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PAR PHARM.
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hydroxyurea 500 mg capsule

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Uses

Chronic Myelogenous Leukemia

Hydroxyurea is indicated in the treatment of resistant chronic myelogenous leukemia (CML). Hydroxyurea is an alternative drug for the palliative treatment of chronic-phase CML in patients who cannot undergo allogeneic bone marrow or stem cell transplantation, which is the only therapy known to be curative for this leukemia; interferon alfa, with or without cytarabine, is a preferred therapy in such patients. Unlike interferon alfa, hydroxyurea has not been associated with prolonged cytogenetic response (i.e., suppression of Philadelphia chromosome-positive cells) in patients with Philadelphia chromosome-positive CML. Hydroxyurea is superior to busulfan for the palliative treatment of CML; in a randomized trial, patients receiving hydroxyurea experienced prolonged median survival and less toxicity compared with those receiving busulfan.

Hydroxyurea is an alternative agent for the palliative treatment of the accelerated phase of CML. Hydroxyurea also is used to reduce the white blood cell count prior to bone marrow transplantation or initiation of interferon alfa therapy.

Sickle Cell Anemia

Overview

Hydroxyurea is used in the palliative treatment of sickle cell anemia generally in patients with recurrent moderate to severe painful crises occurring on at least 3 occasions during the preceding 12 months and is designated an orphan drug by the US Food and Drug Administration for this use. Hydroxyurea is employed in patients with sickle cell anemia in an attempt to increase fetal hemoglobin (Hb F) synthesis and thus potentially reduce sickling of red blood cells and prevent associated clinical sequelae (e.g., painful crises). Therapy with the drug in this condition is not curative, and any beneficial effect will be maintained only as long as an effective regimen of hydroxyurea is continued. In addition, hydroxyurea therapy in patients with sickle cell anemia is prophylactic, and therefore the drug has no role in the treatment of a crisis in progress.

Because hydroxyurea is a cytotoxic agent, the possible risks of therapy with the drug, including long-term risks such as secondary neoplasms (e.g., leukemia), should be weighed carefully against the potential benefits in treating a nonmalignant disease such as sickle cell anemia. In assessing the benefit versus risk, it should be recognized that clinical efficacy to date has been evidenced principally by amelioration of the clinical course (e.g., reduction in painful crises), and the long-term effect, if any, on progression of organ damage and mortality remains to be elucidated. Reversal of previously documented splenic dysfunction has been reported in 2 patients with sickle cell anemia treated with long-term hydroxyurea therapy and may indicate a possible effect of the drug on disease-induced organ damage.

Prophylactic hydroxyurea therapy may not be appropriate for all patients with sickle cell anemia, and evidence of clinical benefit to date has been established principally in patients with severe, recurrent painful episodes. In addition, current evidence suggests that patients with minimal or no increase in hemoglobin F concentrations after an adequate trial of hydroxyurea are not candidates for continued (i.e., long-term) therapy with the drug.

Hematologic Response Trials

Early studies on the effects of hydroxyurea in patients with sickle cell anemia evaluated the hematologic response to treatment, the doses required to produce the responses, and the incidence and severity of myelosuppression associated with the drug. Patients considered responders to therapy exhibited substantial increases in Hb F concentrations, resulting from increased populations of F cells and F reticulocytes, increased concentrations of Hb F per F cell, and/or increased F-cell survival. Increases in median corpuscular volume and median corpuscular hemoglobin also were noted in patients responding to hydroxyurea therapy. Initial dosages of hydroxyurea administered in these studies ranged from 3-50 mg/kg daily. Patient response to hydroxyurea therapy exhibited marked variability in terms of drug-induced increases in Hb F concentrations, and the dose of drug and duration of treatment necessary to produce a hematologic response. Although these early studies were not designed to specifically determine the efficacy of hydroxyurea in ameliorating clinical manifestations of the disease, there also was some evidence of potential clinical benefit from treatment.

Clinical Efficacy Trials

Clinical efficacy of hydroxyurea in ameliorating manifestations of sickle cell anemia has been established to date principally by the Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH), which was a well-designed, placebo-controlled study of the drug's efficacy in reducing the frequency of painful crises in adults with moderate to severe sickle cell anemia who had a history of 3 or more such crises per year. Hydroxyurea produced a 46% reduction in the annual rate of painful crises, with a median of 2.5 or 4.6 crises per year being experienced by patients receiving hydroxyurea or placebo, respectively. When only crises severe enough to result in hospitalization were considered, patients experienced a median of 1 or 2.5 crises per year, respectively. Patients receiving hydroxyurea also developed fewer episodes of chest syndrome (56 versus 101), a life-threatening complication of sickle cell anemia characterized by chest pain, fever, prostration, and pulmonary infiltrates on chest radiographs, and fewer patients required blood transfusions (55 versus 79) than those receiving placebo. Median times to development of the first and second vaso-occlusive crises were 2.76 versus 1.35 months and 6.58 versus 4.13 months in patients receiving hydroxyurea or placebo, respectively. There was no evidence of effect on mortality, stroke, or hepatic sequestration in this study. However, because interim analysis of data from the study indicated important beneficial effects of hydroxyurea in the management of sickle cell anemia, the trial's Data Safety and Monitoring Board recommended that the study be terminated 4 months earlier than the proposed scheduled end date. As a result, the study was stopped, clinical investigators at the participating centers were notified of the safety and efficacy of hydroxyurea in the treatment of sickle cell anemia, patients who had been receiving placebo were immediately offered therapy with the drug, and the National Heart, Lung, and Blood Institute issued a clinical alert regarding potential benefits of hydroxyurea in the treatment of sickle cell anemia. Because the study ended early, only 134 of 299 patients enrolled had completed the 2-year follow-up.

The MSH trial did not address the reversibility of chronic organ damage induced by sickle cell disease, and it currently is unknown whether inhibition of sickling could affect such preexisting lesions. When the study ended, total hemoglobin concentrations, MCV, Hb F concentrations, and proportion of F cells were higher, and the leukocyte, platelet, reticulocyte, and dense cell counts were lower, in the hydroxyurea-treated patients compared with those receiving placebo. Differences between the hydroxyurea and placebo groups in MCV and F-cell production were apparent within 8 weeks of treatment onset,reached a peak at approximately 40 weeks, and then declined. In patients with sickle cell anemia treated with hydroxyurea, fetal hemoglobin (HbF) increases 4-12 weeks following the start of treatment; however, a correlation between HbF or F-cell concentrations and reduced frequency of sickle cell crises has not been clearly demonstrated. In the MSH, the dose-related cytoreductive effect of hydroxyurea (particularly on neutrophils) correlated strongly with reduced crisis frequency.

Use in Children, Pregnancy, and Other Considerations

Safety and efficacy of hydroxyurea in children younger than 18 years of age with sickle cell anemia were not assessed in the multicenter study. In addition, although there was no evidence of adverse effect on pregnancy outcome in this study, hydroxyurea currently is not recommended for use in patients with sickle cell anemia who are likely to become pregnant; therapy with the drug also is not recommended for those unwilling or unable to follow instructions regarding such therapy or give informed consent stating their willingness to comply with given instructions.

Polycythemia Vera

Hydroxyurea has been used in the palliative treatment of polycythemia vera, including use as an adjunct to intermittent phlebotomy. The drug has been employed effectively for its cytoreductive (myelosuppressive) effects to reduce the excess production of platelets and red blood cells and control associated abnormal hematologic indices (e.g., hematocrit) in this condition and thus potentially prevent clinical sequelae such as thrombotic and hemorrhagic complications. Reduction in platelet counts generally occurs more rapidly than control of hematocrit, although at least 80% of patients appear to respond with reduced platelet counts and control of hematocrit within 12 weeks after initiating therapy with the drug.

Therapy with hydroxyurea for polycythemia vera is not curative, and any beneficial effect of the drug will be maintained only as long as an effective regimen of hydroxyurea is continued. If the drug is discontinued, unmaintained remissions usually are of short duration, with thrombocytosis commonly recurring within 7-10 days in patients with high pretreatment platelet counts. Because hydroxyurea is a cytotoxic agent, the possible risks of therapy with the drug, including long-term risks such as secondary neoplasms (e.g., leukemia), should be weighed carefully against the potential benefits in treating a myeloproliferative disorder such as polycythemia vera. Optimum therapy for the management of polycythemia vera has not been established, but drug therapy generally has been reserved for patients whose disease could not be adequately controlled by intermittent phlebotomy alone (i.e., those requiring cytoreductive therapy) or in whom phlebotomy has become impractical or has been associated with thrombotic or other complications. When hydroxyurea is used as an adjunct to phlebotomy, phlebotomy requirements are reduced. In addition, hydroxyurea-induced cytoreduction may be useful in providing symptomatic relief of severe pruritus that is unresponsive to antihistamines and/or phlebotomy in some patients and also may decrease symptomatic splenomegaly. Studies are ongoing to further define the potential risks and benefits and role of various therapies, including drug therapies (e.g., hydroxyurea, interferon alfa), in the management of polycythemia vera.

Adjunctive Therapy for HIV Infection

Because the results of randomized trials have shown inconclusive benefit and serious, including fatal, toxicity, the use of hydroxyurea as an adjunct to antiretroviral therapy for HIV infection is not recommended. Hydroxyurea has been used investigationally as an adjunct to certain antiretroviral drug regimens to enhance antiretroviral activity in the treatment of HIV infection. Early data reporting efficacy of hydroxyurea for this use was derived mostly from uncontrolled studies involving short-term follow-up of small numbers of patients, many of whom had early-stage HIV infection and were treatment-naive; limited data were available from controlled clinical trials. Further study in randomized trials has not clearly demonstrated the benefit of hydroxyurea as an adjunct to HIV therapy. Because of a lack of data from large, randomized, multicenter clinical trials and the potential for serious, sometimes fatal, toxicity, the use of hydroxyurea as a component of combination therapy for HIV infection is not recommended.

Serious toxicity, including fatal and nonfatal pancreatitis, hepatotoxicity (in some cases leading to fatal hepatic failure), and peripheral neuropathy (sometimes severe), has been reported in patients with HIV infection receiving hydroxyurea in combination with antiretroviral agents. One randomized trial was terminated when 3 patients receiving the hydroxyurea-containing regimen died from pancreatitis. Clinical trends and risk analysis indicate an increased risk of peripheral neuropathy in patients receiving hydroxyurea in combination with didanosine and stavudine. Other risks associated with the use of hydroxyurea as an adjunct to antiretroviral therapy in HIV infection, including persistent cytopenias, teratogenic effects, and long-term adverse effects such as secondary neoplasms (e.g., leukemia), also must be considered. The risk of hydroxyurea-induced neutropenia is of particular concern in patients with HIV infection, and some experts have recommended that hydroxyurea not be administered to patients with a baseline absolute neutrophil count (ANC) of less than 1700/mm.

The addition of hydroxyurea to a regimen of didanosine and stavudine or didanosine alone results in moderately enhanced antiretroviral activity. In a small randomized trial involving mostly treatment-naive patients with HIV infection, the addition of hydroxyurea 500 mg twice daily versus placebo to didanosine and stavudine was associated with a greater decrease in plasma HIV-1 RNA levels and a greater proportion of patients with undetectable viremia (defined as plasma HIV-1 RNA less than 200 copies/mL) over a 12-week period. At the end of 12 weeks, the study was unblinded, and patients receiving placebo who had plasma HIV-1 RNA greater than 200 copies/mL were given the option of adding hydroxyurea to their regimen. At a 2-year follow-up, patients receiving hydroxyurea in addition to didanosine and stavudine experienced more toxicity, including nausea and vomiting, fatigue, and peripheral neuropathy, and were more likely to discontinue the treatment than those receiving didanosine and stavudine; most patients in the study stopped the treatment to switch to other regimens containing protease inhibitors. When patients previously treated with a regimen of indinavir, zidovudine, and lamivudine were kept on the same regimen or switched to a regimen of didanosine, stavudine, and indinavir, with or without hydroxyurea (600 mg twice daily), patients receiving the hydroxyurea-containing regimen experienced the highest rate of treatment failure, principally because of drug-related toxicity.

Although hydroxyurea appears to enhance the antiretroviral activity of nucleoside reverse transcriptase inhibitors, such as didanosine, and initially produce greater suppression of the plasma viral load, it also is associated with a decrease in the median CD4 T-cell count. The lack of consistent increase, or eventual decrease, in CD4 T-cell counts may be related to the cytostatic activity and lymphopenic effects of hydroxyurea. The long-term clinical outcome of adding hydroxyurea to antiretroviral regimens is unknown.

The optimum dosage and dosing schedule for hydroxyurea were not established. In the study that was terminated because of 3 deaths from pancreatitis, patients received a higher dose of hydroxyurea (600 mg twice daily) than the typical dose used in previous studies (500 mg twice daily). In a 12-week pilot study among patients receiving chronic didanosine therapy for advanced HIV infection, a greater reduction in plasma viremia was observed with the addition of hydroxyurea 500 mg twice daily versus hydroxyurea 500 mg once daily. In a phase II dosing study, a higher dosage of hydroxyurea (1500 versus 1000 mg daily) administered with didanosine in treatment-naive or previously treated patients with HIV infection was associated with similar efficacy but greater toxicity, particularly neutropenia.

Hydroxyurea acts on a cellular enzyme that is less likely to mutate compared with viral enzymes that typically mutate to confer drug resistance, and suppression of HIV in response to didanosine in combination with hydroxyurea has been observed despite the onset of known genotypic mutations associated with didanosine resistance. Continued suppression of plasma HIV-1 RNA levels has been reported at 1-year follow-up in some patients receiving hydroxyurea and didanosine. Viral rebound did not occur up to 1 year following suspension of all antiretroviral therapy in 2 patients with high baseline CD4 T-cell counts who achieved suppression of HIV-1 RNA levels in plasma and lymph nodes during 1 year of treatment with hydroxyurea and didanosine; this finding suggests that the combination of hydroxyurea and didanosine exerts anti-HIV activity in resting lymphocytes and macrophages, an important reservoir of HIV. Hydroxyurea is thought to contribute to the inhibition of HIV replication by enhancing the activity of nucleoside reverse transcriptase inhibitors (see Pharmacology: Antiviral Effects), and hydroxyurea monotherapy is not effective for the treatment of HIV infection.

Use of hydroxyurea as an adjunct to antiretroviral therapy for HIV infection generally is not recommended; if further study is undertaken to explore the possible role of hydroxyurea in this condition (e.g., salvage regimens, therapy for early-stage disease), patients must be closely monitored for potentially serious toxicity.

Cervical Cancer

Hydroxyurea has been used for the treatment of cervical cancer; however, other agents are considered more effective for the treatment of this neoplasm.

Hydroxyurea mainly has been used as a radiation sensitizer, but evidence from randomized trials indicates that other agents, particularly cisplatin (used alone or in combination), are superior to hydroxyurea for concomitant use with radiation therapy for the treatment of locally advanced cervical cancer. () Limited evidence from a small randomized trial of patients with advanced cervical cancer suggests that cisplatin-based chemotherapy is superior to hydroxyurea, which has minimal activity as a single agent in the treatment of metastatic or recurrent cervical cancer.

Head and Neck Cancer

Hydroxyurea has been used in combination with radiation therapy for local control of primary squamous cell (epidermoid) carcinoma of the head and neck, excluding the lip.

Other Uses

Although hydroxyurea also is labeled for use in the treatment of melanoma and recurrent, metastatic, or inoperable ovarian cancer, other agents are preferred for the treatment of these neoplasms. (See and .)

Hydroxyurea has been used in the treatment of psoriasis and is reportedly beneficial in the treatment of hypereosinophilic syndrome that does not respond to corticosteroid therapy.

Dosage and Administration

Administration

Hydroxyurea is administered orally.

If the patient is unable to swallow the commercially available hydroxyurea capsules, the contents may be emptied into a glass of water and administered immediately. Some inert materials may not dissolve and may float on the surface.

Hydroxyurea is a potent drug that must be handled with care, and the powder should not be allowed to come in contact with skin or mucous membranes. Impervious gloves should be worn to reduce the risk of skin exposure to the drug when handling hydroxyurea or bottles containing hydroxyurea. Impervious gloves should be worn during handling of hydroxyurea or bottles containing hydroxyurea at all times, including unpacking and inspection, transport within a facility, dose preparation, and dose administration. The hands should be washed before and after contact with hydroxyurea or bottles containing hydroxyurea. If the contents of the capsule are spilled, the powder should be wiped up immediately with a damp disposable towel and discarded in a closed container (e.g., a plastic bag). Patients should be cautioned on proper handling, storage, and disposal of the drug.(See Precautions and Contraindications.)

Dosage

Dosage of hydroxyurea must be individualized and should be based on actual body weight unless the patient is obese or has fluid retention. In these latter instances, dosage is based on ideal weight. Clinicians should consult published protocols for the dosage of hydroxyurea and other chemotherapeutic agents and the method and sequence of administration.

Chronic Myelogenous Leukemia

For the treatment of chronic myelogenous leukemia, an adult hydroxyurea dosage of 20-30 mg/kg administered as a single dose daily is recommended. An adequate trial period for determining the antineoplastic effectiveness of hydroxyurea is 6 weeks. Hydroxyurea therapy should be continued indefinitely in patients who show regression or arrest of tumor growth; however, if marked bone marrow depression occurs at any time, therapy should be interrupted.(See Dosage Modification for Toxicity and Contraindications for Continued Therapy: Hematologic Toxicity.)

Solid Tumors

For the treatment of solid tumors, the recommended adult dosage of hydroxyurea is 80 mg/kg administered as a single dose every third day. Alternatively, 20-30 mg/kg may be administered as a single dose daily.

For the treatment of head and neck cancer during concomitant radiation therapy, the recommended adult dosage of hydroxyurea is 80 mg/kg administered as a single dose every third day. Administration of hydroxyurea should begin at least 7 days before initiation of radiation therapy and is continued during irradiation as well as afterwards provided the patient is closely monitored and no unusual or severe reactions occur.

Sickle Cell Anemia

For the palliative treatment of sickle cell anemia with recurrent moderate to severe painful crises in adults, the recommended initial dosage of hydroxyurea is 15 mg/kg daily (based on the patient's actual or ideal weight, whichever is less) administered as a single dose. Some patients receiving the recommended initial dosage of hydroxyurea have experienced severe or life-threatening myelosuppression requiring interruption of therapy and subsequent dosage reduction.

Following initiation of hydroxyurea therapy, dosage should then be adjusted according to the patient's blood cell count, which should be monitored every 2 weeks. If blood cell counts are in an acceptable range (i.e., neutrophil count at least 2500 cells/mm, platelet count at least 95,000/mm, hemoglobin concentration exceeding 5.3 g/dL, and reticulocyte count at least 95,000/mm if hemoglobin concentration is less than 9 g/dL), the dosage of hydroxyurea may be increased in increments of 5 mg/kg daily once every 12 weeks to a maximum tolerated dosage of up to 35 mg/kg daily; the maximum tolerated dosage is defined as the highest daily dose that does not produce hematologic toxicity (i.e., neutrophil count less than 2000 cells/mm, platelet count less than 80,000/mm, hemoglobin concentration less than 4.5 g/dL, and reticulocyte count less than 80,000/mm if hemoglobin concentration is less than 9 g/dL) during 24 consecutive weeks of therapy. If blood cell counts are between the acceptable range and the toxic range, the dosage should not be increased. If a patient's blood cell count is in the toxic range, hydroxyurea should be discontinued until hematologic recovery occurs; treatment may then be resumed at a reduced daily dose of 2.5 mg/kg less than the dose that resulted in toxicity. Titration of the dosage of hydroxyurea may then be resumed by increasing or decreasing the daily dose in increments of 2.5 mg/kg once every 12 weeks to a maximum tolerated dosage (up to 35 mg/kg daily) at which the patient does not experience hematologic toxicity during 24 consecutive weeks of therapy. Further attempts should not be made to titrate to a dosage level that resulted in hematologic toxicity during 2 separate periods of dosage adjustment.

Optimum hydroxyurea dosage for the prevention of clinical manifestations of sickle cell anemia remains to be established. Because the principal study to date establishing clinical benefit in this condition was designed to measure response among patients treated with maximally tolerated hydroxyurea dosages, it is possible that dosages lower than those employed in this study also may be beneficial.

In adults enrolled in the Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH), hydroxyurea therapy was initiated at a dosage of 15 mg/kg daily. Dosage then was increased in increments of 5 mg/kg daily at 12-week intervals as tolerated up to a maximum of 35 mg/kg daily. The median dosage at the time of closure of the study was 20 mg/kg daily, and the median maximum tolerated dosage was 17.5 mg/kg daily. Preliminary results from this trial suggested that the maximally tolerated dosage may not be required to achieve therapeutic benefits.

Polycythemia Vera

Hydroxyurea therapy has been initiated in a dosage of 15-20 mg/kg daily for the management of polycythemia vera. Although therapy also has been initiated with a dosage of 30 mg/kg daily for 1 week, followed by 15 mg/kg daily, omitting the loading dose has resulted in better patient tolerance of initial hydroxyurea therapy. Supplemental phlebotomy can be performed as necessary to control hematocrit. There is considerable interindividual variability in patient response to hydroxyurea, and dosage must be individualized according to hematocrit response (usually to less than 45-50%) and hematologic tolerance of the patient. Although most adults with polycythemia vera respond adequately to hydroxyurea dosages of 500 mg to 1 g daily, some patients may respond to as little as 1.5-2 g weekly (along with occasional phlebotomy), while others may require dosages as high as 1.5-2 g or more daily.

Dosage Modification for Age-related Effects

Pediatric dosage regimens for hydroxyurea have not been established.

Dosage reduction may be necessary in geriatric patients receiving hydroxyurea.

Dosage Modification for Toxicity and Contraindications for Continued Therapy

Hematologic Toxicity

In patients receiving the drug for antineoplastic therapy, hydroxyurea should be withheld when the leukocyte count is less than 2500/mm or the platelet count is less than 100,000/mm. Leukocyte and platelet counts should be reevaluated after 3 days; therapy may be resumed when the counts return to acceptable levels. Because hematopoietic rebound is prompt, it is usually necessary to omit only a few doses. Severe anemia, if it occurs during treatment, may be managed without interrupting hydroxyurea therapy.

If hematologic recovery has not occurred promptly during combined hydroxyurea and radiation therapy, radiation may be interrupted. The need for postponement of radiation therapy has been rare, and irradiation usually has been continued using the recommended dosage and technique.

In patients receiving the drug for sickle cell anemia, hydroxyurea should be withheld when the neutrophil count is less than 2000/mm, the platelet count is less than 80,000/mm, the hemoglobin concentration is less than 4.5 g/dL, or the reticulocyte count is less than 80,000/mm with a hemoglobin concentration of less than 9 g/dL. Recovery from myelosuppression usually is rapid when therapy is interrupted. Following hematologic recovery, hydroxyurea therapy may be resumed at reduced dosage.(See instructions for dosage reduction in Dosage: Sickle Cell Anemia under Dosage and Administration.)

Pancreatic Toxicity

Fatal pancreatitis has occurred in patients receiving hydroxyurea in combination with antiretroviral agents, particularly didanosine, with or without stavudine. Hydroxyurea should be permanently discontinued in patients who develop signs and/or symptoms of pancreatitis.

Hepatic Toxicity

Fatal hepatotoxicity has occurred in patients receiving hydroxyurea in combination with antiretroviral agents, particularly didanosine, with or without stavudine. Hydroxyurea should be discontinued permanently in patients who develop signs and/or symptoms of hepatotoxicity.

GI Toxicity

Hydroxyurea may potentiate some adverse reactions typically observed with radiation therapy alone, such as gastric distress and mucositis. Interruption of hydroxyurea therapy may be required in patients who experience severe GI toxicity.

Dermatologic Toxicity

If cutaneous vasculitic toxicity, such as vasculitic ulcerations or gangrene, develops in patients with myeloproliferative disorders, hydroxyurea therapy should be discontinued and therapy with alternative cytoreductive agents should be initiated as clinically indicated.

Dosage in Renal and Hepatic Impairment

The effect of renal or hepatic impairment on the elimination of hydroxyurea has not been fully evaluated. Specific dosage recommendations for patients with renal or hepatic impairment are not available; however, the manufacturer recommends close monitoring of hematologic parameters in such patients. Reduction of hydroxyurea dosage should be considered for patients with impaired renal function.

Cautions

Hematologic Effects

Hydroxyurea's principal toxic effect is bone marrow depression. Leukopenia is usually the first and most common manifestation of bone marrow toxicity. Thrombocytopenia and anemia occur less often and are usually preceded by leukopenia. Hematologic status must be carefully monitored in patients receiving hydroxyurea.(See Cautions: Precautions and Contraindications.) Recovery from bone marrow depression is usually rapid when hydroxyurea therapy is interrupted; however, persistent cytopenia may occur rarely.

Self-limiting megaloblastic erythropoiesis is often seen soon after the initiation of hydroxyurea therapy and becomes less pronounced as therapy continues. The morphologic change resembles pernicious anemia but is not related to vitamin B12 or folic acid deficiency and is not necessarily accompanied by anemia. Hydroxyurea-induced macrocytosis may mask incidental folic acid deficiency, and the manufacturer recommends prophylactic administration of folic acid. Hemolysis and decreased serum iron values have also been reported. Hydroxyurea may delay plasma iron clearance and reduce the rate of iron utilization by the erythrocytes, but it does not appear to alter the red blood cell survival time.

The principal short-term risk of hydroxyurea in the treatment of sickle cell anemia also is myelosuppression. In early studies in patients receiving initial hydroxyurea dosages of 3-50 mg/kg daily, myelosuppression generally was mild, defined as a neutrophil count less than 2000/mm or reticulocyte or platelet count less than 80,000/mm. Patients did not experience any bleeding episodes nor an increased incidence of infection, although severe anemia was noted rarely. The reported incidence and degree of myelosuppression were greater in patients who responded to hydroxyurea therapy than in those who did not respond. In the multicenter study establishing efficacy of hydroxyurea in preventing painful crises in patients with sickle cell anemia receiving dosages up to 35 mg/kg daily (the Multicenter Study of Hydroxyurea in Sickle Cell Anemia [MSH]), bone marrow suppression, which was reversible following discontinuance of the drug, also was the principal adverse effect observed. Patients were monitored carefully every 2 weeks for evidence of myelosuppression (defined by absolute neutrophil counts less than 2000/mm, absolute reticulocyte counts less than 80,000/mm, a decrease in hemoglobin concentrations from a baseline of 7 g/dL or more to 4.5-5 g/dL, reticulocyte counts less than 320,000/mm, or hemoglobin concentrations less than 4.5 g/dL). No deaths were attributed to treatment with hydroxyurea and no neoplastic disorders developed during the study, which lasted for an average follow-up of 21 months. Treatment was discontinued permanently for medical reasons in about 10% of patients receiving hydroxyurea; in a few such patients, an unacceptable degree of myelotoxicity was experienced at the initial dosage of 2.5 mg/kg daily. Treatment was withheld temporarily in virtually all patients receiving the drug because of bone marrow depression, but blood counts generally recovered within 2 weeks. No patient experienced life-threatening myelosuppression.

Hemoglobin concentrations repeatedly exceeded 12.8 g/dL in about 7% of patients receiving hydroxyurea but not transfusions in the multicenter study of sickle cell anemia; such increase could result in potentially adverse consequences because of increased blood viscosity (if Hb-F levels were not sufficiently high to inhibit sickling of red cells in vivo). Thrombocytosis manifested as platelet counts exceeding 800,000/mm occurred in about 3% of patients receiving the drug in this study. However, no morbidity was associated with the markedly elevated hemoglobin concentrations or platelet counts.

Although hydroxyurea-induced myelosuppression usually is made to therapeutic use in patients with polycythemia vera, dose-dependent myelotoxicity can occur during therapy with the drug in such patients; the risk of clinical toxicity generally can be minimized by adequate monitoring and titration of dosage (e.g., by reducing hydroxyurea dosage and increasing the use of supplemental phlebotomy if necessary). Despite good long-term hematologic control, thrombotic episodes can occur in patients receiving hydroxyurea for polycythemia vera. However, some evidence indicates that the risk of thrombotic complications is reduced overall compared with phlebotomy therapy alone in patients with this disease, at least during for the first several years of such therapy.

GI Effects

Adverse GI effects include stomatitis, nausea, vomiting, anorexia, constipation, and diarrhea; ulceration of the buccal mucosa and GI epithelium may occur with severe hydroxyurea intoxication. Hydroxyurea may potentiate some adverse reactions typically observed with radiation therapy alone, such as gastric distress and mucositis.

Severe gastric distress (e.g., nausea, vomiting, anorexia) resulting from combined hydroxyurea and radiation therapy may usually be controlled by temporarily discontinuing hydroxyurea administration. Severe GI intolerance, which can require discontinuance of the drug, also has occurred when hydroxyurea was used for the treatment of polycythemia vera; stomatitis also has been reported in patients receiving the drug for this disease.

Although inflammation of mucous membranes (mucositis) at the site of irradiation may be attributed to radiation therapy alone, hydroxyurea may exacerbate this effect. Pain or discomfort from mucositis at the site of irradiation usually may be controlled by topical anesthetics and oral analgesics. If inflammation of the mucous membranes is severe, hydroxyurea therapy may be temporarily interrupted, and if it is extremely severe, radiation therapy also may be temporarily postponed; however, it has rarely been necessary to terminate these therapies.

Pancreatic Effects

Pancreatitis, in some cases fatal, has been reported in patients with HIV infection receiving hydroxyurea in combination with antiretroviral agents, particularly didanosine, with or without stavudine.(See Dosage Modification for Toxicity and Contraindications for Continued Therapy: Pancreatic Toxicity.)

Hepatic Effects

Hepatotoxicity, in some cases resulting in fatal hepatic failure, has been reported in patients with HIV infection receiving hydroxyurea in combination with antiretroviral agents. Fatal hepatotoxicity occurred most frequently in patients receiving combination therapy with hydroxyurea, didanosine, and stavudine. Elevation of serum concentrations of hepatic enzymes has been reported in patients receiving hydroxyurea.(See Dosage Modification for Toxicity and Contraindications for Continued Therapy: Hepatic Toxicity.)

Dermatologic Effects

Cutaneous vasculitic toxicities, including vasculitic ulcerations and gangrene, have occurred in patients receiving hydroxyurea for myeloproliferative disorders, particularly in patients who have received or who are receiving interferon therapy.(See Dosage Modification for Toxicity and Contraindications for Continued Therapy: Dermatologic Toxicity.)

Maculopapular rash, skin ulceration, dermatomyositis-like skin changes, and peripheral and facial edema have been reported in patients receiving hydroxyurea. Mild, reversible, dermatologic reactions such as maculopapular rash, facial erythema, and pruritus may occur in some patients. Alopecia has occurred rarely. Hyperpigmentation, atrophy of skin and nails, scaling, and violet papules have occurred in some patients after several years of daily maintenance therapy with the drug. In addition, the development of cutaneous leg ulcers has been reported in patients receiving chronic treatment with hydroxyurea. In most cases, the ulcers resolved completely following discontinuance of the drug. Skin cancer also has been reported.

Nervous System Effects

Peripheral neuropathy, in some cases severe, has occurred in patients with HIV infection receiving hydroxyurea in combination with antiretroviral agents, including didanosine, with or without stavudine. Acute delirium has been reported in a patient receiving hydroxyurea and antiretroviral agents.

Rarely, neurologic disturbances such as headache, dizziness, disorientation, hallucinations, and seizures, have been reported in patients receiving hydroxyurea. The use of large doses of hydroxyurea may produce moderate drowsiness.

Respiratory Effects

Acute pulmonary reactions consisting of diffuse pulmonary infiltrates, fever, and dyspnea have been reported rarely in patients receiving hydroxyurea. Pulmonary fibrosis also has occurred rarely in patients receiving the drug.

Renal Effects

Suppression of renal tubular function has occurred in some patients receiving hydroxyurea and may be accompanied by hyperuricemia and elevated BUN and serum creatinine concentrations. Abnormal retention of sulfobromophthalein also has been reported.

Immunologic Effects

A median decrease in CD4 T-cell count of approximately 100/mm was reported in patients with HIV infection receiving hydroxyurea, didanosine, stavudine, and indinavir in a clinical trial.

Other Adverse Effects

Fever, chills, malaise, edema, and asthenia have occurred in patients receiving hydroxyurea. Dysuria has occurred rarely.

Parvovirus B19 infection developed in at least one patient receiving hydroxyurea for the treatment of sickle cell anemia; however, this infection also occurred in several patients who received placebo in this controlled study, and the virus-induced aplastic crises were not prolonged, with all patients recovering uneventfully. Alopecia, rash, fever, and GI disturbances also were reported in patients with sickle cell anemia, but they occurred comparably in patients receiving the drug or placebo.

Other adverse effects reported in patients receiving hydroxyurea for the treatment of polycythemia vera generally were mild and included fever and hyperbilirubinemia.

Precautions and Contraindications

Hydroxyurea is a highly toxic drug with a low therapeutic index, and a therapeutic response is not likely to occur without some evidence of toxicity. Hydroxyurea therapy may be complicated by severe, sometimes life-threatening or fatal, adverse effects. The drug must be used only under constant supervision by clinicians experienced in therapy with cytotoxic agents or the use of this agent for sickle cell anemia.

Hydroxyurea should be administered with caution to patients who have recently received other cytotoxic drugs or radiation therapy, since bone marrow depression is likely in these patients. In addition, an exacerbation of post-irradiation erythema may occur.

Hematologic status, including bone marrow examination as clinically indicated, should be determined before initiation of therapy and checked repeatedly during treatment with hydroxyurea. Antineoplastic therapy with hydroxyurea should not be initiated in patients with myelosuppression (i.e., leukocyte count less than 2500/mm, platelet count less than 100,000/mm, or severe anemia). Complete blood cell counts including determination of hemoglobin level, total leukocyte counts, and platelet counts should be performed at least weekly during therapy for neoplasms. Hydroxyurea therapy for sickle cell anemia should not be initiated in patients with myelosuppression (i.e., neutrophil count less than 2000/mm, platelet count less than 80,000/mm, hemoglobin concentration less than 4.5 g/dL, or reticulocyte count less than 80,000/mm with a hemoglobin concentration of less than 9 g/dL). Complete blood cell counts should be performed at least every 2 weeks during therapy for sickle cell anemia. Some clinicians perform less frequent monitoring (e.g., weekly until stabilization occurs and then every 2 weeks for the initial months of therapy, followed by monthly or less frequent monitoring once response has been established) when the drug is used chronically and dosage is titrated carefully for sickle cell anemia or polycythemia vera. Careful monitoring of hematologic status is necessary to determine the need for interruption of hydroxyurea therapy and dosage reduction in patients experiencing myelotoxicity (see Dosage Modification for Toxicity and Contraindications for Continued Therapy: Hematologic Toxicity in Dosage and Administration: Dosage).

Renal and liver function should be evaluated before initiation of therapy and checked repeatedly during treatment with hydroxyurea. Hydroxyurea should be used with caution in patients with renal dysfunction.

Hydroxyurea-induced macrocytosis may mask incidental folic acid deficiency; prophylactic administration of folic acid is recommended in patients receiving the drug.

Patients receiving hydroxyurea for sickle cell anemia or polycythemia vera must understand that therapy with the drug is not a cure for these diseases (i.e., beneficial effects of hydroxyurea are maintained only as long as the patient complies with the prescribed dosage) and that the long-term risks associated with such therapy have not been established. Secondary leukemias have been reported in patients receiving long-term therapy with hydroxyurea for myeloproliferative disorders, such as polycythemia vera and thrombocythemia. (See Cautions: Mutagenicity and Carcinogenicity.) Because of the potential risks of cytotoxic therapy, all patients with either of these diseases must be evaluated carefully before initiation of hydroxyurea therapy and monitored during treatment, including for potential myelotoxic effects. The beneficial effects of hydroxyurea usually are not apparent for several months, and its use must be carefully monitored.

Use of hydroxyurea in combination with antiretroviral agents is not recommended because of the inconclusive benefit and serious toxicity associated with such regimens. Close monitoring for clinical manifestations of pancreatitis and hepatotoxicity is necessary in patients with HIV infection receiving hydroxyurea, especially when the drug is administered in combination with didanosine and/or stavudine.

Patients should be cautioned on proper handling of hydroxyurea. Hydroxyurea is a potent drug that must be handled with care, and the powder should not be allowed to come in contact with skin or mucous membranes. Disposable gloves should be worn to reduce the risk of skin exposure to the drug when handling hydroxyurea or bottles containing hydroxyurea. The hands should be washed before and after contact with hydroxyurea or bottles containing hydroxyurea. If the contents of the capsule are spilled, the powder should be wiped up immediately with a damp disposable towel and discarded in a closed container (e.g., a plastic bag). Hydroxyurea capsules should be stored out of reach of children and pets. A clinician should be contacted for instructions on how to discard unused or expired hydroxyurea capsules.

Hydroxyurea is contraindicated in patients with known hypersensitivity to the drug or any component of the formulation.

Pediatric Precautions

Safety and efficacy of hydroxyurea in children have not been established.

Geriatric Precautions

Because geriatric patients may be particularly sensitive to the effects of hydroxyurea, they may require a lower dosage of the drug. Because hydroxyurea is excreted by the kidney, and renal function may be decreased in geriatric patients, dosage should be titrated carefully, usually initiating therapy at the low end of the dosage range, and renal function should be monitored.

Mutagenicity and Carcinogenicity

Long-term risks, including possible carcinogenic potential, associated with hydroxyurea therapy for the treatment of sickle cell anemia or polycythemia vera are not clearly established.

Hydroxyurea is genotoxic in a wide range of test systems and is presumed to be a human carcinogen. Intraperitoneal administration of hydroxyurea 125-250 mg/kg (approximately 0.6-1.2 times the maximum recommended human oral daily dose on a mg/m basis) 3 times weekly for 6 months to female rats resulted in an increased incidence of mammary tumors in rats surviving to 18 months. In vitro tests have shown the drug to be mutagenic to bacteria, fungi, protozoa, and mammalian cells; in addition, in vitro tests in hamster cells and human lymphoblasts and in vivo tests (i.e., SCE assay in rodents, mouse micronucleus assay) have shown hydroxyurea to be clastogenic. Hydroxyurea also causes transformation of rodent embryo cells to a tumorigenic phenotype. According to the results of other studies, hydroxyurea suppressed two-stage carcinogenesis in mouse skin and was considered noncarcinogenic in 2 small studies in animals. Although the risk of carcinogenesis/leukemogenesis in humans treated with hydroxyurea currently is unknown, it should not be discounted.

The most extensive, well-documented clinical evidence of the leukemogenic potential of the drug is inconclusive. Data from the Polycythemia Vera Study Group revealed a 5.9% incidence of acute leukemia after a medical follow-up in 51 patients with polycythemia vera who were treated with hydroxyurea doses somewhat greater than those used to treat sickle cell anemia. The corresponding incidence of acute leukemia in a historical control group of 134 patients with polycythemia vera treated with phlebotomy alone was 1.5%. The 3.9-fold increased incidence was not statistically significant, but the sample size was relatively small; the median observation period was 8.6 years. An update on patients enrolled in the Polycythemia Vera Study Group reported an additional patient treated with hydroxyurea who had developed acute leukemia and a fifth patient who had died of a myeloproliferative syndrome. Recalculation that includes these additional cases as well as 2 additional cases that occurred in patients treated with phlebotomy alone results in an incidence of acute leukemia in hydroxyurea-treated polycythemia vera patients of 7.8%, which was not significantly different from the 3% rate in the phlebotomy group, but the sample size still is relatively small and the possibility of a leukemogenic effect cannot be excluded. In 3 smaller studies involving patients with polycythemia vera who were treated with hydroxyurea as the sole myelosuppressive agent, the reported median incidence of acute leukemia was 10.5%. Non-Hodgkin's lymphoma, a complication of chlorambucil treatment in patients with polycythemia vera, has been reported in at least one patient with polycythemia vera treated with hydroxyurea. The relevance of cancer incidence data in patients with polycythemia vera who received hydroxyurea to that of patients receiving the drug for sickle cell anemia has been questioned, since polycythemia vera, unlike sickle cell anemia, is a myeloproliferative stem-cell disorder that has a tendency to evolve into acute leukemia. However, both diseases are characterized by an intense erythroid turnover.

No cases of secondary leukemia or malignancies were observed in 64 hydroxyurea-treated patients with erythrocytosis secondary to inoperable cyanotic congenital heart disease. These patients received hydroxyurea dosages of 9-21 mg/kg daily for 2-15 years; mean duration of treatment was 5.7 years.

Skin cancer has been reported in patients receiving long-term therapy with hydroxyurea.

Hydroxyurea is a mutagen. The drug also is a clastogen and reportedly a strong inducer of chromosomal breaks in vitro; however, hydroxyurea exhibited only weak activity in inducing sister chromatid exchange. Chromosomal abnormalities have been noted in patients with lung cancer or polycythemia vera who were treated with hydroxyurea, and in cultured cells treated with the drug. Abnormal karyotypes have been observed in lymphocytes from patients with psoriasis who were treated with hydroxyurea, but no control studies were performed in untreated patients with psoriasis. Hydroxyurea's ability to induce chromosomal abnormalities was considered minor in some preliminary studies, but longer follow-up of additional patients receiving the drug for sickle cell anemia or polycythemia vera will be required to assess the risk.

Pregnancy, Fertility, and Lactation

Pregnancy

Hydroxyurea can cause fetal toxicity when administered to pregnant women, but potential benefits from use of the drug may be acceptable in certain conditions despite the possible risks to the fetus. Hydroxyurea crosses the placenta and has been shown to be a potent teratogen in a wide variety of animal models, including mice, hamsters, cats, miniature swine, dogs, and monkeys, when administered in doses within onefold of the human dose based on body surface area. Administration of 180 mg/kg daily (about 0.8 times the maximum recommended human daily dose on a mg/m basis) or 30 mg/kg daily (about 0.3 times the maximum recommended human daily dose on a mg/m basis) of the drug resulted in fetal malformations (including partially ossified cranial bones, absence of eye sockets, hydrocephaly, bipartite sternebrae, and missing lumbar vertebrae) in rats or rabbits, respectively. Embryotoxicity, manifested as decreased fetal viability, reduced live litter sizes, and developmental delays, also was observed. Single doses of 375 mg/kg (approximately 1.7 times the maximum recommended human daily dose on a mg/m basis) in rats resulted in growth retardation and impaired learning ability. In other studies in rats, the teratogenic properties of hydroxyurea were demonstrated at dosages 10- to 20-fold greater than those administered in patients with sickle cell disease, and aspirin was equally teratogenic at comparable dosages.

There are no adequate and well-controlled studies to date using hydroxyurea in pregnant women. Hydroxyurea should be used during pregnancy only in life-threatening situations or severe disease for which safer drugs cannot be used or are ineffective. When the drug is administered during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be informed of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant during therapy with hydroxyurea.

Children born to patients entered in the Multicenter Study of Hydroxyurea in Sickle Cell Anemia and treated with hydroxyurea have shown no evidence of birth defects or developmental abnormalities to date. Women with chronic myelogenous leukemia receiving hydroxyurea therapy have also borne normal children, and there currently are no reports of hydroxyurea-treated males with chronic myelogenous leukemia having fathered a child with genetic abnormalities, but it has not been established whether risks exist to a fetus whose father was being treated with the drug at the time of conception. There currently are no reports establishing hydroxyurea as causing any teratogenic or mutagenic effects in humans; however, because hydroxyurea affects DNA synthesis, its potential as a mutagenic agent should be considered in male or female patients who may contemplate conception. In addition, although the long-term risks of hydroxyurea (including teratogenesis, mutagenesis, leukemogenesis/carcinogenesis, and chromosomal abnormalities) are poorly documented, they should not be ignored. Therefore, hydroxyurea should not be administered to pregnant women or to women of childbearing age who may become pregnant unless the potential benefit to the patient outweighs the possible risk to the fetus. In addition, some clinicians recommend that hydroxyurea not be used for long-term therapy (e.g., sickle cell anemia) in patients likely to become pregnant, and that every effort be made to prevent conception and pregnancy in women who are patients (or partners of patients) receiving the drug chronically.

Fertility

Testicular atrophy, decreased spermatogenesis, and reduced ability to impregnate females were observed in male rats receiving hydroxyurea 60 mg/kg daily (about 0.3 times the maximum recommended human daily dose on a mg/m basis). Hydroxyurea also has been shown to induce abnormalities in sperm morphology and chromatin structure in mice. The cytologic appearance of mouse sperm was altered at hydroxyurea dosages in excess of 25 mg/kg, but no abnormalities have been noted in offspring of male mice treated with the drug.

Lactation

Hydroxyurea is distributed into milk. Because of the potential for serious adverse reactions to hydroxyurea in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

Drug Interactions

Formal studies evaluating potential drug interactions with hydroxyurea have not been performed to date. Concomitant therapy with hydroxyurea and other myelosuppressive agents or radiation therapy may increase the likelihood of bone marrow depression or other adverse effects, and dosage adjustment may be required. Because hydroxyurea therapy may cause increased serum uric acid concentrations, dosage adjustment of uricosuric medication may be required.

Pharmacokinetics

Absorption

Hydroxyurea is readily absorbed from the GI tract. Peak serum concentrations are attained within 1-4 hours following oral administration. Blood concentrations decline rapidly and there is no cumulative effect with repeated administration. For this reason, higher blood concentrations are attained if the regular dosage is given in a large, single oral dose than if it is administered in divided doses. Disproportionate increases in peak plasma concentrations and areas under the concentration-time curve (AUCs) result when drug dosage is increased. The effect of food on the absorption of hydroxyurea has not been determined.

Distribution

Hydroxyurea distributes rapidly throughout the body and concentrates in leukocytes and erythrocytes. The estimated volume of distribution of the drug approximates total body water. Hydroxyurea crosses the blood-brain barrier; peak hydroxyurea CSF concentrations are attained within 3 hours following oral administration. The drug distributes into ascites fluid, resulting in drug concentrations in ascites fluid of 2-7.5 times less than plasma drug concentrations. The drug also is distributed in milk.

Elimination

Studies indicate that up to 50% of an orally administered dose of hydroxyurea is metabolized in the liver; however, the precise metabolic pathways have not been determined. A minor metabolic pathway may involve degradation of the drug by urease, an enzyme produced by intestinal bacteria. Acetohydroxamic acid, possibly resulting from the breakdown of hydroxyurea by urease, was detected in the serum of 3 patients with leukemia treated with hydroxyurea.

Hydroxyurea undergoes nonlinear excretion via 2 separate routes: a saturable pathway most likely involving hepatic metabolism, and a linear pathway comprised of first-order renal excretion. Mean cumulative urinary excretion of 62% of the administered dose at 8 hours was reported in adults with sickle cell anemia.

The pharmacokinetics of hydroxyurea have not been evaluated separately by age, gender, or race. The effects of renal and/or hepatic impairment on the disposition of hydroxyurea have not been fully evaluated. Elimination of hydroxyurea may be impaired in patients with renal and/or hepatic dysfunction.

Studies usingC-labeled hydroxyurea indicate that about one-half an orally administered dose is degraded in the liver and is excreted as respiratory carbon dioxide and in urine as urea. The remaining portion of the drug is excreted intact in urine.

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