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MITOMYCIN

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Mitomycin ophthalmic solution is isolated from Streptomyces verticillus Yingtangensis and mitomycin solution for injection is isolated from Streptomyces caespitosus. Mitomycin is an antibiotic with antimetabolite activity. It causes cross-linking of DNA and inhibits DNA synthesis. It may also inhibit cellular RNA and protein synthesis.

Specific Substances

    1) Ametycine
    2) Mit-C
    3) Mitocin
    4) Mitocin-C
    5) Mitolem
    6) Mito-medac
    7) Mitomycin
    8) Mitomycinum
    9) MMC
    10) Mutamycin
    11) Mutamycine
    12) Mytomycin
    13) NCI-c 04706
    14) NSC 26980
    15) Molecular Formula: C15-H18-N4-O5
    16) CAS 50-07-7
    17) MITOMYCIN-X
    1.2.1) MOLECULAR FORMULA
    1) C15-H18-N4-O5

Available Forms Sources

    A) FORMS
    1) Mitomycin is available in 5 mg, 20 mg, and 40 mg intravenous powder for solution (Prod Info MITOMYCIN intravenous injection, 2009).
    2) Mitomycin (Mitosol(R)) is available as vials containing 0.2 mg mitomycin and 0.4 mg mannitol; the solution contains 0.2 mg/mL mitomycin when reconstituted with sterile water for injection. This product is used topically (Prod Info MITOSOL(R) topical solution powder, 2012).
    B) USES
    1) Mitomycin is indicated for disseminated adenocarcinoma of the stomach and pancreas, in combination with other chemotherapy agents (Prod Info MITOMYCIN intravenous injection, 2009). It has also been used for other cancers, such as cervical, breast, colorectal, or head and neck cancers (Wheelock et al, 1990; Gupta, 1982; Doyle et al, 1984).
    2) Mitomycin ophthalmic topical solution is indicated as an adjunct to ab externa glaucoma surgery (Prod Info MITOSOL(R) topical solution powder, 2012).

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: Mitomycin is indicated for disseminated adenocarcinoma of the stomach and pancreas, in combination with other chemotherapy agents. It has also been used for other cancers, such as cervical, breast, colorectal, or head and neck cancers. Mitomycin ophthalmic topical solution is indicated as an adjunct to ab externa glaucoma surgery.
    B) PHARMACOLOGY: Mitomycin ophthalmic solution is isolated from Streptomyces verticillus Yingtangensis and mitomycin solution for injection is isolated from Streptomyces caespitosus. Mitomycin is an antibiotic with antimetabolite activity. It causes cross-linking of DNA and inhibits DNA synthesis. It may also inhibit cellular RNA and protein synthesis.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) INTRAVENOUS: COMMON: Nausea, vomiting, anorexia, mucositis, fever, and myelosuppression (eg, leukopenia, thrombocytopenia). Leukopenia and thrombocytopenia may occur anytime within 8 weeks after onset of therapy with an average time of 4 weeks. Recovery after cessation of therapy was within 10 weeks. Approximately 25% of leukopenia or thrombocytopenic episodes did not recover. OTHER EFFECTS: Alopecia, diarrhea, ileus, confusion, drowsiness, fatigue, lethargy, headache, syncope, weakness, skin findings (eg, extravasation, desquamation, induration, pruritus, pain on injection, paresthesias, contact dermatitis, necrosis, cellulitis, ulceration, and tissue sloughing at the injection site), renal dysfunction, thrombophlebitis, hepatotoxicity, pulmonary toxicity (eg, hemoptysis, dyspnea, cough, pneumonitis, alveolitis, and pulmonary fibrosis). Hemolytic uremic syndrome, consisting mainly of microangiopathic hemolytic anemia (hematocrit equal to or less than 25%), thrombocytopenia (equal to or less than 100,000/mm(3)), and irreversible renal failure (serum creatinine equal to or greater than 1.6 mg/dL) has been reported in patients receiving systemic mitomycin. Approximately 98% of patients with this syndrome developed microangiopathic hemolysis with fragmented red blood cells on peripheral blood smears. Congestive heart failure has rarely been reported in patients receiving mitomycin. Almost all patients with CHF had previously received doxorubicin.
    2) OPHTHALMIC: Chronic bleb leak, hypotony, hypotony maculopathy, blebitis, endophthalmitis, lenticular changes, cataract formation, corneal reactions (eg, endothelial damage, epithelial defects, anterior synechiae, superficial punctuate keratitis), and vascular reactions (eg, hyphema, central retinal vein occlusion, and retinal hemorrhage) have been reported.
    E) WITH POISONING/EXPOSURE
    1) Limited data are available on mitomycin overdose. The clinical effects reported are those noted during therapeutic use of mitomycin, including high-dose therapy.
    0.2.3) VITAL SIGNS
    A) WITH THERAPEUTIC USE
    1) Fever may occur with therapy.
    0.2.20) REPRODUCTIVE
    A) Mitomycin is classified as FDA pregnancy category X. Teratogenic effects have been observed.
    0.2.21) CARCINOGENICITY
    A) Mitomycin may produce delayed secondary malignancies. At the time of this review, the manufacturer does not report any carcinogenic potential of mitomycin in humans; however, according to a manufacturer of mitomycin injection, there was a 100% and 50% increased risk tumor incidence in rats and female mice, respectively, at the approximate recommended human dose

Laboratory Monitoring

    A) Monitor vital signs, serum electrolytes, renal function, and liver enzymes.
    B) Monitor serial CBC (with differential) and platelet count until there is evidence of bone marrow recovery. Myelosuppression has been reported. Leukopenia and thrombocytopenia may occur anytime within 8 weeks after onset of therapy with an average time of 4 weeks. Recovery after cessation of therapy was within 10 weeks. About 25% of leukopenia or thrombocytopenic episodes did not recover.
    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.
    D) Clinically evaluate patients for the development of mucositis.
    E) Monitor injection site for signs of extravasation.
    F) Monitor patients closely for the development of hemolytic uremic syndrome.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Treat persistent nausea and vomiting with several antiemetics of different classes. Administer colony stimulating factors (filgrastim or sargramostim) as these patients are at risk for severe neutropenia.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Administer colony stimulating factors (filgrastim or sargramostim) as these patients are at risk for severe neutropenia. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia, or hemorrhage. Severe nausea and vomiting may respond to a combination of agents from different drug classes.
    C) INTRATHECAL INJECTION
    1) No clinical reports available, information derived from experience with other antineoplastics. 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). For large overdoses, consult a neurosurgeon for placement of a ventricular catheter and begin ventriculolumbar perfusion (infuse warmed preservative-free normal saline or lactated ringers through the ventricular catheter, drain fluid from lumbar catheter. Typical volumes 80 to 150 mL/hr for 18 to 24 hours). Dexamethasone 4 mg intravenously every 6 hours to prevent arachnoiditis.
    D) AIRWAY MANAGEMENT
    1) Endotracheal intubation and mechanical ventilation may be required in patients with severe respiratory symptoms, cardiotoxicity, or acute allergic reactions.
    E) ANTIDOTE
    1) None.
    F) MYELOSUPPRESSION
    1) Administer colony stimulating factors following a significant overdose as these patients are at risk for severe neutropenia. Filgrastim: 5 mcg/kg/day IV or subQ. Sargramostim: 250 mcg/m(2)/day IV over 4 hours. Monitor CBC with differential and platelet count daily for evidence of bone marrow suppression until recovery has occurred. 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. Transfer to a bone marrow transplant center should be considered.
    G) HYPERSENSITIVITY REACTION
    1) MILD/MODERATE: Antihistamines with or without inhaled beta agonists, corticosteroids or epinephrine. SEVERE: Oxygen, aggressive airway management, antihistamines, epinephrine, corticosteroids, ECG monitoring, and IV fluids.
    H) NAUSEA AND VOMITING
    1) Treat severe nausea and vomiting with agents from several different classes. For example: 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).
    I) STOMATITIS/MUCOSITIS
    1) 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 an mitomycin overdose in whom neutropenia and mucositis would be anticipated, administer palifermin 60 mcg/kg/day IV bolus injection starting 24 hours after the overdose for 3 consecutive days.
    J) EXTRAVASATION INJURY
    1) Mitomycin, a vesicant, can produce cellulitis, ulceration, and tissue sloughing at the mitomycin 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 dimethyl sulfoxide (DMSO - see dosing below). Elevate the affected area. Apply ice packs for 15 to 20 minutes at least 4 times daily. Do not apply excessive cold to avoid tissue injury. Cold can cause local vasoconstriction and reduces fluid absorption. 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 (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. DIMETHYL SULFOXIDE (DMSO): Treat site with topical DMSO (for a minimum of 7 days and maximum of 14 days); however, if blistering develops, discontinue DMSO and review site. Another source recommended DMSO 99% solution topically and allow to air dry. Cover with a nonocclusive dressing within 10 to 25 min. Repeat every 8 hours for 1 week.
    K) ENHANCED ELIMINATION
    1) It is unknown if hemodialysis would be effective.
    L) PATIENT DISPOSITION
    1) HOME CRITERIA: There is no data to support home management. All overdoses should be evaluated in a healthcare facility.
    2) OBSERVATION CRITERIA: Exposed patients should be evaluated and observed for 6 hours. If patients are asymptomatic for 6 hours, they may be sent home, but toxic effects may be delayed, so patients should return to a healthcare provider for any symptoms and should have blood work monitored as an outpatient (eg, CBC for myelosuppression).
    3) ADMISSION CRITERIA: Any symptomatic patient should be admitted to the hospital, and depending on the severity of their symptoms, either to the floor or ICU. Criteria for discharge should be resolution of symptoms and laboratory abnormalities.
    4) CONSULT CRITERIA: Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with an overdose. Consult a nephrologist if hemolytic uremic syndrome develops.
    5) TRANSFER CRITERIA: Patients with large overdoses or severe myelosuppression may benefit from early transfer to a cancer treatment or bone marrow transplant center.
    M) PITFALLS
    1) Symptoms of overdose are similar to reported side effects of the medication. Early symptoms of overdose may be delayed or not evident (ie, particularly myelosuppression), so reliable follow-up is imperative. Patients receiving mitomycin may have severe co-morbidities and may be receiving other drugs that may produce synergistic effects (ie, myelosuppression).
    N) PHARMACOKINETICS
    1) Mitomycin disappears rapidly from the blood, is widely distributed. Vd: 22 L/m(2) Metabolism: Liver. Excretion: A small amount (up to 10%) is excreted unchanged in the urine. Elimination half-life: Following IV doses of 30, 20, and 10 mg were 17, 10, and 9 minutes, respectively.
    O) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause myelosuppression or renal dysfunction.
    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) INTRATHECAL INJECTION: No clinical reports available, information derived from experience with other antineoplastics. 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). For large overdoses, consult a neurosurgeon for placement of a ventricular catheter and begin ventriculolumbar perfusion (infuse warmed preservative-free normal saline or lactated ringers through the ventricular catheter, drain fluid from lumbar catheter. Typical volumes 80 to 150 mL/hr for 18 to 24 hours). Dexamethasone 4 mg intravenously every 6 hours to prevent arachnoiditis.

Range Of Toxicity

    A) TOXICITY: An adult received 70 mg and recovered with supportive care. Increased toxicity without enhanced efficacy has been reported with total doses greater than 20 mg/m(2)/day. Renal toxicity increases above cumulative dose of 120 mg. Reports of pulmonary toxicity have occurred at total dosages as low as 40 mg, but the average cumulative toxic dose resulting in pulmonary toxicity is 78 mg.
    B) THERAPEUTIC DOSES: ADULTS: INTRAVENOUS: 20 mg/m(2)/dose IV every 6 to 8 weeks. OPHTHALMIC: Saturated sponges with entire vial of 0.2 mg/mL reconstituted mitomycin solution is applied topically in a single layer to treatment area and left on for 2 minutes. CHILDREN: The safety and efficacy of mitomycin have not been established in pediatric patients. A phase II study was designed to reevaluate mitomycin in children using the dose considered to be optimal based upon adult data (20 mg/m(2)) at 6 to 8 week intervals. Toxicity was tolerable in the 9 evaluable patients with refractory solid tumors.

Clinical Effects

Summary Of Exposure

    A) USES: Mitomycin is indicated for disseminated adenocarcinoma of the stomach and pancreas, in combination with other chemotherapy agents. It has also been used for other cancers, such as cervical, breast, colorectal, or head and neck cancers. Mitomycin ophthalmic topical solution is indicated as an adjunct to ab externa glaucoma surgery.
    B) PHARMACOLOGY: Mitomycin ophthalmic solution is isolated from Streptomyces verticillus Yingtangensis and mitomycin solution for injection is isolated from Streptomyces caespitosus. Mitomycin is an antibiotic with antimetabolite activity. It causes cross-linking of DNA and inhibits DNA synthesis. It may also inhibit cellular RNA and protein synthesis.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) INTRAVENOUS: COMMON: Nausea, vomiting, anorexia, mucositis, fever, and myelosuppression (eg, leukopenia, thrombocytopenia). Leukopenia and thrombocytopenia may occur anytime within 8 weeks after onset of therapy with an average time of 4 weeks. Recovery after cessation of therapy was within 10 weeks. Approximately 25% of leukopenia or thrombocytopenic episodes did not recover. OTHER EFFECTS: Alopecia, diarrhea, ileus, confusion, drowsiness, fatigue, lethargy, headache, syncope, weakness, skin findings (eg, extravasation, desquamation, induration, pruritus, pain on injection, paresthesias, contact dermatitis, necrosis, cellulitis, ulceration, and tissue sloughing at the injection site), renal dysfunction, thrombophlebitis, hepatotoxicity, pulmonary toxicity (eg, hemoptysis, dyspnea, cough, pneumonitis, alveolitis, and pulmonary fibrosis). Hemolytic uremic syndrome, consisting mainly of microangiopathic hemolytic anemia (hematocrit equal to or less than 25%), thrombocytopenia (equal to or less than 100,000/mm(3)), and irreversible renal failure (serum creatinine equal to or greater than 1.6 mg/dL) has been reported in patients receiving systemic mitomycin. Approximately 98% of patients with this syndrome developed microangiopathic hemolysis with fragmented red blood cells on peripheral blood smears. Congestive heart failure has rarely been reported in patients receiving mitomycin. Almost all patients with CHF had previously received doxorubicin.
    2) OPHTHALMIC: Chronic bleb leak, hypotony, hypotony maculopathy, blebitis, endophthalmitis, lenticular changes, cataract formation, corneal reactions (eg, endothelial damage, epithelial defects, anterior synechiae, superficial punctuate keratitis), and vascular reactions (eg, hyphema, central retinal vein occlusion, and retinal hemorrhage) have been reported.
    E) WITH POISONING/EXPOSURE
    1) Limited data are available on mitomycin overdose. The clinical effects reported are those noted during therapeutic use of mitomycin, including high-dose therapy.

Vital Signs

    3.3.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Fever may occur with therapy.
    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) Fever was reported in 14% (n=1281) of patients treated with mitomycin (Prod Info MITOMYCIN intravenous injection, 2009).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH THERAPEUTIC USE
    a) Confusion, drowsiness, fatigue, lethargy, headache, syncope, and weakness may occur during therapy (Prod Info MITOMYCIN intravenous injection, 2009; Dorr & Fritz, 1980). These symptoms do not appear to be dose related (Prod Info MITOMYCIN intravenous injection, 2009).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) During clinical trials, nausea and vomiting, and loss of appetite occurred in 14% (n=1281) of patients treated with mitomycin (Prod Info MITOMYCIN intravenous injection, 2009).
    b) Anorexia, nausea, and vomiting usually develop within 1 to 2 hours and may persist for several hours following therapy (Dorr & Fritz, 1980).
    c) Nausea and vomiting has been reported in 100% of 122 patients who received mitomycin. The onset of symptoms was usually within 1 to 2 hours of a mitomycin dose, with vomiting lasting 3 to 4 hours and nausea persisting for 2 to 3 days (Godfrey & Wilbur, 1972).
    B) INFLAMMATORY DISEASE OF MUCOUS MEMBRANE
    1) WITH THERAPEUTIC USE
    a) Stomatitis has been reported with therapy (Dorr & Fritz, 1980).
    b) Mucositis occurred in 20% of patients after the first course of high-dose mitomycin (30 to 50 mg/m(2)) and in 40% after the second course (Tannir et al, 1984).
    C) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Diarrhea has been associated with mitomycin administration (Prod Info MITOMYCIN intravenous injection, 2009; Tannir et al, 1984).
    D) DRUG-INDUCED ILEUS
    1) WITH THERAPEUTIC USE
    a) Ileus may occur with therapeutic use (Tannir et al, 1984).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) VENO-OCCLUSIVE DISEASE OF THE LIVER
    1) WITH THERAPEUTIC USE
    a) Mitomycin has hepatotoxic potential (Knoben, 1979).
    b) Veno-occlusive disease of the liver was reported in patients who received high-dose mitomycin and autologous bone marrow transplantation therapy (Lazarus, 1982; Gottfried & Sudilovsky, 1982).
    c) CASE SERIES: Lazarus et al (1982) reported that 6 of 29 patients who received mitomycin (60, 75 or 90 mg/m(2) IV) developed the syndrome, characterized by progressive abnormalities in liver enzymes, abdominal pain, and ascites 15 to 70 days after therapy (Lazarus, 1982).

Heent

    3.4.3) EYES
    A) ANIMAL STUDIES
    1) RABBITS: Destruction of most of the cells of the retina occurred in rabbits following injection of mitomycin into the vitreous humor. A dose of less than 2 mcg or 0.8 mcg/mL was not significantly toxic to the rabbit retina (Grant, 1986).
    2) RABBITS: CORNEAL OPACITY and progressive irreversible bullous keratopathy with necrosis of the iris and ciliary body have been reported in rabbits given intracameral injections of mitomycin C (Derick et al, 1991).
    a) A circular cloudy area developed in the lens on the first day after exposure to mitomycin C and progressed to nuclear opacity by the twelfth day (HSDB , 1991).
    B) WITH THERAPEUTIC USE
    1) A chronic bleb leak, hypotony, hypotony maculopathy, blebitis, endophthalmitis, lenticular changes, cataract formation, corneal reactions (eg, endothelial damage, epithelial defects, anterior synechiae, superficial punctuate keratitis), and vascular reactions (eg, hyphema, central retinal vein occlusion, and retinal hemorrhage) were among the most frequent adverse reaction reported in patients with open-angle glaucoma who received topical application to the eye of mitomycin 0.2 mg/mL solution with a sponge. These effects were felt to be an extension of the pharmacologic activity of mitomycin (Prod Info MITOSOL(R) topical solution powder, 2012).
    2) In 16 eyes exposed to low dose mitomycin after trabeculectomy, no spontaneous bleb leakage was observed; however, after applying digital pressure, leakage was observed in 5 (31.2%) eyes as determined by the Seidel test. Bleb leakage is a potentially serious complication of mitomycin therapy because it may predispose patients to endophthalmitis, a flat anterior chamber, hypotony, peripheral anterior synechiae, or choroidal detachment. Mitomycin 0.2 mg/mL was applied to the scleral flap for 3 minutes during the surgical procedure. All patients were assessed for at least 6 months after surgery (Susanna et al, 1996).
    3) Reversible blepharo-conjunctivitis has been reported following instillation of a 0.04% solution of mitomycin eyedrops 3 to 6 times daily for one week following surgical treatment of pterygium. Degeneration of the sclera, later iridocyclitis, and secondary glaucoma have been reported following more extensive use (Grant, 1986).
    C) WITH POISONING/EXPOSURE
    1) CASE REPORT: A patient developed iris atrophy, pigmentations, temporal corneal edema, and cystoid macular edema after inadvertently receiving a mitomycin C intraocular injection. A Goldmann visual field showed central scotoma. On 6 months follow-up after a vitrectomy, temporal corneal edema was reduced; however, the patient still had iris atrophy and cystoid macular edema (Ryoo et al, 2013).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) CONGESTIVE HEART FAILURE
    1) WITH THERAPEUTIC USE
    a) Congestive heart failure has rarely been reported in patients receiving mitomycin. Almost all patients with CHF had previously received doxorubicin (Prod Info MITOMYCIN intravenous injection, 2009).
    b) Cardiac disorder has been suggested in man and experimental animals (Ravry, 1979).
    c) CASE REPORT: A 57-year-old woman with cancer of the cervix received 5 courses of mitomycin C (15 mg/m(2) at 3 weekly intervals) and 3 weeks after the last course developed acute congestive heart failure and died (Sivanesaratnam & Jayalakshmi, 1989).
    d) CASE SERIES: Two patients who received 20 to 50 mg/m(2)/course of mitomycin plus a total life-time dose of 450 mg/m(2) of doxorubicin developed intractable congestive heart failure (Tannir et al, 1984).
    e) Congestive heart failure in 14 of 91 (15.3%) patients receiving doxorubicin (Adriamycin(R)), megestrol acetate, and mitomycin was thought to be due to a synergistic cardiotoxic effect of the drugs. A similar regimen without mitomycin resulted in congestive heart failure in 3 of 89 patients (3.4%) (Buzdar et al, 1978).
    f) CASE SERIES: Two patients who received 20 to 50 mg/m(2)/course of mitomycin plus a total life-time dose of 450 mg/m(2) of doxorubicin developed intractable congestive heart failure (Tannir et al, 1984).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) ABNORMAL RENAL FUNCTION
    1) WITH THERAPEUTIC USE
    a) Increasing BUN, creatinine, and glomerular degeneration are occasionally seen. Approximately 10% of patients who receive mitomycin develop renal failure (Dorr & Fritz, 1980; Early et al, 1973). Renal impairment appears to be total-dose-related and most patients develop renal symptoms after receiving at least 60 mg of mitomycin C (Ravikumar et al, 1984; Valavaara & Nordman, 1985).
    b) The renal morphologic changes reveal a glomerular and vascular process associated with microangiopathic hemolytic anemia. In patients with malignancies, it may be that the use of mitomycin C alone or in combination with other drugs causes endothelial vascular damage with subsequent activation of the coagulation system (Ravikumar et al, 1984).
    c) Three of 32 patients with metastatic carcinomas treated with mitomycin C developed renal toxicity within 6 to 7 months of therapy; the toxic effect was primarily on the glomerular tuft, particularly on the nuclei (Liu et al, 1971a).
    B) HEMOLYTIC UREMIC SYNDROME
    1) WITH THERAPEUTIC USE
    a) Hemolytic uremic syndrome, consisting mainly of microangiopathic hemolytic anemia (hematocrit equal to or less than 25%), thrombocytopenia (equal to or less than 100,000/mm(3), and irreversible renal failure (serum creatinine equal to or greater than 1.6 mg/dL) has been reported in patients receiving systemic mitomycin. Approximately 98% of patients with this syndrome developed microangiopathic hemolysis with fragmented red blood cells on peripheral blood smears (Prod Info MITOMYCIN intravenous injection, 2009; Cantrell et al, 1985; Giroux et al, 1985; Liu et al, 1971).
    b) There is frequently a delay between treatment and onset suggesting that a combination of factors is required, which may include concomitant exposure to the appropriate phage-containing organisms and mitomycin; individual susceptibility may also play a role. It may also be due to a direct toxic effect of mitomycin on the vascular endothelium (Acheson & Donohue-Rolfe, 1989; Cordonnier et al, 1985).
    c) It is characterized by a slow and late occurrence, extra-renal (primarily respiratory) manifestations, and by its pathological aspects. An increased urinary protein in conjunction with a high MCV may provide an early clue to its detection; however, in some instances, laboratory tests are not helpful in predicting its occurrence. Plasma exchange may improve long-term prognosis in severe cases (Cordonnier et al, 1985) Verwey, 1987).
    d) CASE SERIES: Mitomycin therapy was associated with hemolytic-uremic syndrome in 4 patients following 5 to 11 months of treatment (total doses, 45 to 199 mg). Autopsy findings in all 4 patients revealed a microangiopathy typical of the hemolytic-uremic syndrome with thromboses in glomerular capillaries and arterioles, fibrin deposition in the mesangium, and prominent cellular intimal proliferation of the interlobular arteries. It was concluded that the development of hemolytic-uremic syndrome contributed to death in all 4 patients (Proia et al, 1984).
    e) CASE SERIES: Pavy et al (1982) and Rabadi et al (1982) described case reports of 3 patients who developed renal microangiopathy involving small arterioles and glomerular capillaries, microangiopathic hemolytic anemia and a consumptive thrombocytopenia following therapy with mitomycin (Pavy et al, 1982; Rabadi et al, 1982).
    f) CASE REPORT: One study reported a case of a form of hemolytic-uremic syndrome following the use of adjuvant chemotherapy with mitomycin C and 5-FU. The authors state that the syndrome may develop with little warning. An increased urinary protein in conjunction with a high MCV may provide an early clue to its detection (Willis et al, 1983).
    g) CASE SERIES: Hemolytic-uremic syndrome developed 68 and 160 days after mitomycin C therapy in two gastric cancer patients, respectively. Serum creatinine levels eventually returned to normal in one case and to about 2 mg/dL in the other (Motoo et al, 1994).
    C) URINARY SYSTEM FINDING
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Wajsman (1983) reported a case of severe bladder contracture following intravesical therapy with mitomycin. Bladder capacity went from 400 mL to only 75 mL approximately 3 months after mitomycin instillation (Wajsman et al, 1983).
    b) CASE REPORT: A 62-year-old man developed bladder fibrosis and contracture with resultant renal failure after intravesical therapy with mitomycin C. The patient initially received 40 mg mitomycin C weekly for 8 weeks then monthly, after 6 months of treatment signs of renal failure began (Farha & Krauss, 1989).
    D) INCREASED FREQUENCY OF URINATION
    1) WITH THERAPEUTIC USE
    a) Urinary frequency and urgency have been reported following intravesical therapy with mitomycin C (Farha & Krauss, 1989).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) MYELOSUPPRESSION
    1) WITH THERAPEUTIC USE
    a) Bone marrow suppression occurred in 605 of 937 patients (64.4%), the most common adverse effect observed during clinical trials (Prod Info MITOMYCIN intravenous injection, 2009).
    b) Leukopenia and thrombocytopenia may occur anytime within 8 weeks after onset of therapy with an average time of 4 weeks. Recovery after cessation of therapy was within 10 weeks. About 25% of leukopenia or thrombocytopenic episodes did not recover (Prod Info MITOMYCIN intravenous injection, 2009). Myelosuppression becomes more profound and prolonged after repeated doses of mitomycin (Dorr & Fritz, 1980a).
    c) One study reported more frequent and longer lasting myelosuppression following the mitomycin arm of MMM (mitomycin, mitoxantrone, methotrexate) regimen in 28 patients. Thrombocytopenia (29% of patients had grade III to IV) and leukopenia (50% of patients had grade III to IV) were more frequent and longer lasting following mitomycin administration as compared to mitoxantrone and methotrexate (Muhonen et al, 1992).
    B) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) Leukopenia and thrombocytopenia may occur anytime within 8 weeks after onset of therapy with an average time of 4 weeks. Recovery after cessation of therapy was within 10 weeks. About 25% of leukopenia or thrombocytopenic episodes did not recover (Prod Info MITOMYCIN intravenous injection, 2009).
    C) ARTERIAL EMBOLUS AND THROMBOSIS
    1) WITH THERAPEUTIC USE
    a) Arterial thrombosis has been noted from intraarterial administration of mitomycin (Dorr & Fritz, 1980).
    D) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) Leukopenia and thrombocytopenia may occur anytime within 8 weeks after onset of therapy with an average time of 4 weeks. Recovery after cessation of therapy was within 10 weeks. About 25% of leukopenia or thrombocytopenic episodes did not recover (Prod Info MITOMYCIN intravenous injection, 2009).
    b) Mitomycin 30 to 50 mg/m(2)/course produced irreversible thrombocytopenia in some patients (Tannir et al, 1984).
    E) DISSEMINATED INTRAVASCULAR COAGULATION
    1) WITH THERAPEUTIC USE
    a) Disseminated intravascular coagulation (DIC) was reported as a complication associated with high-dose mitomycin (30 to 50 mg/m(2)/course) (Tannir et al, 1984).
    b) CASE REPORT: A 45-year-old man developed disseminated intravascular coagulation with mitomycin therapy for hepatocellular carcinoma. Autopsy upon death revealed encapsulated hepatocellular cancer, completely necrotized without metastases. Fibrin thrombi in the kidney accounted for the intravascular coagulation (Harada et al, 1978).
    F) MICROANGIOPATHIC HEMOLYTIC ANEMIA
    1) WITH THERAPEUTIC USE
    a) Hemolytic uremic syndrome, consisting mainly of microangiopathic hemolytic anemia (hematocrit equal to or less than 25%), thrombocytopenia (equal to or less than 100,000/mm(3), and irreversible renal failure (serum creatinine equal to or greater than 1.6 mg/dL) has been reported in patients receiving systemic mitomycin. Approximately 98% of patients with this syndrome developed microangiopathic hemolysis with fragmented red blood cells on peripheral blood smears (Prod Info MITOMYCIN intravenous injection, 2009; Cantrell et al, 1985; Giroux et al, 1985; Liu et al, 1971).
    b) CASE SERIES: Pavy et al (1982) and Rabadi et al (1982) described case reports of 3 patients who developed renal microangiopathy involving small arterioles and glomerular capillaries, microangiopathic hemolytic anemia and a consumptive thrombocytopenia following therapy with mitomycin (Pavy et al, 1982; Rabadi et al, 1982).
    c) Microangiopathic hemolytic anemia has developed in patients treated with mitomycin combinations (Tiggs et al, 1982).
    d) CASE REPORT: Microangiopathic hemolytic anemia developed in a 71-year-old patient treated for gastric adenocarcinoma with 5-FU, mitomycin C, and doxorubicin. The syndrome resolved upon discontinuation of therapy (Perry, 1983).
    G) THROMBOPHLEBITIS
    1) WITH THERAPEUTIC USE
    a) Thrombophlebitis has been associated with mitomycin administration (Prod Info MITOMYCIN intravenous injection, 2009).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ALOPECIA
    1) WITH THERAPEUTIC USE
    a) Hair loss has occurred in approximately 4% of patients (Dorr & Fritz, 1980; EPA, 1985; HSDB , 2000).
    B) NAIL FINDING
    1) WITH THERAPEUTIC USE
    a) Purple-colored bands occur in nail bed corresponding to repeated doses of mitomycin (Dorr & Fritz, 1980).
    C) DISORDER OF SKIN
    1) WITH THERAPEUTIC USE
    a) Desquamation, induration, pruritus, pain on injection, paresthesias, and necrosis occurs in approximately 4% of patients (HSDB , 2000).
    D) DERMATITIS
    1) WITH THERAPEUTIC USE
    a) Vesicular hand, feet, and groin dermatitis has been reported in approximately 9% of patients receiving mitomycin C via intravesicular instillation (Christensen, 1990; DeGroot & Conemans, 1990; Giorgini et al, 1991).
    b) CASE SERIES: Two patients receiving Mitomycin-C intravesically (40 mg in 50 mL water/treatment) reportedly developed a pruritic rash of the palms, legs, and soles of feet, along with fever, chills, and edema of the eyelids. The rash remitted spontaneously with skin desquamation in 8 to 10 days (Arregui et al, 1991).
    c) A delayed hypersensitivity reaction mediated transvesically has been suggested as the responsible factor for the dermatitis resulting from intravesical mitomycin C therapy, rather than an immediate-type hypersensitivity (Clover et al, 1990).
    E) CONTACT DERMATITIS
    1) WITH THERAPEUTIC USE
    a) Allergic contact dermatitis has been reported.
    b) CASE REPORT: A nurse who previously had handled mitomycin C with a history of dermatitis of the hands developed a severe eruption of the penis, thighs, lower abdomen, and buttocks after the first intravesical instillation of mitomycin C. The severe allergic reaction may be due to previous sensitization to the drug (Fisher, 1991).
    1) It has been suggested that the distinctive pattern of dermatitis of the hands and genitals is related to direct contact with urine containing mitomycin C. However, a systemic reaction cannot be ruled out (Fisher, 1991).
    F) INJECTION SITE EXTRAVASATION
    1) WITH THERAPEUTIC USE
    a) Extravasation during injection has resulted in necrosis and sloughing of tissue with mitomycin use (Prod Info MITOMYCIN intravenous injection, 2009).
    b) Cellulitis, ulceration, and tissue sloughing at the injection site may develop if extravasation of drug occurs (Prod Info MITOMYCIN intravenous injection, 2009; EPA, 1985; HSDB , 2000).
    c) Delayed extravasation injury (several days to weeks after therapy) was reported in 2 patients following administration of mitomycin which included erythema, ulceration, and necrosis at sites where other intravenous preparations had been administered but distant to the mitomycin injection site (Patel & Krusa, 1999). The wounds healed, but significant scarring was reported in one patient.

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ACUTE ALLERGIC REACTION
    1) WITH THERAPEUTIC USE
    a) Mediated transvesically has been suggested as the responsible factor for the dermatitis resulting from intravesical mitomycin C therapy, rather than immediate-type hypersensitivity (Colver et al, 1990).

Reproductive

    3.20.1) SUMMARY
    A) Mitomycin is classified as FDA pregnancy category X. Teratogenic effects have been observed.
    3.20.2) TERATOGENICITY
    A) CHROMOSOME DISORDER
    1) Mitomycin causes chromosomal aberrations and is a potent teratogen and carcinogen (Dorr & Fritz, 1980).
    B) ANIMAL STUDIES
    1) SKELETAL MALFORMATION
    a) Skeletal defects were noted in a teratogenicity study in mice. One study in rats found up to 28% of the fetuses were abnormal and another study found negative results (Schardein, 1985).
    2) FETOTOXICITY
    a) Toxic effects such as fetotoxicity and fetal death were observed in rat and mouse studies (RTECS , 2000).
    3) CONGENITAL ANOMALY
    a) RAT studies showed specific developmental abnormalities of the urogenital system and changes in litter size (RTECS , 2000).
    b) MOUSE studies showed specific developmental abnormalities of the craniofacial area, including nose and throat, and the musculoskeletal system. Extra embryonic structures and toxic effects on fertility were also observed (RTECS , 2000).
    c) Cytological changes, including somatic cell genetic material and other toxic effects on the embryo or fetus, occurred in both the hamster and mouse (RTECS , 2000).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Mitomycin is classified as FDA pregnancy category X(Prod Info MITOSOL(R) topical solution powder, 2012).
    B) ANIMAL STUDIES
    1) FERTILITY DECREASED FEMALE
    a) In a study of female mice, mitomycin C had no effect on ovulation but decreased the fertilization rate. Doses of 2 and 4 mg/kg arrested cleavage and implantation (Hashimoto et al, 1986).
    2) TESTIS DISORDER
    a) Observed toxic effects on male rats and mice included changes in spermatogenesis, testes, epididymis, sperm duet, prostate, and related glands (RTECS , 1991).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Breastfeeding is not recommended due to the potential for severe toxicity in a nursing infant (Prod Info MITOSOL(R) topical solution powder, 2012; Prod Info MITOMYCIN intravenous injection, 2009).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS50-07-7 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) IARC Classification
    a) Listed as: Mitomycin C
    b) Carcinogen Rating: 2B
    1) The agent (mixture) is possibly carcinogenic to humans. The exposure circumstance entails exposures that are possibly carcinogenic to humans. This category is used for agents, mixtures and exposure circumstances for which there is limited evidence of carcinogenicity in humans and less than sufficient evidence of carcinogenicity in experimental animals. It may also be used when there is inadequate evidence of carcinogenicity in humans but there is sufficient evidence of carcinogenicity in experimental animals. In some instances, an agent, mixture or exposure circumstance for which there is inadequate evidence of carcinogenicity in humans but limited evidence of carcinogenicity in experimental animals together with supporting evidence from other relevant data may be placed in this group.
    3.21.2) SUMMARY/HUMAN
    A) Mitomycin may produce delayed secondary malignancies. At the time of this review, the manufacturer does not report any carcinogenic potential of mitomycin in humans; however, according to a manufacturer of mitomycin injection, there was a 100% and 50% increased risk tumor incidence in rats and female mice, respectively, at the approximate recommended human dose
    3.21.3) HUMAN STUDIES
    A) LACK OF INFORMATION
    1) At the time of this review, the manufacturer does not report any carcinogenic potential of mitomycin C in humans (Prod Info MITOSOL(R) topical solution powder, 2012).
    B) CARCINOMA
    1) Potential delayed effects of antineoplastics may be secondary malignancies (USP, 1991).
    C) CHROMOSOME DISORDER
    1) Mitomycin causes chromosomal aberrations and is a potent teratogen and carcinogen (Dorr & Fritz, 1980).
    3.21.4) ANIMAL STUDIES
    A) CARCINOMA
    1) In mice, subcutaneous injection of mitomycin is carcinogenic; it is also carcinogenic in rats when administered intraperitoneally or intravenously. At the time of this review, no epidemiological studies or case reports were found of carcinogenicity in humans.
    2) In rat studies, mitomycin C was found to be neoplastic and carcinogenic by RTECS criteria with tumors at the site of application (gastrointestinal tumors and skin and appendage tumors) (RTECS , 2000).
    3) In mouse studies, it was found to be carcinogenic by RTECS criteria and tumorigenic with tumors at the site of application (RTECS , 2000).
    4) In the NCI Carcinogenesis Studies (IPR) clear evidence for carcinogenicity was found in the rat; no evidence was found in the mouse (RTECS , 2000); however, according to a manufacturer of mitomycin injection, there was a 100% and 50% increased risk tumor incidence in rats and female mice, respectively, at the approximate recommended human dose (Prod Info MITOMYCIN intravenous injection, 2009; Prod Info MITOSOL(R) topical solution powder, 2012).
    5) The following have been reported in experimental animals following exposure to mitomycin: local sarcomas, peritoneal sarcomas, lymphosarcomas, abdominal polymorphic-cell sarcomas, fibrosarcomas, mammary carcinomas or sarcomas, carcinoma and sarcoma of the bladder, reticulum-cell sarcoma of the liver, carcinosarcoma of the esophagus, salivary gland sarcoma, hemangiosarcoma of the paw, squamous carcinomas of the lung, pheochromocytoma, adenocarcinoma of pyloric mucosa, and abdominal hemangioendothelioma (Ikegami et al, 1967; HSDB , 2000).

Genotoxicity

    A) DNA damage and synthesis, mutations and chromosome aberrations have been observed.

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) DISORDER OF RESPIRATORY SYSTEM
    1) WITH THERAPEUTIC USE
    a) SUMMARY: Mitomycin has the potential to cause pneumonitis, alveolitis, and pulmonary fibrosis during therapeutic use (HSDB , 2000).
    b) INCIDENCE: Approximately 1% to 1.5% of patients receiving mitomycin may develop pulmonary toxicity, which includes hemoptysis, dyspnea, cough, and pneumonia.
    c) CASE REPORT: Several patients have developed interstitial pneumonia thought to be secondary to mitomycin. Signs/symptoms on presentation were cough, dyspnea, and occasionally fever. Reticular infiltrates were noted on chest x-ray. Alveolitis and pulmonary fibrosis have also been reported (Dorr & Fritz, 1980; Tannir et al, 1984; HSDB , 2000).
    d) CASE REPORT: It is not clear whether the incidence of mitomycin C pulmonary toxicity is increased with the concomitant use of metronidazole; an additive or synergistic toxicity has been suggested with the concomitant use of mitomycin C and chlorozotocin (Goedert et al, 1983; Chang et al, 1986).
    e) CASE REPORT: Pulmonary toxicity has been reported in patients receiving combinations of mitomycin C and vincristine, cisplatin, metronidazole, and chlorozotocin. A dramatic response was noted in patients who received glucocorticoids; however, stopping or early withdrawal resulted in aggravation of dyspnea and pulmonary infiltrate (Goedert et al, 1983; Chang et al, 1986; Stewart et al, 1987).
    f) CASE SERIES: One study described 14 patients enrolled in several clinical trials who developed pulmonary toxicity following mitomycin. Pulmonary toxicity developed after a median of four cycles of mitomycin (range 2 to 5), with a median cumulative dose of 29 mg/m(2). Symptoms initially improved with corticosteroids in all patients, but 40% of patients had progressive respiratory insufficiency despite high-dose corticosteroid therapy. The authors observed that patients with limited initial pulmonary function may develop persistent toxicity which can lead to respiratory failure and death (Okuno & Frytak, 1997).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs, serum electrolytes, renal function, and liver enzymes.
    B) Monitor serial CBC (with differential) and platelet count until there is evidence of bone marrow recovery. Myelosuppression has been reported. Leukopenia and thrombocytopenia may occur anytime within 8 weeks after onset of therapy with an average time of 4 weeks. Recovery after cessation of therapy was within 10 weeks. About 25% of leukopenia or thrombocytopenic episodes did not recover.
    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.
    D) Clinically evaluate patients for the development of mucositis.
    E) Monitor injection site for signs of extravasation.
    F) Monitor patients closely for the development of hemolytic uremic syndrome.
    4.1.2) SERUM/BLOOD
    A) HEMATOLOGIC
    1) Myelosuppression has been reported. Leukopenia and thrombocytopenia may occur anytime within 8 weeks after onset of therapy with an average time of 4 weeks. Recovery after cessation of therapy was within 10 weeks. About 25% of leukopenia or thrombocytopenic episodes did not recover (Prod Info MITOMYCIN intravenous injection, 2009).
    4.1.3) URINE
    A) URINALYSIS
    1) Monitoring urinalysis for the development of hematuria and proteinuria may provide an early clue to the presence of hemolytic-uremic syndrome (Willis et al, 1983).

Radiographic Studies

    A) CHEST RADIOGRAPH
    1) Obtain a Chest x-ray if pulmonary symptoms occur.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Any symptomatic patient should be admitted to the hospital, and depending on the severity of their symptoms, either to the floor or ICU. Criteria for discharge should be resolution of symptoms and laboratory abnormalities.
    6.3.1.2) HOME CRITERIA/ORAL
    A) There is no data to support home management. All overdoses should be evaluated in a healthcare facility.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with an overdose. Consult a nephrologist if hemolytic uremic syndrome develops.
    6.3.1.4) PATIENT TRANSFER/ORAL
    A) Patients with large overdoses or severe myelosuppression may benefit from early transfer to a cancer treatment or bone marrow transplant center.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Exposed patients should be evaluated and observed for 6 hours. If patients are asymptomatic for 6 hours, they may be sent home, but toxic effects may be delayed, so patients should return to a healthcare provider for any symptoms and should have blood work monitored as an outpatient (eg, CBC for myelosuppression).

Monitoring

    A) Monitor vital signs, serum electrolytes, renal function, and liver enzymes.
    B) Monitor serial CBC (with differential) and platelet count until there is evidence of bone marrow recovery. Myelosuppression has been reported. Leukopenia and thrombocytopenia may occur anytime within 8 weeks after onset of therapy with an average time of 4 weeks. Recovery after cessation of therapy was within 10 weeks. About 25% of leukopenia or thrombocytopenic episodes did not recover.
    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.
    D) Clinically evaluate patients for the development of mucositis.
    E) Monitor injection site for signs of extravasation.
    F) Monitor patients closely for the development of hemolytic uremic syndrome.

Oral Exposure

    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) Monitor vital signs, serum electrolytes, renal function, and liver enzymes in symptomatic patients.
    2) Monitor serial CBC (with differential) and platelet count until there is evidence of bone marrow recovery. Myelosuppression has been reported. Leukopenia and thrombocytopenia may occur anytime within 8 weeks after onset of therapy with an average time of 4 weeks. Recovery after cessation of therapy was within 10 weeks. About 25% of leukopenia or thrombocytopenic episodes did not recover.
    3) 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.
    4) Clinically evaluate patients for the development of mucositis.
    5) Monitor injection site for signs of extravasation.
    6) Monitor patients closely for the development of hemolytic uremic syndrome.
    B) MYELOSUPPRESSION
    1) Bone marrow suppression occurred in 605 of 937 patients (64.4%), the most common adverse effect observed during clinical trials (Prod Info MITOMYCIN intravenous injection, 2009).
    2) Leukopenia and thrombocytopenia may occur anytime within 8 weeks after onset of therapy with an average time of 4 weeks. Recovery after cessation of therapy was within 10 weeks. About 25% of leukopenia or thrombocytopenic episodes did not recover (Prod Info MITOMYCIN intravenous injection, 2009).
    3) Colony stimulating factors have been shown to shorten the duration of severe neutropenia in patients receiving cancer chemotherapy (Stull et al, 2005; Hartman et al, 1997).
    4) Patients with severe neutropenia should be in protective isolation. Monitor CBC with differential daily. If fever or infection develops during leukopenic phase, 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.
    C) NEUTROPENIA
    1) COLONY STIMULATING FACTORS
    a) DOSING
    1) FILGRASTIM: The recommended starting dose for adults is 5 mcg/kg/day administered as a single daily subQ injection, by short IV infusion (15 to 30 minutes), or by continuous subQ or IV infusion (Prod Info NEUPOGEN(R) IV, subcutaneous injection, 2010). According to the American Society of Clinical Oncology (ASCO), treatment should be continued until the ANC is at least 2 to 3 x 10(9)/L (Smith et al, 2006).
    2) SARGRAMOSTIM: The recommended dose is 250 mcg/m(2) day administered intravenously over a 4-hour period. Treatment should be continued until the ANC is at least 2 to 3 x 10(9)/L (Smith et al, 2006).
    D) STOMATITIS
    1) 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 (eg, morphine, hydrocodone, oxycodone, fentanyl). 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. Patients who are receiving myelosuppressive therapy may receive 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 (Bensinger et al, 2008).
    2) 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 these patients, palifermin is administered before and after chemotherapy. DOSES: 60 mcg/kg/day IV bolus injection for 3 consecutive days before and 3 consecutive days after myelotoxic therapy for a total of 6 doses. Palifermin should not be given within 24 hours before, during infusion, or within 24 hours after administration of myelotoxic chemotherapy, as this has been shown to increase the severity and duration of mucositis. (Hensley et al, 2009; Prod Info KEPIVANCE(TM) IV injection, 2005). In patients with an mitomycin overdose in whom neutropenia and mucositis would be anticipated, administer palifermin 60 mcg/kg/day IV bolus injection starting 24 hours after the overdose for 3 consecutive days.
    3) Total parenteral nutrition may provide nutritional requirements during the healing phase of drug-induced oral ulceration, mucositis, and esophagitis.
    E) VOMITING
    1) TREATMENT OF BREAKTHROUGH NAUSEA AND VOMITING
    a) Treat patients with high-dose 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); diphenhydramine may be required to prevent dystonic reactions from dopamine antagonists, phenothiazines, and antipsychotics. It may be necessary to treat with multiple concomitant agents, from different drug classes, using alternating schedules or alternating routes. In general, rectal medications should be avoided in patients with neutropenia.
    b) DOPAMINE RECEPTOR ANTAGONISTS: Metoclopramide: Adults: 10 to 40 mg orally or IV and then every 4 or 6 hours, as needed. Dose of 2 mg/kg IV every 2 to 4 hours for 2 to 5 doses may also be given. Monitor for dystonic reactions; add diphenhydramine 25 to 50 mg orally or IV every 4 to 6 hours as needed for dystonic reactions (None Listed, 1999). Children: 0.1 to 0.2 mg/kg IV every 6 hours; MAXIMUM: 10 mg/dose (Dupuis & Nathan, 2003).
    c) PHENOTHIAZINES: Prochlorperazine: Adults: 25 mg suppository as needed every 12 hours or 10 mg orally or IV every 4 or 6 hours as needed; Children (2 yrs or older): 20 to 29 pounds: 2.5 mg orally 1 to 2 times daily (MAX 7.5 mg/day); 30 to 39 pounds: 2.5 mg orally 2 to 3 times daily (MAX 10 mg/day); 40 to 85 pounds: 2.5 mg orally 3 times daily or 5 mg orally twice daily (MAX 15 mg/day) OR 2 yrs or older and greater than 20 pounds: 0.06 mg/pound IM as a single dose (Prod Info COMPAZINE(R) tablets, injection, suppositories, syrup, 2004; Prod Info Compazine(R), 2002). Promethazine: Adults: 12.5 to 25 mg orally or IV every 4 hours; Children (2 yr and older) 12.5 to 25 mg OR 0.5 mg/pound orally every 4 to 6 hours as needed (Prod Info promethazine hcl rectal suppositories, 2007). Chlorpromazine: Children: greater than 6 months of age, 0.55 mg/kg orally every 4 to 6 hours, or IV every 6 to 8 hours; max of 40 mg per dose if age is less than 5 years or weight is less than 22 kg (None Listed, 1999).
    d) SEROTONIN 5-HT3 ANTAGONISTS: Dolasetron: Adults: 100 mg orally daily or 1.8 mg/kg IV or 100 mg IV. Granisetron: Adults: 1 to 2 mg orally daily or 1 mg orally twice daily or 0.01 mg/kg (maximum 1 mg) IV or transdermal patch containing 34.3 mg granisetron. Ondansetron: Adults: 16 mg orally or 8 mg IV daily (Kris et al, 2006; None Listed, 1999); Children (older than 3 years of age): 0.15 mg/kg IV 4 and 8 hours after chemotherapy (None Listed, 1999).
    e) BENZODIAZEPINES: Lorazepam: Adults: 1 to 2 mg orally or IM/IV every 6 hours; Children: 0.05 mg/kg, up to a maximum of 3 mg, orally or IV every 8 to 12 hours as needed (None Listed, 1999).
    f) STEROIDS: Dexamethasone: Adults: 10 to 20 mg orally or IV every 4 to 6 hours; Children: 5 to 10 mg/m(2) orally or IV every 12 hours as needed; methylprednisolone: children: 0.5 to 1 mg/kg orally or IV every 12 hours as needed (None Listed, 1999).
    g) ANTIPSYCHOTICS: Haloperidol: Adults: 1 to 4 mg orally or IM/IV every 6 hours as needed (None Listed, 1999).
    F) EXTRAVASATION INJURY
    1) Mitomycin is a vesicant (Gippsland Oncology Nurses Group, 2010). Cellulitis, ulceration, and tissue sloughing at the injection site may develop if extravasation of mitomycin occurs (Prod Info MITOMYCIN intravenous injection, 2009).
    2) 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 dimethyl sulfoxide (DMSO - see dosing below). Elevate the affected area. Apply ice packs for 15 to 20 minutes at least 4 times daily. Do not apply excessive cold to avoid tissue injury. Cold can cause local vasoconstriction and reduces fluid absorption. 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 (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 (The University of Kansas Hospital, 2009; Gippsland Oncology Nurses Group, 2010; Wengstrom et al, 2008; National Institutes of Health Clinical Center Nursing Department, 1999; Bellin et al, 2002; Cohan et al, 1996; Upton et al, 1979; Brown et al, 1979; Banerjee et al, 1987; Chait & Dinner, 1975; Dorr & Fritz, 1980; Hirsh & Conlon, 1983; Hoff et al, 1979; Ignoffo & Friedman, 1980; Larson, 1982; Loth & Eversmann, 1986; Lynch et al, 1979; Upton et al, 1979a; Yosowitz et al, 1975).
    3) DIMETHYL SULFOXIDE (DMSO): Treat site with topical DMSO (for a minimum of 7 days and maximum of 14 days); however, if blistering develops, discontinue DMSO and review site (Gippsland Oncology Nurses Group, 2010). Another source recommended DMSO 99% solution topically and allow to air dry. Cover with a nonocclusive dressing within 10 to 25 min. Repeat every 8 hours for 1 week (Wengstrom et al, 2008).
    a) A single topical application of 100% dimethyl sulfoxide solution significantly reduced ulceration following intradermal injection of 0.75 milligrams of mitomycin and completely prevented ulceration following intradermal injection of 0.025 mg of mitomycin in an animal model (Dorr et al, 1986).
    4) SODIUM THIOSULFATE: Subcutaneous sodium thiosulfate 2% (sodium hyposulfite) added to therapy with subcutaneous hydrocortisone and topical betamethasone decreased the healing time by half for cytotoxic drug extravasation (including mitomycin) when compared to therapy without sodium thiosulfate (Tsavaris et al, 1992).
    5) PYRIDOXINE: The use of subcutaneous pyridoxine (vitamin B6) may slow or prevent necrosis and decrease pain and tenderness associated with mitomycin extravasation. Effective doses have been 75 to 300 mg injected at the site of extravasation. The volume of injected pyridoxine ideally should be the same as the volume of extravasated mitomycin, if known. Local pain associated with pyridoxine injections has been a limiting factor, however. Pain might be minimized by diluting the pyridoxine injection by one- to three-fold, thus increasing the pH of the solution. It is postulated that the efficacy of pyridoxine is due to its conversion in tissue to pyridoxal and pyridoxal-5-phosphate, thus forming shift-base complexes with the extravasated mitomycin (Rentschler & Wilbur, 1988).
    6) Ineffective antidotes for mitomycin extravasation include hyaluronidase, hydrocortisone, vitamin E, N-acetylcysteine, and diphenhydramine (Dorr, 1994).
    7) CASE REPORTS: Delayed extravasation injury (several days to weeks after therapy) was reported in 2 patients following administration of mitomycin C which included erythema, ulceration, and necrosis at sites where other intravenous preparations had been administered but distant to the mitomycin C injection site (Patel & Krusa, 1999). The wounds healed following topical antibiotic treatment and whirlpool therapy. Significant scarring, however, was reported in one patient.
    G) INTERSTITIAL PNEUMONIA
    1) Patients may respond to corticosteroid therapy.
    H) FUMARIC ACID
    1) Concurrent administration of fumaric acid 40 milligrams/kilogram reduced the incidence of perinuclear irregularity, aggregation of chromatins, and abnormal cytoplasmic organella in liver associated with two intraperitoneal injections of 4 milligrams/kilogram of mitomycin C at an interval of 48 hours in ICR mice (Kuroda et al, 1982).
    2) Conclusion: THIS TREATMENT CANNOT BE RECOMMENDED AT THIS TIME. Additional animal and human studies are required to demonstrate therapeutic efficacy of fumaric acid treatment.
    I) ACUTE ALLERGIC REACTION
    1) SUMMARY
    a) Mild to moderate allergic reactions may be treated with antihistamines with or without inhaled beta adrenergic agonists, corticosteroids or epinephrine. Treatment of severe anaphylaxis also includes oxygen supplementation, aggressive airway management, epinephrine, ECG monitoring, and IV fluids.
    2) BRONCHOSPASM
    a) ALBUTEROL
    1) ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007). CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 mg/kg (up to 10 mg) every 1 to 4 hours as needed, or 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    3) CORTICOSTEROIDS
    a) Consider systemic corticosteroids in patients with significant bronchospasm.
    b) PREDNISONE: ADULT: 40 to 80 milligrams/day. CHILD: 1 to 2 milligrams/kilogram/day (maximum 60 mg) in 1 to 2 divided doses divided twice daily (National Heart,Lung,and Blood Institute, 2007).
    4) MILD CASES
    a) DIPHENHYDRAMINE
    1) SUMMARY: Oral diphenhydramine, as well as other H1 antihistamines can be used as indicated (Lieberman et al, 2010).
    2) ADULT: 50 milligrams orally, or 10 to 50 mg intravenously at a rate not to exceed 25 mg/min or may be given by deep intramuscular injection. A total of 100 mg may be administered if needed. Maximum daily dosage is 400 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    3) CHILD: 5 mg/kg/24 hours or 150 mg/m(2)/24 hours. Divided into 4 doses, administered intravenously at a rate not exceeding 25 mg/min or by deep intramuscular injection. Maximum daily dosage is 300 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    5) MODERATE CASES
    a) EPINEPHRINE: INJECTABLE SOLUTION: It should be administered early in patients by IM injection. Using a 1:1000 (1 mg/mL) solution of epinephrine. Initial Dose: 0.01 mg/kg intramuscularly with a maximum dose of 0.5 mg in adults and 0.3 mg in children. The dose may be repeated every 5 to 15 minutes, if no clinical improvement. Most patients respond to 1 or 2 doses (Nowak & Macias, 2014).
    6) SEVERE CASES
    a) EPINEPHRINE
    1) INTRAVENOUS BOLUS: ADULT: 1 mg intravenously as a 1:10,000 (0.1 mg/mL) solution; CHILD: 0.01 mL/kg intravenously to a maximum single dose of 1 mg given as a 1:10,000 (0.1 mg/mL) solution. It can be repeated every 3 to 5 minutes as needed. The dose can also be given by the intraosseous route if IV access cannot be established (Lieberman et al, 2015). ALTERNATIVE ROUTE: ENDOTRACHEAL ADMINISTRATION: If IV/IO access is unavailable. DOSE: ADULT: Administer 2 to 2.5 mg of 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube. CHILD: DOSE: 0.1 mg/kg to a maximum of 2.5 mg administered as a 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube (Lieberman et al, 2015).
    2) INTRAVENOUS INFUSION: Intravenous administration may be considered in patients poorly responsive to IM or SubQ epinephrine. An epinephrine infusion may be prepared by adding 1 mg (1 mL of 1:1000 (1 mg/mL) solution) to 250 mL D5W, yielding a concentration of 4 mcg/mL, and infuse this solution IV at a rate of 1 mcg/min to 10 mcg/min (maximum rate). CHILD: A dosage of 0.01 mg/kg (0.1 mL/kg of a 1:10,000 (0.1 mg/mL) solution up to 10 mcg/min (maximum dose 0.3 mg) is recommended for children (Lieberman et al, 2010). Careful titration of a continuous infusion of IV epinephrine, based on the severity of the reaction, along with a crystalloid infusion can be considered in the treatment of anaphylactic shock. It appears to be a reasonable alternative to IV boluses, if the patient is not in cardiac arrest (Vanden Hoek,TL,et al).
    7) AIRWAY MANAGEMENT
    a) OXYGEN: 5 to 10 liters/minute via high flow mask.
    b) INTUBATION: Perform early if any stridor or signs of airway obstruction.
    c) CRICOTHYROTOMY: Use if unable to intubate with complete airway obstruction (Vanden Hoek,TL,et al).
    d) BRONCHODILATORS are recommended for mild to severe bronchospasm.
    e) ALBUTEROL: ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007).
    f) ALBUTEROL: CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 milligram/kilogram (maximum 10 milligrams) every 1 to 4 hours as needed OR administer 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    8) MONITORING
    a) CARDIAC MONITOR: All complicated cases.
    b) IV ACCESS: Routine in all complicated cases.
    9) HYPOTENSION
    a) If hypotensive give 500 to 2000 milliliters crystalloid initially (20 milliliters/kilogram in children) and titrate to desired effect (stabilization of vital signs, mentation, urine output); adults may require up to 6 to 10 L/24 hours. Central venous or pulmonary artery pressure monitoring is recommended in patients with persistent hypotension.
    1) VASOPRESSORS: Should be used in refractory cases unresponsive to repeated doses of epinephrine and after vigorous intravenous crystalloid rehydration (Lieberman et al, 2010).
    2) DOPAMINE: Initial Dose: 2 to 20 micrograms/kilogram/minute intravenously; titrate to maintain systolic blood pressure greater than 90 mm Hg (Lieberman et al, 2010).
    10) H1 and H2 ANTIHISTAMINES
    a) SUMMARY: Antihistamines are second-line therapy and are used as supportive therapy and should not be used in place of epinephrine (Lieberman et al, 2010).
    1) DIPHENHYDRAMINE: ADULT: 25 to 50 milligrams via a slow intravenous infusion or IM. PEDIATRIC: 1 milligram/kilogram via slow intravenous infusion or IM up to 50 mg in children (Lieberman et al, 2010).
    b) RANITIDINE: ADULT: 1 mg/kg parenterally; CHILD: 12.5 to 50 mg parenterally. If the intravenous route is used, ranitidine should be infused over 10 to 15 minutes or diluted in 5% dextrose to a volume of 20 mL and injected over 5 minutes (Lieberman et al, 2010).
    c) Oral diphenhydramine, as well as other H1 antihistamines, can also be used as indicated (Lieberman et al, 2010).
    11) DYSRHYTHMIAS
    a) Dysrhythmias and cardiac dysfunction may occur primarily or iatrogenically as a result of pharmacologic treatment (epinephrine) (Vanden Hoek,TL,et al). Monitor and correct serum electrolytes, oxygenation and tissue perfusion. Treat with antiarrhythmic agents as indicated.
    12) OTHER THERAPIES
    a) There have been a few reports of patients with anaphylaxis, with or without cardiac arrest, that have responded to vasopressin therapy that did not respond to standard therapy. Although there are no randomized controlled trials, other alternative vasoactive therapies (ie, vasopressin, norepinephrine, methoxamine, and metaraminol) may be considered in patients in cardiac arrest secondary to anaphylaxis that do not respond to epinephrine (Vanden Hoek,TL,et al).
    J) INTRATHECAL INJECTION
    1) There are no published reports of therapy for intrathecal mitomycin C overdose. The following recommendations are based on experience with other antineoplastic drugs.
    2) POSITIONING - Keep the patient upright if possible to delay flow of drug to the cisterna magnum (Blaney et al, 1995).
    3) CEREBROSPINAL FLUID DRAINAGE - Immediately remove at least 20 mL of CSF through a lumbar catheter. The optimal amount of CSF to remove is unknown. Adults have tolerated removal of 10 to 70 mL CSF after intrathecal methotrexate overdose(Gosselin & Isbister, 2005; Addiego et al, 1981).
    4) CSF EXCHANGE - Serial removal of 20 milliliter portions of CSF and replacement with corresponding volumes of warmed preservative-free normal saline or lactated ringers should be performed after CSF removal, while preparations for ventriculolumbar perfusion are being made.
    5) VENTRICULOLUMBAR PERFUSION - For large overdoses or neurotoxic agents, consider ventriculolumbar perfusion. Consult a neurosurgeon for placement of a ventricular catheter. Infuse warmed, preservative-free normal saline or lactated ringers through the ventricular catheter and drain fluid from the lumbar catheter. Typical volumes in case reports have been in the range of 80 to 150 mL/hr for 18 to 24 hours(O'Marcaigh et al, 1996; Meggs & Hoffman, 1998). Ventriculolumbar perfusion is likely to be more effective at removing drug from the CSF than simple CSF exchange (Addiego et al, 1981).
    6) STEROIDS - Steroids are usually administered to prevent arachnoiditis. A typical regimen is dexamethasone 4 milligrams every 6 hours (Widemann et al, 2004).

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) 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) It is unknown if hemodialysis would be effective.

Abstracts

Case Reports

    A) ADULT
    1) Only one case of overdose has been reported to the manufacturer. The patient received 70 mg mitomycin and recovered with good supportive care only (Personal Communication, 1988).

Range Of Toxicity

Summary

    A) TOXICITY: An adult received 70 mg and recovered with supportive care. Increased toxicity without enhanced efficacy has been reported with total doses greater than 20 mg/m(2)/day. Renal toxicity increases above cumulative dose of 120 mg. Reports of pulmonary toxicity have occurred at total dosages as low as 40 mg, but the average cumulative toxic dose resulting in pulmonary toxicity is 78 mg.
    B) THERAPEUTIC DOSES: ADULTS: INTRAVENOUS: 20 mg/m(2)/dose IV every 6 to 8 weeks. OPHTHALMIC: Saturated sponges with entire vial of 0.2 mg/mL reconstituted mitomycin solution is applied topically in a single layer to treatment area and left on for 2 minutes. CHILDREN: The safety and efficacy of mitomycin have not been established in pediatric patients. A phase II study was designed to reevaluate mitomycin in children using the dose considered to be optimal based upon adult data (20 mg/m(2)) at 6 to 8 week intervals. Toxicity was tolerable in the 9 evaluable patients with refractory solid tumors.

Therapeutic Dose

    7.2.1) ADULT
    A) INTRAVENOUS: 20 mg/m(2)/dose IV every 6 to 8 weeks (Prod Info MITOMYCIN intravenous injection, 2009)
    B) OPHTHALMIC: Mitomycin (Mitosol(R)) is available as vials containing 0.2 mg mitomycin and 0.4 mg mannitol; the solution contains 0.2 mg/mL mitomycin when reconstituted with sterile water for injection. Saturated sponges with entire vial of 0.2 mg/mL reconstituted mitomycin solution is applied topically in a single layer to treatment area and left on for 2 minutes (Prod Info MITOSOL(R) topical solution powder, 2012)
    7.2.2) PEDIATRIC
    A) The safety and efficacy of mitomycin have not been established in pediatric patients. (Prod Info MITOSOL(R) topical solution powder, 2012; Prod Info MITOMYCIN intravenous injection, 2009).
    B) A phase II study was designed to reevaluate mitomycin in children using the dose considered to be optimal based upon adult data (20 mg/m(2)) at 6 to 8 week intervals. Toxicity was tolerable in the 9 evaluable patients with refractory solid tumors (Gutierrez et al, 1981).
    C) For all doses of mitomycin in children over the age of 12, the Department of Pharmacy at M.D. Anderson Hospital and Tumor Institute administers the drug in 50 mL of normal saline over 15 minutes (p 4).

Minimum Lethal Exposure

    A) Minimum lethal exposure has not been established.
    B) CASE REPORTS
    1) ADULTS: A 57-year-old woman with cancer of the cervix received 5 courses of mitomycin C (15 milligrams/square meter at 3 weekly intervals) and 3 weeks after the last course developed acute congestive heart failure and died (Sivanesaratnam & Jayalakshmi, 1989).

Maximum Tolerated Exposure

    A) GENERAL/SUMMARY
    1) Increased toxicity without enhanced efficacy has been reported with total doses greater than 20 mg/m(2)/day (Dorr & Fritz, 1980).
    2) Reports of pulmonary toxicity have occurred at total dosages as low as 40 mg, but the average cumulative dose resulting in pulmonary toxicity is 78 mg (JEF Reynolds , 2000).
    3) When the total cumulative mitomycin dose exceeds 120 mg, the incidence of renal toxicity significantly increases (JEF Reynolds , 2000).
    B) CASE REPORT
    1) Only one case of overdose has been reported to the manufacturer. The patient received 70 mg mitomycin and recovered with good supportive care only (Personal Communication, 1988).

Workplace Standards

    A) ACGIH TLV Values for CAS50-07-7 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS50-07-7 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS50-07-7 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): 2B ; Listed as: Mitomycin C
    a) 2B : The agent (mixture) is possibly carcinogenic to humans. The exposure circumstance entails exposures that are possibly carcinogenic to humans. This category is used for agents, mixtures and exposure circumstances for which there is limited evidence of carcinogenicity in humans and less than sufficient evidence of carcinogenicity in experimental animals. It may also be used when there is inadequate evidence of carcinogenicity in humans but there is sufficient evidence of carcinogenicity in experimental animals. In some instances, an agent, mixture or exposure circumstance for which there is inadequate evidence of carcinogenicity in humans but limited evidence of carcinogenicity in experimental animals together with supporting evidence from other relevant data may be placed in this group.
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS50-07-7 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (INTRAPERITONEAL)MOUSE:
    1) 4 mg/kg ((RTECS, 2000))
    B) LD50- (ORAL)MOUSE:
    1) 23 mg/kg ((RTECS, 2000))
    C) LD50- (SUBCUTANEOUS)MOUSE:
    1) 7300 mcg/kg ((RTECS, 2000))
    D) LD50- (INTRAPERITONEAL)RAT:
    1) 2 mg/kg ((RTECS, 2000))
    E) LD50- (ORAL)RAT:
    1) 30 mg/kg ((RTECS, 2000))
    F) LD50- (SUBCUTANEOUS)RAT:
    1) 3250 mcg/kg ((RTECS, 2000))

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Mitomycin solution, isolated from Streptomyces verticillus Yingtangensis, and mitomycin injection, isolated from Streptomyces caespitosus is an antibiotic with antimetabolite activity. Mitomycin causes cross-linking of DNA and inhibits DNA synthesis and to a lesser extent also inhibits RNA and protein synthesis (Prod Info MITOSOL(R) topical solution powder, 2012; Prod Info MITOMYCIN intravenous injection, 2009).

Toxicologic Mechanism

    A) Mitomycin is not cell cycle-phase specific. However, cell kinetic effects are maximized if cells are treated in late G1 or early S phase.
    1) Mitomycin is a bifunctional or possibly a trifunctional alkylating agent, following activation, that cross-links DNA.
    2) DNA synthesis inhibition is the result of DNA cross-linking. Degree of induced cross-linking is related to cytosine and guanine content (Dorr & Fritz, 1980; Prod Info MITOMYCIN intravenous injection, 2009).
    B) Mitomycin causes chromosomal aberrations and is a potent teratogen and carcinogen (Dorr & Fritz, 1980). Cellular RNA and protein synthesis are also suppressed at high drug concentrations(Prod Info MITOMYCIN intravenous injection, 2009).
    C) Mitomycin is reported to be less immunosuppressive than most other alkylating agents (Dorr & Fritz, 1980).

Physicochemical

Physical Characteristics

    A) Mitomycin is a blue-violet crystalline powder (Prod Info MITOMYCIN intravenous injection, 2009; Prod Info MITOSOL(R) topical solution powder, 2012) which is soluble in acetone, butyl acetate, cyclohexanone, and methyl alcohol (JEF Reynolds , 2000); slightly soluble in benzene, carbon tetrachloride, ether (Windholz et al, 1983), and water (JEF Reynolds , 2000); and practically insoluble in petroleum ether (Windholz et al, 1983).

Ph

    A) 6 to 8 (reconstituted injection solution) (Prod Info MITOMYCIN intravenous injection, 2009); 5 to 8 (reconstituted topical solution) (Prod Info MITOSOL(R) topical solution powder, 2012)

Molecular Weight

    A) 334.33 (Prod Info MITOSOL(R) topical solution powder, 2012; Prod Info MITOMYCIN intravenous injection, 2009)

References

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