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HYDROXYUREA

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Hydroxyurea is an antineoplastic agent. The precise mechanism of action is not completely understood; however, it is hypothesized that hydroxyurea inhibits DNA synthesis without interfering with the synthesis of RNA or proteins.

Specific Substances

    1) Hydroxycarbamide
    2) NSC-32065
    3) SQ-1089
    4) WR-83799
    5) CAS 127-07-1
    1.2.1) MOLECULAR FORMULA
    1) CH4N2O2

Available Forms Sources

    A) FORMS
    1) Hydroxyurea is available as 200 mg, 300 mg, 400 mg, and 500 mg capsules (Prod Info HYDREA(R) oral capsules, 2012; Prod Info DROXIA(R) oral capsules, 2012).
    B) USES
    1) Hydroxyurea is an antineoplastic agent used to treat melanoma, resistant chronic myelocytic leukemia, recurrent, metastatic, or inoperable carcinoma of the ovary, and primary squamous cell carcinomas of the head and neck (Prod Info HYDREA(R) oral capsules, 2012).
    2) Hydroxyurea is also used to decrease the frequency of painful crises and to decrease the need for blood transfusions in patients with sickle cell anemia with recurrent moderate to severe painful crisis (Prod Info DROXIA(R) oral capsules, 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: Hydroxyurea is an antineoplastic agent used to treat melanoma, resistant chronic myelocytic leukemia, recurrent, metastatic, or inoperable carcinoma of the ovary, and primary squamous cell carcinomas of the head and neck. Hydroxyurea is also used to decrease the frequency of painful crises and to decrease the need for blood transfusions in patients with sickle cell anemia with recurrent moderate to severe painful crisis.
    B) PHARMACOLOGY: Hydroxyurea is classified as an antimetabolite. It is thought to be cell cycle–specific for the S phase of cell division. The exact mechanism of antineoplastic activity is unknown but is thought to involve interference with synthesis of DNA, with no effect on synthesis of RNA or protein.
    C) TOXICOLOGY: Hydroxyurea inhibits DNA synthesis, thus resulting in its major toxicity of myelosuppression. Inhibition of DNA synthesis with no modification of RNA synthesis may result in red blood cells becoming megaloblastic.
    D) EPIDEMIOLOGY: Overdose is rare.
    E) WITH THERAPEUTIC USE
    1) COMMON: Myelosuppression (leukopenia, anemia, thrombocytopenia). Recovery has usually been observed within 2 weeks. OTHER EFFECTS: Nausea, vomiting, diarrhea, constipation, rash, skin ulceration, mucositis, and melanonychia. RARE EFFECTS: Drowsiness, dizziness, disorientation, hallucinations, seizures, headache, fever, malaise, edema, elevated liver enzymes, dyspnea, pulmonary fibrosis, pulmonary infiltrates, and reversible renal toxicity. Severe and sometimes fatal hepatitis have been associated with hydroxyurea therapy.
    F) WITH POISONING/EXPOSURE
    1) Overdose data are limited. Acute mucocutaneous toxicity, soreness, violet erythema, edema on palms and soles, scaling of hands and feet, severe generalized hyperpigmentation of the skin, and stomatitis have been reported in patients receiving hydroxyurea doses several times the therapeutic dose. A child developed only mild myelosuppression after ingesting an entire 35-day supply of hydroxyurea. A woman developed agitation, widespread myoclonic jerks, oculogyric crisis, sinus tachycardia, and myelosuppression after ingesting 60 grams of hydroxyurea.
    0.2.20) REPRODUCTIVE
    A) Hydroxyurea can cause fetal harm if used during pregnancy. Advise women to avoid pregnancy during hydroxyurea administration. If pregnancy occurs, apprise patients of the potential hazard to the fetus. It crosses the placenta in animals, is excreted into human breast milk, and is embryotoxic. Advise women to avoid breastfeeding during hydroxyurea therapy.
    0.2.21) CARCINOGENICITY
    A) Leukemogenic effects of hydroxyurea have been described in case reports. Skin carcinoma has been described following hydroxyurea therapy.
    B) Hydroxyurea is mutagenic and clastogenic.

Laboratory Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    C) Monitor CBC with differential and platelet count for several weeks after overdose, as nadir counts may be delayed. Recovery has usually been observed within 2 weeks.
    D) 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.
    E) Monitor renal function and liver enzymes in symptomatic patients.
    F) Monitor arterial blood gases, pulse oximetry, and pulmonary function tests, and obtain a chest x-ray in any patient with respiratory symptoms.

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 and IV fluids as needed.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Significant toxicity is not expected after hydroxyurea overdose. Administer colony stimulating factors (filgrastim or sargramostim) to patients with severe neutropenia. Monitor CBC with differential and platelet count. 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. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur.
    C) DECONTAMINATION
    1) PREHOSPITAL: Prehospital gastrointestinal decontamination is generally not recommended.
    2) HOSPITAL: Administer activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with severe respiratory symptoms.
    E) ANTIDOTE
    1) None.
    F) MYELOSUPPRESSION
    1) 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. 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.
    G) NEUTROPENIA
    1) Prophylactic therapy with a fluoroquinolone should be considered in high risk patients with expected prolonged (more than 7 days), and profound neutropenia (ANC 100 cells/mm(3) or less).
    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) 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. It has not been studied in the setting of chemotherapy overdose. In patients with a hydroxyurea overdose, administer palifermin 60 mcg/kg/day IV bolus injection starting 24 hours after the overdose for 3 consecutive days.
    J) HYPERTHERMIA
    1) Hyperthermia should be managed with antipyretics, cold compresses and/or cooling blankets.
    K) ENHANCED ELIMINATION
    1) Hemodialysis would not be likely to be of significant benefit in hydroxyurea overdoses due to its high protein binding.
    L) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic, need to be monitored for several hours to assess electrolyte and fluid balance. Patients that remain asymptomatic can be discharged.
    3) ADMISSION CRITERIA: Patients should be admitted for severe vomiting, profuse diarrhea, severe abdominal pain, dehydration, and electrolyte abnormalities. Patients with myelosuppression should be closely monitored in an inpatient setting, with daily monitoring of CBC with differential until bone marrow suppression is resolved.
    4) CONSULT CRITERIA: Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    5) TRANSFER CRITERIA: Patients with severe neutropenia may benefit from early transfer to a cancer treatment or bone marrow transplant center.
    M) PITFALLS
    1) Symptoms of overdose are likely similar to reported side effects of hydroxyurea. Early symptoms of overdose may be delayed or not evident (ie, myelosuppression), so reliable follow-up is imperative. Patients taking hydroxyurea may have severe co-morbidities and may be receiving other drugs that may produce synergistic effects (ie, myelosuppression).
    N) PHARMACOKINETICS
    1) Bioavailability: Oral, immediate release: 108%; only 79% oral bioavailability reported in cancer patients. Tmax: 1 to 4 hours. Protein binding: 75% to 80%. Vd: 20 liters/m(2) or 0.48 to 1.62 L/kg. Extensive metabolism is reported to occur in the liver, with excretion in the urine as urea and unchanged drug. Renal excretion: 36% to 62%. Elimination half-life: 2 to 4.5 hours.
    O) DIFFERENTIAL DIAGNOSIS
    1) Clinical events (eg, myelosupression) may be related to other chemotherapeutic agents that may be used in combination with hydroxyurea therapy.

Range Of Toxicity

    A) TOXICITY: ADULTS: Myelosuppression appears to be the dose-limiting toxicity of hydroxyurea and develops at 800 mg/m(2) in adults. A woman developed agitation, widespread myoclonic jerks, oculogyric crisis, sinus tachycardia, and myelosuppression after ingesting 60 grams of hydroxyurea. She recovered following supportive care. CHILDREN: A 2-year-old girl developed only mild myelosuppression after ingesting an entire 35-day supply of hydoxyurea (total dose, 612 mg/kg or 15.4 g/m(2)). She recovered gradually by day 7.
    B) THERAPEUTIC DOSES: ADULTS: Initial: 15 mg/kg as a single daily dose. Maintenance: Increase the daily dose by 5 mg/kg every 12 weeks. MAX dose, 35 mg/kg/day. CHILDREN: The safety and efficacy of hydroxyurea in children for any indication have not been established. SICKLE CELL DISEASE: In studies, doses of 9 to 30 mg/kg/day for 4 days per week have been used in children with sickle cell anemia.

Clinical Effects

Summary Of Exposure

    A) USES: Hydroxyurea is an antineoplastic agent used to treat melanoma, resistant chronic myelocytic leukemia, recurrent, metastatic, or inoperable carcinoma of the ovary, and primary squamous cell carcinomas of the head and neck. Hydroxyurea is also used to decrease the frequency of painful crises and to decrease the need for blood transfusions in patients with sickle cell anemia with recurrent moderate to severe painful crisis.
    B) PHARMACOLOGY: Hydroxyurea is classified as an antimetabolite. It is thought to be cell cycle–specific for the S phase of cell division. The exact mechanism of antineoplastic activity is unknown but is thought to involve interference with synthesis of DNA, with no effect on synthesis of RNA or protein.
    C) TOXICOLOGY: Hydroxyurea inhibits DNA synthesis, thus resulting in its major toxicity of myelosuppression. Inhibition of DNA synthesis with no modification of RNA synthesis may result in red blood cells becoming megaloblastic.
    D) EPIDEMIOLOGY: Overdose is rare.
    E) WITH THERAPEUTIC USE
    1) COMMON: Myelosuppression (leukopenia, anemia, thrombocytopenia). Recovery has usually been observed within 2 weeks. OTHER EFFECTS: Nausea, vomiting, diarrhea, constipation, rash, skin ulceration, mucositis, and melanonychia. RARE EFFECTS: Drowsiness, dizziness, disorientation, hallucinations, seizures, headache, fever, malaise, edema, elevated liver enzymes, dyspnea, pulmonary fibrosis, pulmonary infiltrates, and reversible renal toxicity. Severe and sometimes fatal hepatitis have been associated with hydroxyurea therapy.
    F) WITH POISONING/EXPOSURE
    1) Overdose data are limited. Acute mucocutaneous toxicity, soreness, violet erythema, edema on palms and soles, scaling of hands and feet, severe generalized hyperpigmentation of the skin, and stomatitis have been reported in patients receiving hydroxyurea doses several times the therapeutic dose. A child developed only mild myelosuppression after ingesting an entire 35-day supply of hydroxyurea. A woman developed agitation, widespread myoclonic jerks, oculogyric crisis, sinus tachycardia, and myelosuppression after ingesting 60 grams of hydroxyurea.

Vital Signs

    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) Fever is a rare adverse effect (less than 0.1%) of hydroxyurea therapy, perhaps under-recognized. Fourteen reports of suspected hydroxyurea-induced fever are on file with the Australian Adverse Drug Reactions Advisory Committee between 1977 and 1998 (Grace et al, 1998). Drug fever due to hydroxyurea is seen on drug re-challenge and is thought to be due to a hypersensitivity reaction (Cheung et al, 1999; van der Klooster et al, 1997).
    2) Hydroxyurea-induced fever occurred in a 63-year-old man with a 30-year history of bronchial asthma. The patient received hydroxyurea 1 gram for thrombocytosis, and developed fever 12 hours later (39 degrees Celsius); temperature returned to normal within 30 hours. Re-challenge both one week and one year later produced similar results. A review of the literature revealed only 2 other unequivocal cases of hydroxyurea-induced fever (Lossos & Matzner, 1995).
    3) Onset of fever progressively shortened from 18 days, to 3 days, to within hours in one patient re-challenged on 2 separate occasions after the initial reaction (Grace et al, 1998).
    4) A case of drug fever was substantiated by re-challenge in a 56-year-old woman receiving hydroxyurea for psoriasis (Bauman et al, 1981).

Heent

    3.4.3) EYES
    A) WITH POISONING/EXPOSURE
    1) OCULOGYRIC CRISIS: A woman developed agitation, widespread myoclonic jerks, oculogyric crisis, sinus tachycardia, and myelosuppression after ingesting 60 grams of hydroxyurea (Litt et al, 2013).
    3.4.6) THROAT
    A) WITH THERAPEUTIC USE
    1) Persistent oral ulceration has been reported as an adverse effect of hydroxyurea therapy in patients with hematological abnormalities. Onset of ulceration does not appear to be related to dose or duration of therapy (Paleri & Lindsey, 2000). Stomatitis has been reported in patients receiving several times the therapeutic dose (Prod Info Mylocel(TM), hydroxyurea tablets, 2001).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) TACHYCARDIA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A woman developed agitation, widespread myoclonic jerks, oculogyric crisis, sinus tachycardia, and myelosuppression after ingesting 60 grams of hydroxyurea (Litt et al, 2013).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) PNEUMONITIS
    1) WITH THERAPEUTIC USE
    a) Acute pulmonary reactions (diffuse pulmonary infiltrates, fever, dyspnea, pulmonary fibrosis) are reported only rarely (Prod Info DROXIA(R) oral capsules, 2012; Prod Info HYDREA(R) oral capsules, 2012). Grace et al (1998) reported pyrexia, cough and dyspnea in a patient 3 weeks after starting hydroxyurea 500 mg three times daily and allopurinol 300 mg/day. The symptoms cleared on drug discontinuation, but recurred when re-challenged with hydroxyurea (Grace et al, 1998).
    B) FIBROSIS OF LUNG
    1) WITH THERAPEUTIC USE
    a) Acute interstitial lung disease was reported in a 78-year-old woman receiving hydroxyurea. The patient had received hydroxyurea 500 mg every third day, initially, and then 500 mg daily. Upon discontinuation of hydroxyurea and supportive therapy, the patient had dramatic improvement in symptoms and chest X-ray at 4-week follow-up (Kavuru et al, 1994).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH THERAPEUTIC USE
    a) Drowsiness, dizziness, disorientation, hallucinations, seizures, and headaches have rarely occurred with therapeutic hydroxyurea administration (Prod Info HYDREA(R) oral capsules, 2012; JEF Reynolds , 2000).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 50-year-old woman who was taking hydroxycarbamide (hydroxyurea) for essential thrombocythemia, presented with mild agitation, widespread myoclonic jerks, and global hyperreflexia after ingesting about 60 grams of hydroxycarbamide (hydroxyurea) with alcohol. On presentation, she had a Glasgow Coma Score (GCS) of 10/15. At this time, all laboratory results were normal. An ECG revealed sinus tachycardia. Her GCS decreased to 5/15 over the next 12 hours and she developed oculogyric crisis, which was treated with procyclidine. On day 5, her CBC parameters started to decrease. On day 8, her neutrophils reached a nadir of below detectable limits, despite treatment with granulocyte colony stimulating factor (G-CSF; filgrastim, 300 mcg once daily) starting on day 7. Other laboratory results included the platelet count of 74 x 10(9)/L and hemoglobin concentration of 93 g/L. Examination of blood films revealed macrocytosis and neutropenia. Following supportive care, including prophylactic antibacterial for neutropenia, both her laboratory results and neurological symptoms gradually resolved (Litt et al, 2013).
    B) NEUROPATHY
    1) WITH THERAPEUTIC USE
    a) The risk of neuropathy in HIV-infected patients is increased when hydroxyurea is added to a treatment regimen consisting of nucleoside reverse transcriptase inhibitors. The crude incidence rates for neuropathy are estimated as 6.8 cases per 100 person-years for didanosine alone, 17.5 cases per 100 person-years for didanosine-stavudine, and 28.6 cases per 100 person-years for the combination of didanosine-stavudine-hydroxyurea (Moore et al, 2000).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea, vomiting, diarrhea, constipation, and anorexia have occurred with hydroxyurea (Prod Info HYDREA(R) oral capsules, 2012; Prod Info DROXIA(R) oral capsules, 2012). Unless in the setting of concomitant radiation therapy, nausea and vomiting are usually mild, occurring in approximately 25% of patients. Grace et al (1998) reported vomiting and some diarrhea within 3 weeks of starting hydroxyurea in an adult, which abated on drug withdrawal (Grace et al, 1998).
    B) STOMATITIS
    1) WITH THERAPEUTIC USE
    a) Irritation of mucous membranes has occurred with hydroxyurea, usually with concomitant radiation; topical anesthetics and orally administered analgesics may be helpful in controlling associated pain from mucositis. Although rarely necessary, hydroxyurea or irradiation may be temporarily postponed to control severe mucositis (Prod Info HYDREA(R) oral capsules, 2012; JEF Reynolds , 2000). Aphthous ulcers were rare (3 cases among over 200 elderly patients) during low-dose hydroxyurea maintenance treatment for polycythemia vera (Najean & Rain, 1997).
    2) WITH POISONING/EXPOSURE
    a) Stomatitis has been reported in patients receiving hydroxyurea doses several times the therapeutic dose (Prod Info HYDREA(R) oral capsules, 2012).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) TOXIC HEPATITIS
    1) WITH THERAPEUTIC USE
    a) Two cases of hepatic toxicity in HIV-positive patients receiving hydroxyurea have been described. The first case was a 45-year-old woman diagnosed with HIV who had her antiviral therapy changed from zidovudine, lamivudine, and saquinavir to nelfinavir, stavudine, didanosine, and hydroxyurea (500 milligrams twice daily). The patient developed severe abdominal pain, nausea, and vomiting. She later died of fulminant hepatitis. The second case was a 42-year-old man diagnosed with HIV and positive for hepatitis C antibody. Antiviral therapy included didanosine, stavudine, ritonavir, and saquinavir. Hydroxyurea (500 milligrams twice daily) was later added. The patient began to complain of abdominal pain and nausea. Antiviral therapy was withheld, and after improvement of liver function, was later restarted without hydroxyurea. Liver function tests remained stable. The authors propose that in the first case, hydroxyurea potentiated mitochondrial toxicity of the nucleoside analogues by enhancing their uptake and thus leading to hepatic failure. In the second case, hydroxyurea may have caused immune reactivation with an inflammatory response in hepatocytes infected with hepatitis C (Weissman et al, 1999).
    b) Hepatitis developed in a 64-year-old man receiving hydroxyurea 1 g daily for poorly controlled psoriasis. The patient presented with a 6-day history of lassitude, malaise and rigors with a more recent 4-day history of nausea and vomiting; he had been receiving the drug for a total of 18 days. Symptoms resolved within 36 hours of discontinuing the drug, all laboratory values (alkaline phosphatase, aspartate aminotransferase, lactate dehydrogenase, bilirubin) were normal 2 weeks later (Heddle & Calvert, 1980).
    c) Hydroxyurea-induced fever and liver function abnormalities in 4 patients have been reported. All patients were receiving hydroxyurea 1 gram/day for various diagnoses (polycythemia vera, essential thrombocythemia, thrombocytosis). One patient was also receiving hydroxyzine embonate, 1 patient atenolol and aspirin, and another allopurinol and sodium valproate. Each patient developed fever and liver function abnormalities after initiating hydroxyurea. Biopsy-proven granulomatous hepatitis was noted in one patient. Upon discontinuation of hydroxyurea, all responded with fever disappearance and liver function normalization. In 3 patients, hydroxyurea was reintroduced and in all 3 recurrence of symptoms appeared. Symptoms again resolved upon discontinuation of hydroxyurea (Westerman et al, 1998).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) RENAL TUBULAR DISORDER
    1) WITH THERAPEUTIC USE
    a) Hydroxyurea administration has resulted in temporary renal tubular dysfunction accompanied by elevations in serum uric acid, blood urea nitrogen, and creatinine levels (Prod Info HYDREA(R) oral capsules, 2012). Dysuria has rarely occurred with hydroxyurea therapy. Renal test abnormalities are generally transient and reversible (Maserati, 1999).
    B) CYSTITIS
    1) WITH THERAPEUTIC USE
    a) Recurrent cystitis was reported rarely (3 cases among over 200 elderly patients) during low-dose hydroxyurea maintenance treatment for polycythemia vera (Najean & Rain, 1997).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) MYELOSUPPRESSION
    1) WITH THERAPEUTIC USE
    a) Bone marrow depression, most frequently leukopenia, occurs. Thrombocytopenia (platelets less than 100,000 cells/mm(3)) and anemia may also occur, usually in addition to leukopenia (Prod Info HYDREA(R) oral capsules, 2012; Prod Info DROXIA(R) oral capsules, 2012; Zappala et al, 2012; Goodrich & Khardori, 1999; de Montalembert et al, 1999; Maserati, 1999; Kinney et al, 1999). Recovery has usually been observed within 2 weeks (Prod Info DROXIA(R) oral capsules, 2012).
    b) Hydroxyurea can cause macrocytosis which may mask the development of folic acid deficiency. The prophylactic administration of folic acid is recommended (Prod Info DROXIA(R) oral capsules, 2012).
    c) CASE REPORT: Goodrich & Khardori (1999) reported a 35-year-old HIV infected man who developed prolonged hydroxyurea-induced marrow suppression (platelet count of 4000/mm(3)). Prior to adding hydroxyurea to his antiretroviral therapy regimen, his platelet count was 177,000/mm(3). Platelet transfusions were required for 3 months after stopping hydroxyurea (Goodrich & Khardori, 1999).
    d) CASE SERIES: In a retrospective study of 101 children given long-term (medium 22 months) therapy with hydroxyurea for sickle cell disease, neutropenia (between 500 and 1500/mm(3)) developed in 5 cases, thrombocytopenia (between 90,000 and 100,000/mm(3)) developed in 4 cases, and reticulocytopenia (between 80,000 and 90,000/mm(3)) developed in 5 cases (de Montalembert et al, 1999).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 2-year-old girl who was receiving hydroxyurea 17.5 mg/kg/day for sickle cell anemia, developed only mild myelosuppression after ingesting an entire 35-day supply of hydroxyurea (98 mL of a 100 mg/mL suspension; total dose, 612 mg/kg or 15.4 g/m(2)). Her serum hydroxyurea concentration was 7756 mcM approximately 4 hours postingestion. She recovered gradually by day 7 (Miller et al, 2011).
    b) CASE REPORT: A 50-year-old woman who was taking hydroxycarbamide (hydroxyurea) for essential thrombocythemia, presented with mild agitation, widespread myoclonic jerks, and global hyperreflexia after ingesting about 60 grams of hydroxycarbamide (hydroxyurea) with alcohol. On presentation, she had a Glasgow Coma Score (GCS) of 10/15. At this time, all laboratory results were normal. An ECG revealed sinus tachycardia. Her GCS decreased to 5/15 over the next 12 hours and she developed oculogyric crisis, which was treated with procyclidine. On day 5, her CBC parameters started to decrease. On day 8, her neutrophils reached a nadir of below detectable limits, despite treatment with granulocyte colony stimulating factor (G-CSF; filgrastim, 300 mcg once daily) starting on day 7. Other laboratory results included the platelet count of 74 x 10(9)/L and hemoglobin concentration of 93 g/L. Examination of blood films revealed macrocytosis and neutropenia. Following supportive care, including prophylactic antibacterial for neutropenia, both her laboratory results and neurological symptoms gradually resolved (Litt et al, 2013).
    B) LEUKEMIA
    1) WITH THERAPEUTIC USE
    a) Secondary leukemia has been reported in conjunction with patients receiving long-term hydroxyurea for myeloproliferative disorders such as polycythemia vera and thrombocythemia (Prod Info DROXIA(R) oral capsules, 2012).
    b) Acute myeloid leukemia and myelodysplasia have developed in patients receiving long-term (7 to 10.5 years) hydroxyurea therapy for essential thrombocythemia. Patients often had no prior exposure to radiation or alkylating agents (Furgerson et al, 1996; Weinfeld et al, 1994).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) Hydroxyurea has been associated with maculopapular rash, skin ulceration, and facial erythema. Alopecia occurs rarely (Prod Info HYDREA(R) oral capsules, 2012; de Montalembert et al, 1999; Kennedy, 1998; Kido et al, 1998). Prophylaxis with oral dexamethasone (2 mg) and diphenhydramine (25 mg) prevents skin rash (Newman et al, 1997).
    b) CASE REPORT: A 71-year-old woman developed pain, warmth, and redness over the right ankle and toe pads of both feet 4 days after beginning treatment of chronic myelogenous leukemia with hydroxyurea (3 grams/day). The patient was also receiving allopurinol 300 milligrams/day. The symptoms resolved after hydroxyurea was discontinued and indomethacin was begun (no dose specified). On re-challenge with hydroxyurea at 1 gram/day, the symptoms recurred with greater severity. The dose was reduced to 500 milligrams/day, however, the acral erythema persisted. Symptoms gradually resolved upon discontinuation of the drug (Silver et al, 1983).
    c) CASE REPORTS: A cutaneous rash developed in a child 10 days after starting therapy with hydroxyurea for sickle cell disease. The drug was stopped. A leg ulcer developed in an 18-year-old after 23 months of treatment, necessitating discontinuance of the drug (de Montalembert et al, 1999).
    d) DERMATOMYOSITIS-LIKE ERUPTION
    1) Senet et al (1995) reported 6 patients who developed hydroxyurea-induced dermatomyositis-like eruptions. The cutaneous eruptions were typical, with scaly, linear erythema on the dorsa of the hands (Senet et al, 1995). In 2 cases, leg ulcerations also occurred. No muscle involvement was observed. All patients had a benign course, even when hydroxyurea was not stopped. In another patient, high-dose steroid therapy did not improve the hydroxyurea-induced dermatomyositis-like eruption, but a change of therapy to interferon-alpha did result in gradual improvement (Young et al, 2000).
    2) CASE REPORT: A 66-year-old woman who had been taking hydroxyurea 1 g twice daily for 5 years, presented with an 8-month history of dorsal hand lesions. Severe generalized xerosis and prominent palmar erythema with violaceous, keratotic lesions and painful ulcers were observed during examination. She also had megaloblastic anemia (Hb 92 g/L; mean cell volume [MCV] 114 fL), but no other laboratory abnormalities were observed. Histopathological findings revealed a lichenoid inflammation with vacuolar change in the basal layer, occasional Civatte body formation and apoptotic keratinocytes in the epidermis. A mild lymphocytic infiltrate within the superficial dermis was also noted. The diagnosis of hydroxyurea-induced dermatomyositis-like eruption was made and hydroxyurea was discontinued. Her hands improved gradually over the next 6 months (Zappala et al, 2012).
    2) WITH POISONING/EXPOSURE
    a) Acute mucocutaneous toxicity, soreness, violet erythema, edema on palms and soles, scaling of hands and feet, severe generalized hyperpigmentation of the skin, and stomatitis have been reported in patients receiving hydroxyurea doses several times the therapeutic dose (Prod Info HYDREA(R) oral capsules, 2012).
    B) SKIN ULCER
    1) WITH THERAPEUTIC USE
    a) Hydroxyurea-induced leg ulcers have been reported following chronic therapeutic doses due to cutaneous atrophy and poor wound healing. There is no consistent correlation between dose and duration of hydroxyurea therapy. Ulcers generally improve following discontinuation of therapy and in one case, additional application of a tissue-engineered human skin hastened recovery (Flores et al, 2000; Yasuda et al, 2000; Young et al, 2000).
    b) CASE SERIES: One study described 41 adult patients who developed leg ulcerations while on therapy with hydroxyurea (mean therapy duration, 5 years). No underlying vascular diseases were identified. Complete recovery occurred following discontinuation of hydroxyurea in 33 (80%) of the patients (Sirieix et al, 1999).
    C) LICHENOID DERMATITIS
    1) WITH THERAPEUTIC USE
    a) Ulcerative lichen planus-like dermatitis has been described following both acute and prolonged therapy with hydroxyurea (Radaelli et al, 1998; Bohn et al, 1998; Kirby & Rogers, 1998). One case developed in a 56-year-old woman with chronic myelogenous leukemia following 2 to 3 grams/day for 4 years (Renfro et al, 1991), while a 67-year-old man presented with skin lesions present for the past 2 years while on 2 g daily (Bohn et al, 1998). Lesions have also appeared within 15 days (Radaelli et al, 1998).
    1) Dermatologic findings have included facial (cheek) erythema, leukokeratotic and erosive buccal mucosal lesions, palmar erythematous scaling, and ulcerative lesions on the plantar side of the feet or the dorsa of the hands. Histology suggested lichen ruber planus with polymorphonuclear infiltrates in the papillary and reticular dermis. Both anti-skin antibody and antinuclear antibody tests have been negative. Lesions failed to clear with either steroids or acitretin while hydroxyurea was continued. After withdrawing hydroxyurea and substituting busulfan, skin lesions faded over 6 weeks to 4 months (Bohn et al, 1998; Radaelli et al, 1998).
    D) NAIL FINDING
    1) WITH THERAPEUTIC USE
    a) Hydroxyurea therapy has been associated with development of multiple longitudinal pigmented nail bands (melanonychia) (Kelsey, 1992; Vomvouras et al, 1991). Patterns described have included diffuse black pigmentation, a less-severe diffuse brown discoloration sparing the distal nail and lunula (Kwong, 1996), or brown-colored longitudinal bands 1 to 4 millimeters wide in both the fingernails and toenails (Cakir et al, 1997). Seven children in a retrospective study (n=101) of hydroxyurea therapy for sickle cell disease developed melanonychia (de Montalembert et al, 1999).
    E) DISCOLORATION OF SKIN
    1) WITH THERAPEUTIC USE
    a) Severe generalized hyperpigmentation of the skin has been reported in patients receiving hydroxyurea at dosages several time the therapeutic dose (Prod Info Mylocel(TM), hydroxyurea tablets, 2001).
    F) GANGRENE
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: After 3 years of continuous therapy with hydroxyurea and IFN-alpha for chronic myelogenous leukemia, a 53-year-old woman developed gangrene of some toes on both feet. Following transmetatarsal amputation, she developed painful ulcers and patchy cutaneous gangrene on both amputated edges. Hydroxyurea was discontinued and the ulcers and patchy cutaneous gangrene cleared over the following 3 months (Yasuda et al, 2000).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) DRUG-INDUCED LUPUS ERYTHEMATOSUS
    1) WITH THERAPEUTIC USE
    a) Lupus erythematosus occurred in a 62-year-old woman following 8 years of hydroxyurea 1.5 grams/day; the patient had a 30-year history of psoriasis. Upon discontinuation of hydroxyurea, the patient had a dramatic improvement in lupus symptoms (Layton et al, 1994).

Reproductive

    3.20.1) SUMMARY
    A) Hydroxyurea can cause fetal harm if used during pregnancy. Advise women to avoid pregnancy during hydroxyurea administration. If pregnancy occurs, apprise patients of the potential hazard to the fetus. It crosses the placenta in animals, is excreted into human breast milk, and is embryotoxic. Advise women to avoid breastfeeding during hydroxyurea therapy.
    3.20.2) TERATOGENICITY
    A) LACK OF EFFECT
    1) CASE REPORT: A healthy infant with normal blood counts and no congenital abnormalities was delivered at 37 weeks to a patient with chronic myelogenous leukemia receiving hydroxyurea up to 3 g/day (Jackson et al, 1993).
    2) CASE REPORT: A 19-year-old woman gave birth to a healthy baby after receiving hydroxyurea for 50 months for her sickle cell disease (de Montalembert et al, 1999).
    3) In a review of 14 published cases of hydroxyurea use in pregnancy, 3 pregnancies were terminated with elective abortions, one woman with eclampsia delivered a phenotypically normal stillborn infant, and the other pregnancies resulted in normal live infants (Byrd et al, 1999).
    B) ANIMAL STUDIES
    1) During animal studies, administration of hydroxyurea at doses at least 0.3 times the maximum recommended daily human dose resulted in teratogenic effects including embryotoxicity (eg, decreased viability, reduce live litter size, developmental delays) and fetal malformation (eg, partially ossified cranial bones, absence of eye sockets, hydrocephaly, bipartite sternebrae, and missing lumbar vertebrae). Growth retardation and impaired learning ability were associated with single hydroxyurea doses approximately 1.7 times the maximum recommended human dose (Prod Info HYDREA oral capsules, 2016; Prod Info DROXIA oral capsules, 2016).
    3.20.3) EFFECTS IN PREGNANCY
    A) RISK SUMMARY
    1) Based on animal studies and the mechanism of action of hydroxyurea, use during pregnancy can cause fetal harm. Advise women to avoid pregnancy during hydroxyurea administration. If pregnancy occurs, apprise patients of the potential hazard to the fetus (Prod Info HYDREA oral capsules, 2016; Prod Info DROXIA oral capsules, 2016).
    B) CONTRACEPTION
    1) Use of adequate contraception is required in female patients of reproductive potential during treatment and for at least 6 months after discontinuation. Male patients with a female partner of reproductive potential must use adequate contraception during treatment and for at least 1 year after discontinuation (Prod Info HYDREA oral capsules, 2016; Prod Info DROXIA oral capsules, 2016).
    C) ANIMAL STUDIES
    1) During animal studies, administration of hydroxyurea at doses at least 0.3 times the maximum recommended daily human dose resulted in teratogenic effects including embryotoxicity (eg, decreased viability, reduce live litter size, developmental delays) and fetal malformation (eg, partially ossified cranial bones, absence of eye sockets, hydrocephaly, bipartite sternebrae, and missing lumbar vertebrae). Growth retardation and impaired learning ability were associated with single hydroxyurea doses approximately 1.7 times the maximum recommended human dose (Prod Info HYDREA oral capsules, 2016; Prod Info DROXIA oral capsules, 2016).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Hydroxyurea is excreted into human breast milk. Advise women to avoid breastfeeding during hydroxyurea therapy (Prod Info HYDREA(R) oral capsules, 2015; Prod Info DROXIA(R) oral capsules, 2015).
    2) Hydroxyurea was excreted into the breast milk of a patient with myelogenous leukemia. The patient was receiving 500 mg orally 3 times daily, with milk samples collected 2 hours following the last dose of the drug each day for 7 days. Only 3 samples were reported to clear adequately following the extraction process to ensure reliable spectrophotometric readings; these concentrations were 6.1, 3.8, and 8.4 mg/L on days 1, 3, and 4, respectively (mean, 6.1 mg/L). At these concentrations, it was calculated 3 to 4 mg/day would be received by the infant. Although amounts ingested by a breastfeeding infant would appear to be low, it is recommended that hydroxyurea be avoided during the breastfeeding period as the effects of exposure are undetermined (Sylvester et al, 1987a).
    3.20.5) FERTILITY
    A) AZOOSPERMIA
    1) Potentially reversible azoospermia and oligospermia has been observed in men (Prod Info HYDREA oral capsules, 2016; Prod Info DROXIA oral capsules, 2016).
    B) ANIMAL STUDIES
    1) Fertility effects, including testicular atrophy, decreased spermatogenesis, and significantly reduced ability to impregnate females, were observed in male rats administered hydroxyurea at doses approximately 0.3 times the maximum recommended human daily dose, based on mg/m(2) (Prod Info HYDREA(R) oral capsules, 2015; Prod Info DROXIA(R) oral capsules, 2015).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) Leukemogenic effects of hydroxyurea have been described in case reports. Skin carcinoma has been described following hydroxyurea therapy.
    B) Hydroxyurea is mutagenic and clastogenic.
    3.21.3) HUMAN STUDIES
    A) CARCINOMA
    1) In a 10-year retrospective review of the Howard University Center for Sickle Cell Disease database, cancer incidence in sickle cell patients was 5 cases per 2,864 patients or 1.74 cases per 1,000 patient years. The 95% confidence interval for this estimate was 0.64 cases to 4.32 cases per 1,000 patient years. Cancer mortality rate was 3 deaths per 2,873 patients or 1.04 deaths per 1,000 patient years. The authors did not evaluate implications of long-term hydroxyurea treatment in patients with sickle cell disease but suggested that this data may prove useful in establishing baseline cancer rates in this patient population (Dawkins et al, 1997).
    B) SKIN CARCINOMA
    1) Long-term hydroxyurea therapy has been reported to cause skin cancer in some patients (Prod Info DROXIA oral capsules, 2016).
    2) Five male patients 64- to 76-years-old who had received hydroxyurea treatment for 2 to 10 years for either thrombocytopenia or polycythemia vera in cumulative doses ranging between 650 to 3600 mg developed cutaneous carcinoma (both squamous cell carcinoma as well as basal cell carcinoma). Factors attributing these events to hydroxyurea included the sudden onset of tumors in 1 patient, the large number and size of tumors in 2 patients, and the resolution and absence of recurrence after hydroxyurea withdrawal in 2 patients in whom follow up was possible (Callot-Mellot et al, 1996).
    C) LEUKEMIA
    1) In a retrospective review of data from 2 institutions, hydroxyurea treatment was associated with leukemogenic potential in patients with essential thrombocythemia. Of 357 patients with essential thrombocythemia, hydroxyurea was used in 251 patients. After a mean follow-up of 98 months, 6 patients developed acute myelogenous leukemia (AML) and 11 patients developed myelodysplastic syndrome (MDS). Fourteen of these patients had received hydroxyurea as part of a treatment regimen; 7 had received hydroxyurea alone. In the 17 patients progressing to AML or MDS, 13 were evaluated for chromosomal abnormalities. Seven patients had 17p deletions and had received hydroxyurea; 6 of these patients had additional chromosomal abnormalities, including abnormalities in chromosomes 5 and/or 7 (Sterkers et al, 1998).
    2) Leukemogenic effects of hydroxyurea have been described in case reports. Acute myelogenous leukemia (AML) developed in two patients receiving long-term (7 to 10.5 years) hydroxyurea therapy for essential thrombocythemia. Neither patient had prior exposure to radiation or alkylating agents (Furgerson et al, 1996).
    a) An additional case describes AML developing from polycythemia vera and myelodysplastic syndrome during 4-year treatment. Arguing against this latter case representing normal disease progression rather than a drug-induced effect was the presence of massive trilineage hyperplasia with marked cytologic abnormalities and the intervening myelodysplastic phase prior to frank leukemia (Pulik et al, 1996).
    b) In another series of 58 patients, 3 (5.2%) developed leukemic transformation after 47, 81, and 90 months therapy with hydroxyurea. Two of these patients died; one shortly after being diagnosed with acute leukemia with minimal myeloid differentiation, and the other 1 year after diagnosis of refractory anemia with excess blasts in transformation (Liozon et al, 1997).
    3) Leukemia (n=9) and myelodysplastic syndrome (n=1) were observed in a series of 50 consecutive patients treated with long-term hydroxyurea therapy. The patients were being treated for polycythemia (n=30), thrombocythemia (n=10) or myelofibrosis (n=10). Control of erythrocytosis and thrombocytosis was achieved in 70% of patients; decreased spleen size occurred in all patients in whom adequate doses were allowed. Patients usually received a dose of 60 mg/kg/day for the first week, then a 50% dose reduction with subsequent adjustment according to blood counts. During maintenance, hydroxyurea was administered at a dose of 0.5 to 1.5 grams/day. In addition to leukemia, chromosome abnormalities developed during therapy in 7 of 19 previously untreated patients with initially normal karyotypes (Weinfeld et al, 1994).

Genotoxicity

    A) Hydroxyurea is mutagenic and clastogenic, and therefore, a presumed trans-species carcinogen with potential human harm. It is unknown whether the leukemogenic effect noted during long-term treatment of myeloproliferative disorders is directly related to hydroxyurea or due to the underlying disease (Prod Info HYDREA oral capsules, 2016; Prod Info DROXIA oral capsules, 2016).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    C) Monitor CBC with differential and platelet count for several weeks after overdose, as nadir counts may be delayed. Recovery has usually been observed within 2 weeks.
    D) 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.
    E) Monitor renal function and liver enzymes in symptomatic patients.
    F) Monitor arterial blood gases, pulse oximetry, and pulmonary function tests, and obtain a chest x-ray in any patient with respiratory symptoms.

Methods

    A) CHROMATOGRAPHY
    1) Pujari et al (1997) described a high-performance liquid chromatography (HPLC) method using electrochemical detection for the quantitative determination of hydroxyurea in plasma and peritoneal fluid. The limit of quantitation in plasma was 25 micrograms/liter (approximately 0.33 micromoles/liter), and in peritoneal fluid was 5 micrograms/liter (approximately 0.066 micromole/liter) (Pujari et al, 1997).

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) Patients should be admitted for severe vomiting, profuse diarrhea, severe abdominal pain, dehydration, and electrolyte abnormalities. Patients with myelosuppression should be closely monitored in an inpatient setting, with daily monitoring of CBC with differential until bone marrow suppression is resolved.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.4) PATIENT TRANSFER/ORAL
    A) Patients with severe neutropenia may benefit from early transfer to a cancer treatment or bone marrow transplant center.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, and those who are symptomatic, need to be monitored for several hours to assess electrolyte and fluid balance. Patients that remain asymptomatic can be discharged.

Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    C) Monitor CBC with differential and platelet count for several weeks after overdose, as nadir counts may be delayed. Recovery has usually been observed within 2 weeks.
    D) 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.
    E) Monitor renal function and liver enzymes in symptomatic patients.
    F) Monitor arterial blood gases, pulse oximetry, and pulmonary function tests, and obtain a chest x-ray in any patient with respiratory symptoms.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital gastrointestinal decontamination is generally not recommended.
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    2) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    3) Monitor CBC with differential and platelet count for several weeks after overdose, as nadir counts may be delayed. Recovery has usually been observed within 2 weeks.
    4) 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.
    5) Monitor renal function and liver enzymes in symptomatic patients.
    6) Monitor arterial blood gases, pulse oximetry, and pulmonary function tests, and obtain a chest x-ray in any patient with respiratory symptoms.
    B) MYELOSUPPRESSION
    1) Bone marrow depression, most frequently leukopenia, occurs. Thrombocytopenia (platelets less than 100,000 cells/mm(3)) and anemia may also occur, usually in addition to leukopenia (Prod Info HYDREA(R) oral capsules, 2012; Prod Info DROXIA(R) oral capsules, 2012; Goodrich & Khardori, 1999; de Montalembert et al, 1999).
    2) Patients with severe neutropenia should be in protective isolation.
    3) 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) Should be considered in patients with severe neutropenia.
    b) 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 OR 250 mcg/m(2)/day SubQ once daily. Treatment should be continued until the ANC is at least 2 to 3 x 10(9)/L (Smith et al, 2006).
    2) HIGH-DOSE THERAPY
    a) Higher doses of filgrastim, such as those used for bone marrow transplant, may be indicated after overdose.
    b) FILGRASTIM: In patients receiving bone marrow transplant (BMT), the recommended dose of filgrastim is 10 mcg/kg/day given as an IV infusion of 4 or 24 hours, or as a continuous 24 hour subQ infusion. The daily dose of filgrastim should be titrated based on neutrophil response (ie, absolute neutrophil count (ANC)) as follows (Prod Info NEUPOGEN(R) IV, subcutaneous injection, 2010):
    1) When ANC is greater than 1000/mm(3) for 3 consecutive days; reduce filgrastim to 5 mcg/kg/day.
    2) If ANC remains greater than 1000/mm(3) for 3 more consecutive days; discontinue filgrastim.
    3) If ANC decreases again to less than 1000/mm(3); resume filgrastim at 5 mcg/kg/day.
    c) In BMT studies, patients received up to 138 mcg/kg/day without toxic effects. However, a flattening of the dose response curve occurred at daily doses of greater than 10 mcg/kg/day (Prod Info NEUPOGEN(R) IV, subcutaneous injection, 2010).
    d) SARGRAMOSTIM: This agent has been indicated for the acceleration of myeloid recovery in patients after autologous or allogenic BMT. Usual dosing is 250 mcg/m(2)/day as a 2-hour IV infusion OR 250 mcg/m(2)/day SubQ once daily (Prod Info LEUKINE(R) subcutaneous, IV injection, 2008; Smith et al, 2006). Duration is based on neutrophil recovery (Prod Info LEUKINE(R) subcutaneous, IV injection, 2008).
    3) SPECIAL CONSIDERATIONS
    a) In pediatric patients, the use of colony stimulating factors (CSFs) can reduce the risk of febrile neutropenia. However, this therapy should be limited to patients at high risk due to the potential of developing a secondary myeloid leukemia or myelodysplastic syndrome associated with the use of CSFs. Careful consideration is suggested in using CSFs in children with acute lymphocytic leukemia (ALL) (Smith et al, 2006).
    D) 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, olanzapine); 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).
    E) 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 a hydroxyurea overdose, 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.
    F) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    G) BODY TEMPERATURE ABOVE REFERENCE RANGE
    1) Cold compresses and cooling blankets should be used in cases of hyperthermia. Administer antipyretics and evaluate for neutropenia and sepsis.

Enhanced Elimination

    A) HEMODIALYSIS
    1) Hemodialysis would not be likely to be of significant benefit in hydroxyurea overdoses due to its high protein binding.

Range Of Toxicity

Summary

    A) TOXICITY: ADULTS: Myelosuppression appears to be the dose-limiting toxicity of hydroxyurea and develops at 800 mg/m(2) in adults. A woman developed agitation, widespread myoclonic jerks, oculogyric crisis, sinus tachycardia, and myelosuppression after ingesting 60 grams of hydroxyurea. She recovered following supportive care. CHILDREN: A 2-year-old girl developed only mild myelosuppression after ingesting an entire 35-day supply of hydoxyurea (total dose, 612 mg/kg or 15.4 g/m(2)). She recovered gradually by day 7.
    B) THERAPEUTIC DOSES: ADULTS: Initial: 15 mg/kg as a single daily dose. Maintenance: Increase the daily dose by 5 mg/kg every 12 weeks. MAX dose, 35 mg/kg/day. CHILDREN: The safety and efficacy of hydroxyurea in children for any indication have not been established. SICKLE CELL DISEASE: In studies, doses of 9 to 30 mg/kg/day for 4 days per week have been used in children with sickle cell anemia.

Therapeutic Dose

    7.2.1) ADULT
    A) Initial: 15 mg/kg as a single daily dose (Prod Info HYDREA(R) oral capsules, 2015; Prod Info DROXIA(R) oral capsules, 2015).
    B) Maintenance: Increase the daily dose by 5 mg/kg every 12 weeks. MAX dose, 35 mg/kg/day (Prod Info DROXIA(R) oral capsules, 2015)
    7.2.2) PEDIATRIC
    A) The safety and efficacy of hydroxyurea in children for any indication have not been established (Prod Info HYDREA(R) oral capsules, 2015; Prod Info DROXIA(R) oral capsules, 2015).
    B) SICKLE CELL DISEASE: Doses of 9 to 30 mg/kg/day for 4 days per week have been used in children with sickle cell anemia in experimental studies (de Montalembert et al, 1999). In another study, doses starting at 15 mg/kg/day to a maximum 30 mg/kg/day were given once daily for a mean duration of 137 weeks (Hoppe et al, 2000).

Maximum Tolerated Exposure

    A) ADULT
    1) At oral doses of 800 mg/m(2) every 4 hours and intravenous doses of 3 mg/m(2)/minute for 72 hours, myelosuppression was reported to be the dose-limiting toxic parameter, with both granulocytes and platelets involved during a study of six patients receiving 8 courses of hydroxyurea (Belt et al, 1980).
    2) CASE REPORT: A woman developed agitation, widespread myoclonic jerks, oculogyric crisis, sinus tachycardia, and myelosuppression after ingesting 60 grams of hydroxyurea. She recovered following supportive care (Litt et al, 2013).
    B) CHILDREN
    1) A 2-year-old girl who was receiving hydroxyurea 17.5 mg/kg/day for sickle cell anemia, developed only mild myelosuppression after ingesting an entire 35-day supply of hydroxyurea (98 mL of a 100 mg/mL suspension; total dose, 612 mg/kg or 15.4 g/m(2)). Her serum hydroxyurea concentration was 7756 mcM approximately 4 hours postingestion. She recovered gradually by day 7 (Miller et al, 2011).

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) ADULT
    a) Ranges in peak plasma levels are 2-fold, reflecting large interindividual differences (Belt et al, 1980).
    b) Mean peak plasma level was 1006 micromoles/liter after a 2 gram infusion over 30 minutes (Rodriguez et al, 1998).
    c) Non-linear relationships between dose and plasma levels are commonly described; pharmacokinetic modeling is consistent with MICHAELIS-MENTON elimination (Gwilt & Tracewell, 1998; Belt et al, 1980).
    d) Tmax: 1 to 4 hours (Prod Info HYDREA(R) oral capsules, 2012; Prod Info DROXIA(R) oral capsules, 2012; Rodriguez et al, 1998).
    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) CASE REPORT: A 2-year-old girl who was receiving hydroxyurea 17.5 mg/kg/day for sickle cell anemia, developed only mild myelosuppression after ingesting an entire 35-day supply of hydroxyurea (98 mL of a 100 mg/mL suspension; total dose, 612 mg/kg or 15.4 g/m(2)). Her serum hydroxyurea concentration was 7756 mcM approximately 4 hours postingestion. She recovered gradually by day 7 (Miller et al, 2011).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ANIMAL DATA
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 5800 mg/kg (RTECS , 2002)
    2) LD50- (ORAL)MOUSE:
    a) 7330 mg/kg (RTECS , 2002)
    3) LD50- (INTRAPERITONEAL)RAT:
    a) >4700 mg/kg (RTECS , 2002)
    4) LD50- (ORAL)RAT:
    a) 5760 mg/kg (RTECS , 2002)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) ANTINEOPLASTIC: Hydroxyurea is considered a cell-cycle specific agent effective in the S-phase of mitosis. Hydroxyurea inhibits the conversion of DNA bases by blocking ribonucleotide reductase. Since the drug causes cells to arrest at the G1-S interface, and irradiation sensitivity is maximum during this time, concomitant hydroxyurea and irradiation result in synergistic toxicity (Gilman et al, 1990; van der Klooster et al, 1997).
    B) ANTIRETROVIRAL: Hydroxyurea theoretically reduces deoxyribonucleotide triphosphate (dNTP) pools within cells. Endogenous dNTPs compete with reverse transcriptase inhibitors for binding sites on HIV reverse transcriptase. Hydroxyurea, by depleting dNTP pools and reducing competition for binding sites, may potentiate the activity of reverse transcriptase inhibitors (e.g., zidovudine, didanosine, lamivudine). Additionally, hydroxyurea may increase the intracellular phosphorylation of these drugs, which is a necessary step in the activation of nucleoside reverse transcriptase inhibitors. Resistance and onset of resistance to the nucleoside reverse transcriptase inhibitors is not delayed by hydroxyurea (Romanelli et al, 1999) Lori & Lisziewicz, 2000). Additionally, the cytostatic effect of hydroxyurea on CD4+ T lymphocytes (host cells for HIV-1) can produce additional beneficial effects (Lori & Lisziewicz, 2000).

Toxicologic Mechanism

    A) Hydroxyurea inhibits DNA synthesis, thus resulting in its major toxicity of myelosuppression (Maserati, 1999). Inhibition of DNA synthesis with no modification of RNA synthesis may result in red blood cells becoming megaloblastic (Sirieix et al, 1999).
    B) Nail bed discoloration may be due to a direct toxic effect on nail bed; focal melanocyte stimulation; photosensitivity; drug deposition in nail bed (Cakir et al, 1997).
    C) Leg ulcerations resulting from hydroxyurea therapy may in part be due to cutaneous atrophy and impaired wound healing. Megaloblastic erythrocytes, due to hydroxyurea, may circulate poorly throughout the capillary network, contributing to leg ulcerations (Sirieix et al, 1999).

Physicochemical

Physical Characteristics

    A) Hydroxyurea is a tasteless, white crystalline powder (Prod Info hydroxyurea oral capsules, 2006).

Molecular Weight

    A) 76.06 (Prod Info hydroxyurea oral capsules, 2006)

References

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