicochemical

Physical Characteristics

    A) VinCRIStine Sulfate: A white to off-white powder that is soluble in methanol, freely soluble in water, but only slightly soluble in 95% ethanol (Prod Info vincristine sulfate injection, 2004).

Ph

    A) VinCRIStine Sulfate: (injection solution) 4.0 to 5.0 using sulfuric acid or sodium hydroxide (Prod Info vincristine sulfate injection, 2004)

Molecular Weight

    A) VinCRIStine: 824.98 (Prod Info Marqibo(R) intravenous injection, 2012)
    B) VinCRIStine Sulfate: 923.04 (Prod Info Marqibo(R) intravenous injection, 2012)

Animal Toxicology

Clinical Effects

    11.1.3) CANINE/DOG
    A) Signs of overdose include arrest of spermatogenesis, bone marrow suppression, lymphoid hypoplasia, necrosis of intestinal mucosa, and elevation of aspartate aminotransferase, alkaline phosphatase, and lactate dehydrogenase (USPDI, 1999).

Treatment

    11.2.1) SUMMARY
    A) DOG
    1) Treatment is symptomatic and supportive. Monitor complete blood cell and platelet counts.

Range Of Toxicity

    11.3.1) THERAPEUTIC DOSE
    A) CAT
    1) The usual dose is 0.5 to 0.75 milligram/square meter of body surface intravenously once weekly (USPDI, 1999).
    B) DOG
    1) The usual dose is 0.5 to 0.75 milligram/square meter of body surface intravenously once weekly (USPDI, 1999).
    11.3.2) MINIMAL TOXIC DOSE
    A) LACK OF INFORMATION
    1) No specific information on a minimal toxic dose was available at the time of this review.

Continuing Care

    11.4.1) SUMMARY
    11.4.1.2) DECONTAMINATION/TREATMENT
    A) DOG
    1) Treatment is symptomatic and supportive. Monitor complete blood cell and platelet counts.

Kinetics

    11.5.1) ABSORPTION
    A) LACK OF INFORMATION
    1) There was no specific information on absorption at the time of this review.
    11.5.3) METABOLISM
    A) DOG
    1) Elimination is primarily biliary (USPDI, 1999).
    11.5.4) ELIMINATION
    A) DOG
    1) The beta-phase half-life is 75 minutes (USPDI, 1999).

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