英文药名: Droxia(Hydroxyurea Capsules) 中文药名: 羟基脲胶囊 生产厂家: Bristol Meyers Squibb 药品简介 羟基脲是一种核苷二磷酸还原酶抑制剂，可阻止核苷酸还原为脱氧核苷酸，干扰嘌呤及嘧啶碱基生物合成，选择性地阻碍DNA合成，对RNA及蛋白质合成无阻断作用。周期特异性药，S期细胞敏感。适用于对慢性粒细胞白血病（CML），并可用于对马利兰耐药的CML；对黑色素瘤、肾癌、头颈部癌有一定疗效，与放疗联合对头颈部及宫颈鳞癌有效。CML每日20～60mg/kg，每周两次，6周为一疗程；头颈癌、宫颈鳞癌等每次80mg/kg，每三天1次，需与放疗合用。 羟基脲片的副作用常见的有： 1．骨髓抑制：为剂量限制性毒性，可致白细胞和血小板减少，停药后1～2周可恢复； 2．有时出现胃肠道反应，尚有致睾丸萎缩和致畸胎的报道； 3．偶有中枢神经系统症状和脱发，亦有本药引起药物性发热的报道，重复给药时可再出现。水痘、带状疱疹及各种严重感染时禁用羟基脲片。服用本品可使患者免疫机能受到抑制，故用药期间避免接种死或活病毒疫苗，一般停药3个月至1年才可考虑接种疫苗。服用本品时应适当增加液体的摄入量，以增加尿量及尿酸的排泄。定期监测白细胞、血小板、血中尿素氮、尿酸及肌苷浓度。 本品有诱变、致畸胎及致癌的潜在可能，孕妇及哺乳期妇女禁用。老年患者对本品敏感，肾功能可能较差，故服用本品时应适当减少剂量。羟基脲片可能减少5－Fu转变为活性代谢物（Fd-UMP），二者并用应慎重；本品对中枢神经系统有抑制作用，故用本品时慎用巴比妥类、安定类、麻醉药等；本品有可能提高患者血中尿酸的浓度，故与别嘌呤醇、秋水仙碱、丙磺舒等合用治疗痛风时，须调整上述药物剂量。本品与别嘌呤醇合用能预防并逆转其所致的高尿酸血症，与烷化剂无交叉耐药。 Bristol-Myers Squibb生产的羟基脲现以商品名Droxia用于治疗镰状细胞性贫血(该药原为抗肿瘤药物)。它适用于复发性中度或重度疼痛危象的成年人(通常在12个月内发作3次或3次以上)， 以减少危象复发频率和输血的需要。羟基脲对这类病人的有效性是通过多中心安慰剂对照试验证实的。 其有效性可能与其提高红细胞中血红蛋白F的水平，减少中性白细胞，增加红细胞中水的含量，增强镰状细胞的变形性以及改变红细胞对内膜的粘连有关。 该产品标签上警告羟基脲有致突变作用而致癌。骨髓增生障碍的病人如长期使用可能继发白血病。 美国食品药品监督管理局（FDA）发布信息： 百时美施贵宝公司修改了羟基脲（hydroxyurea,商品名：Hydrea、Droxia）胶囊的说明书，增加了有关皮肤血管毒性的警告。 修改的说明书在“警告”和“不良反应”项下增加了以下内容： 在骨髓增殖异常的病人中，使用羟基脲出现了皮肤血管毒性（cutaneous vasculitic）反应，包括血管溃疡（vasculitic ulcerations）和血管坏死（gangrene）。而报道出现血管毒性的病人大多数曾经或者正在接受干扰素治疗。由于血管溃疡潜在的严重后果，如果溃疡再继续发展，羟基脲就应该被停用。 在“患者须知”（Information for Patients）和“用法用量”部分增加了以下内容： 对羟基脲的处理过程应该谨慎。不服用羟基脲者不要接触此药。为了降低接触该药的风险，配药或接触装有羟基脲的药瓶时应该戴上一次性手套。任何人在接触含有羟基脲的药瓶或胶囊前后都要洗手。如果药粉不小心从胶囊中洒出，应该用一次性湿毛巾将其拭去，并丢弃在密闭的容器（如塑料袋）中。该药应该远离儿童和宠物。 DROXIA WARNING Treatment of patients with DROXIA may be complicated by severe, sometimes life-threatening, adverse effects. DROXIA should be administered under the supervision of a physician experienced in the use of this medication for the treatment of sickle cell anemia. Hydroxyurea is mutagenic and clastogenic, and causes cellular transformation to a tumorigenic phenotype. Hydroxyurea is thus unequivocally genotoxic and a presumed transspecies carcinogen which implies a carcinogenic risk to humans. In patients receiving long-term hydroxyurea for myeloproliferative disorders, such as polycythemia vera and thrombocythemia, secondary leukemias have been reported. It is unknown whether this leukemogenic effect is secondary to hydroxyurea or is associated with the patient’s underlying disease. The physician and patient must very carefully consider the potential benefits of DROXIA relative to the undefined risk of developing secondary malignancies. DESCRIPTION DROXIA® (hydroxyurea capsules, USP) is available for oral use as capsules providing 200 mg, 300 mg, and 400 mg hydroxyurea. Inactive ingredients: citric acid, gelatin, lactose, magnesium stearate, sodium phosphate, titanium dioxide, and capsule colorants; FD&C Blue #1 and FD&C Green #3 (200 mg capsules); D&C Red #28, D&C Red #33, and FD&C Blue #1 (300 mg capsules); D&C Red #28, D&C Red #33, and D&C Yellow #10 (400 mg capsules). Hydroxyurea is an essentially tasteless, white crystalline powder. Its structural formula is:   Hydroxyurea Chemical Structure CLINICAL PHARMACOLOGY Mechanism of Action The precise mechanism by which hydroxyurea produces its cytotoxic and cytoreductive effects is not known. However, various studies support the hypothesis that hydroxyurea causes an immediate inhibition of DNA synthesis by acting as a ribonucleotide reductase inhibitor, without interfering with the synthesis of ribonucleic acid or of protein. The mechanisms by which DROXIA produces its beneficial effects in patients with sickle cell anemia (SCA) are uncertain. Known pharmacologic effects of DROXIA that may contribute to its beneficial effects include increasing hemoglobin F levels in RBCs, decreasing neutrophils, increasing the water content of RBCs, increasing deformability of sickled cells, and altering the adhesion of RBCs to endothelium. Pharmacokinetics Absorption Hydroxyurea is readily absorbed after oral administration. Peak plasma levels are reached in 1 to 4 hours after an oral dose. With increasing doses, disproportionately greater mean peak plasma concentrations and AUCs are observed. There are no data on the effect of food on the absorption of hydroxyurea. Distribution Hydroxyurea distributes rapidly and widely in the body with an estimated volume of distribution approximating total body water. Plasma to ascites fluid ratios range from 2:1 to 7.5:1. Hydroxyurea concentrates in leukocytes and erythrocytes. Metabolism Up to 60% of an oral dose undergoes conversion through metabolic pathways that are not fully characterized. One pathway is probably saturable hepatic metabolism. Another minor pathway may be degradation by urease found in intestinal bacteria. Acetohydroxamic acid was found in the serum of three leukemic patients receiving hydroxyurea and may be formed from hydroxylamine resulting from action of urease on hydroxyurea. Excretion Excretion of hydroxyurea in humans is likely a linear first-order renal process. In adults with SCA, mean cumulative urinary recovery of hydroxyurea was about 40% of the administered dose. Special Populations Geriatric, Gender, Race No information is available regarding pharmacokinetic differences due to age, gender, or race. Pediatric No pharmacokinetic data are available in pediatric patients treated with hydroxyurea for SCA. Renal Insufficiency As renal excretion is a pathway of elimination, consideration should be given to decreasing the dosage of hydroxyurea in patients with renal impairment. In adult patients with sickle cell disease, an open-label, non-randomized, single-dose, multicenter study was conducted to assess the influence of renal function on the pharmacokinetics of hydroxyurea. Patients in the study with normal renal function (creatinine clearance [CrCl] >80 mL/min), mild (CrCl 50-80 mL/min), moderate (CrCl = 30-<50 mL/min), or severe (<30 mL/min) renal impairment received hydroxyurea as a single oral dose of 15 mg/kg, achieved by using combinations of the 200 mg, 300 mg, or 400 mg capsules. Patients with end-stage renal disease (ESRD) received two doses of 15 mg/kg separated by 7 days, the first was given following a 4-hour hemodialysis session, the second prior to hemodialysis. In this study, the mean exposure (AUC) in patients whose creatinine clearance was <60 mL/min (or ESRD) was approximately 64% higher than in patients with normal renal function. The results suggest that the initial dose of hydroxyurea should be reduced when used to treat patients with renal impairment. (See PRECAUTIONS and DOSAGE AND ADMINISTRATION .) The table below describes the recommended dosage modification. *On dialysis days, hydroxyurea should be administered to patients with ESRD following hemodialysis. Creatinine Clearance (mL/min) Recommended DROXIA Initial Dose (mg/kg daily) ≥60 15 <60 or ESRD* 7.5 Close monitoring of hematologic parameters is advised in these patients. Hepatic Insufficiency There are no data that support specific guidance for dosage adjustment in patients with hepatic impairment. Close monitoring of hematologic parameters is advised in these patients. Drug Interactions There are no data on concomitant use of hydroxyurea with other drugs in humans. Clinical Studies The efficacy of hydroxyurea in sickle cell anemia was assessed in a large clinical study (Multicenter Study of Hydroxyurea in Sickle Cell Anemia).1 The study was a randomized, double-blind, placebo-controlled trial that evaluated 299 adult patients (≥18 years) with moderate to severe disease (≥3 painful crises yearly). The trial was stopped by the Data Safety Monitoring Committee, after accrual was completed but before the scheduled 24 months of follow-up was completed in all patients, based on observations of fewer painful crises among patients receiving hydroxyurea. Compared to placebo treatment, treatment with hydroxyurea resulted in a significant decrease in the yearly rate of painful crises, the yearly rate of painful crises requiring hospitalization, the incidence of chest syndrome, the number of patients transfused, and units of blood transfused. Hydroxyurea treatment significantly increased the median time to both first and second painful crises. Although patients with 3 or more painful crises during the preceding 12 months were eligible for the study, most of the benefit in crisis reduction was seen in the patients with 6 or more painful crises during the preceding 12 months. EVENT HYDROXYUREA (N=152) PLACEBO (N=147) PERCENT CHANGE VS PLACEBO P-VALUE * A painful crisis was defined in the study as acute sickling-related pain that resulted in a visit to a medical facility, that lasted more than 4 hours, and that required treatment with a parenteral narcotic or NSAID. Chest syndrome, priapism, and hepatic sequestration were also included in this definition. Median yearly rate of painful crises* 2.5 4.6 −46 =0.001 Median yearly rate of painful crises requiring hospitalization 1.0 2.5 −60 =0.0027 Median time to first painful crisis (months) 2.76 1.35 +104 =0.014 Median time to second painful crisis (months) 6.58 4.13 +59 =0.0024 Incidence of chest syndrome (# episodes) 56 101 −45 =0.003 Number of patients transfused 55 79 −30 =0.002 Number of units of blood transfused 423 670 −37 =0.003 No deaths were attributed to treatment with hydroxyurea, and none of the patients developed neoplastic disorders during the study. Treatment was permanently stopped for medical reasons in 14 hydroxyurea-treated (2 patients with myelotoxicity) and 6 placebo-treated patients. (See ADVERSE REACTIONS .) Fetal Hemoglobin In patients with SCA treated with hydroxyurea, fetal hemoglobin (HbF) increases 4 to 12 weeks after initiation of treatment. In general, average HbF levels correlate with dose and plasma level with possible plateauing at higher dosages. A clear relation between reduction in crisis frequency and increased HbF or F-cell levels has not been demonstrated. The dose-related cytoreductive effects of hydroxyurea, particularly on neutrophils, was the factor most strongly correlated with reduced crisis frequency. INDICATIONS AND USAGE DROXIA (hydroxyurea capsules, USP) is indicated to reduce the frequency of painful crises and to reduce the need for blood transfusions in adult patients with sickle cell anemia with recurrent moderate to severe painful crises (generally at least 3 during the preceding 12 months). CONTRAINDICATIONS DROXIA is contraindicated in patients who have demonstrated a previous hypersensitivity to hydroxyurea or any other component of its formulation. WARNINGS DROXIA is a cytotoxic and myelosuppressive agent. DROXIA should not be given if bone marrow function is markedly depressed, as indicated by neutrophils below 2000 cells/mm3; a platelet count below 80,000/mm3; a hemoglobin level below 4.5 g/dL; or reticulocytes below 80,000/mm3 when the hemoglobin concentration is below 9 g/dL. Neutropenia is generally the first and most common manifestation of hematologic suppression. (See DOSAGE AND ADMINISTRATION .) Thrombocytopenia and anemia occur less often, and are seldom seen without a preceding leukopenia. Recovery from myelosuppression is usually rapid when therapy is interrupted. DROXIA causes macrocytosis, which may mask the incidental development of folic acid deficiency. Prophylactic administration of folic acid is recommended. In HIV-infected patients during therapy with hydroxyurea and didanosine, with or without stavudine, fatal and nonfatal pancreatitis have occurred. Hepatotoxicity and hepatic failure resulting in death have been reported during postmarketing surveillance in HIV-infected patients treated with hydroxyurea and other antiretroviral agents. Fatal hepatic events were reported most often in patients treated with the combination of hydroxyurea, didanosine, and stavudine. This combination should be avoided. Peripheral neuropathy, which was severe in some cases, has been reported in HIV-infected patients receiving hydroxyurea in combination with antiretroviral agents, including didanosine, with or without stavudine. Cutaneous vasculitic toxicities, including vasculitic ulcerations and gangrene, have occurred in patients with myeloproliferative disorders during therapy with hydroxyurea. These vasculitic toxicities were reported most often in patients with a history of, or currently receiving, interferon therapy. Due to potentially severe clinical outcomes for the cutaneous vasculitic ulcers reported in patients with myeloproliferative disease, hydroxyurea should be discontinued if cutaneous vasculitic ulcerations develop. Carcinogenesis and Mutagenesis (See BOXED WARNING .) Hydroxyurea is genotoxic in a wide range of test systems and is thus presumed to be a human carcinogen. In patients receiving long-term hydroxyurea for myeloproliferative disorders, such as polycythemia vera and thrombocythemia, secondary leukemia has been reported. It is unknown whether this leukemogenic effect is secondary to hydroxyurea or is associated with the patient’s underlying disease. Skin cancer has also been reported in patients receiving long-term hydroxyurea. Conventional long-term studies to evaluate the carcinogenic potential of DROXIA have not been performed. However, intraperitoneal administration of 125 to 250 mg/kg hydroxyurea (about 0.6-1.2 times the maximum recommended human oral daily dose on a mg/m2 basis) thrice weekly for 6 months to female rats increased the incidence of mammary tumors in rats surviving to 18 months compared to control. Hydroxyurea is mutagenic in vitro to bacteria, fungi, protozoa, and mammalian cells. Hydroxyurea is clastogenic in vitro (hamster cells, human lymphoblasts) and in vivo (SCE assay in rodents, mouse micronucleus assay). Hydroxyurea causes the transformation of rodent embryo cells to a tumorigenic phenotype. Pregnancy DROXIA can cause fetal harm when administered to a pregnant woman. Hydroxyurea has been demonstrated to be a potent teratogen in a wide variety of animal models, including mice, hamsters, cats, miniature swine, dogs, and monkeys at doses within 1-fold of the human dose given on a mg/m2 basis. Hydroxyurea is embryotoxic and causes fetal malformations (partially ossified cranial bones, absence of eye sockets, hydrocephaly, bipartite sternebrae, missing lumbar vertebrae) at 180 mg/kg/day (about 0.8 times the maximum recommended human daily dose on a mg/m2 basis) in rats and at 30 mg/kg/day (about 0.3 times the maximum recommended human daily dose on a mg/m2 basis) in rabbits. Embryotoxicity was characterized by decreased fetal viability, reduced live litter sizes, and developmental delays. Hydroxyurea crosses the placenta. Single doses of ≥375 mg/kg (about 1.7 times the maximum recommended human daily dose on a mg/m2 basis) to rats caused growth retardation and impaired learning ability. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant. PRECAUTIONS General Therapy with DROXIA requires close supervision. Some patients treated at the recommended initial dose of 15 mg/kg/day have experienced severe or life-threatening myelosuppression, requiring interruption of treatment and dose reduction. The hematologic status of the patient, as well as kidney and liver function should be determined prior to, and repeatedly during treatment. Treatment should be interrupted if neutrophil levels fall to <2000/mm3; platelets fall to <80,000/mm3; hemoglobin declines to less than 4.5 g/dL; or if reticulocytes fall below 80,000/mm3 when the hemoglobin concentration is below 9 g/dL. Following recovery, treatment may be resumed at lower doses (see DOSAGE AND ADMINISTRATION ). Hydroxyurea should be used with caution in patients with renal dysfunction. Data from a single-dose study of the pharmacokinetics of hydroxyurea in patients with sickle cell anemia suggest that the initial dose of hydroxyurea should be reduced in patients with renal impairment. (See CLINICAL PHARMACOLOGY: Special Populations and DOSAGE AND ADMINISTRATION .) Patients must be able to follow directions regarding drug administration and their monitoring and care. Hydroxyurea is not indicated for the treatment of HIV infection; however, if HIV-infected patients are treated with hydroxyurea, and in particular, in combination with didanosine and/or stavudine, close monitoring for signs and symptoms of pancreatitis is recommended. Patients who develop signs and symptoms of pancreatitis should permanently discontinue therapy with hydroxyurea. (See WARNINGS and ADVERSE REACTIONS .) An increased risk of hepatotoxicity, which may be fatal, may occur in patients treated with hydroxyurea, and in particular, in combination with didanosine and stavudine. This combination should be avoided. Carcinogenesis, Mutagenesis, Impairment of Fertility See WARNINGS and BOXED WARNING for Carcinogenesis and Mutagenesis information. Impairment of Fertility: Hydroxyurea administered to male rats at 60 mg/kg/day (about 0.3 times the maximum recommended human daily dose on a mg/m2 basis) produced testicular atrophy, decreased spermatogenesis, and significantly reduced their ability to impregnate females. Pregnancy Pregnancy Category D. (See WARNINGS .) Nursing Mothers Hydroxyurea is excreted in human milk. Because of the potential for serious adverse reactions with hydroxyurea, a decision should be made either to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Drug Interactions Prospective studies on the potential for hydroxyurea to interact with other drugs have not been performed. Studies have shown that there is an analytical interference of hydroxyurea with the enzymes (urease, uricase, and lactic dehydrogenase) used in the determination of urea, uric acid and lactic acid, rendering falsely elevated results of these in patients treated with hydroxyurea. Information for Patients (See Patient Information at end of labeling.) Patients should be reminded that this medication must be handled with care. People who are not taking DROXIA should not be exposed to it. To decrease the risk of exposure, wear disposable gloves when handling DROXIA or bottles containing DROXIA. Anyone handling DROXIA should wash their hands before and after contact with the bottle or capsules. If the powder from the capsule is spilled, it should be wiped up immediately with a damp disposable towel and discarded in a closed container, such as a plastic bag. The medication should be kept away from children and pets. Contact your doctor for instructions on how to dispose of outdated capsules. The necessity of monitoring blood counts every two weeks, throughout the duration of therapy, should be emphasized. For additional information, see the accompanying Patient Information leaflet. ADVERSE REACTIONS Sickle Cell Anemia In patients treated for sickle cell anemia in the Multicenter Study of Hydroxyurea in Sickle Cell Anemia,1 the most common adverse reactions were hematologic, with neutropenia, and low reticulocyte and platelet levels necessitating temporary cessation in almost all patients. Hematologic recovery usually occurred in two weeks. Non-hematologic events that possibly were associated with treatment include hair loss, skin rash, fever, gastrointestinal disturbances, weight gain, bleeding, and parvovirus B-19 infection; however, these non-hematologic events occurred with similar frequencies in the hydroxyurea and placebo treatment groups. Melanonychia has also been reported in patients receiving DROXIA for SCA. Other Adverse events associated with the use of hydroxyurea in the treatment of neoplastic diseases, in addition to hematologic effects include: gastrointestinal symptoms (stomatitis, anorexia, nausea, vomiting, diarrhea, and constipation), and dermatological reactions such as maculopapular rash, skin ulceration, dermatomyositis-like skin changes, peripheral erythema, and facial erythema. Hyperpigmentation, atrophy of skin and nails, scaling, and violet papules have been observed in some patients after several years of long-term daily maintenance therapy with hydroxyurea. Skin cancer has been reported. Cutaneous vasculitic toxicities, including vasculitic ulcerations and gangrene, have occurred in patients with myeloproliferative disorders during therapy with hydroxyurea. These vasculitic toxicities were reported most often in patients with a history of, or currently receiving, interferon therapy (see WARNINGS ). Dysuria and alopecia have been reported. Large doses may produce drowsiness. Neurological disturbances have occurred and were limited to headache, dizziness, disorientation, hallucinations, and convulsions. Hydroxyurea may cause temporary impairment of renal tubular function accompanied by elevations in serum uric acid, blood urea nitrogen (BUN), and creatinine levels. Abnormal bromsulphalein (BSP) retention has been reported. Fever, chills, malaise, edema, asthenia, and elevation of hepatic enzymes have also been reported. The association of hydroxyurea with the development of acute pulmonary reactions consisting of diffuse pulmonary infiltrates, fever, and dyspnea has been reported. Pulmonary fibrosis also has been reported. In HIV-infected patients who received hydroxyurea in combination with antiretroviral agents, in particular, didanosine plus stavudine, fatal and nonfatal pancreatitis and hepatotoxicity, and severe peripheral neuropathy have been reported. Patients treated with hydroxyurea in combination with didanosine, stavudine, and indinavir in Study ACTG 5025 showed a median decline in CD4 cells of approximately 100/mm3. (See WARNINGS and PRECAUTIONS .) OVERDOSAGE Acute mucocutaneous toxicity has been reported in patients receiving hydroxyurea at dosages several times the therapeutic dose. Soreness, violet erythema, edema on palms and soles followed by scaling of hands and feet, severe generalized hyperpigmentation of the skin, and stomatitis have been observed. DOSAGE AND ADMINISTRATION Procedures for proper handling and disposal of cytotoxic drugs should be considered. Several guidelines on this subject have been published.2-5 To minimize the risk of dermal exposure, always wear impervious gloves when handling bottles containing DROXIA capsules. DROXIA capsules should not be opened. Personnel should avoid exposure to crushed or opened capsules. If contact with crushed or opened capsules occurs, wash immediately and thoroughly. More information is available in the references listed below. Dosage should be based on the patient’s actual or ideal weight, whichever is less. The initial dose of DROXIA is 15 mg/kg/day as a single dose. The patient’s blood count must be monitored every two weeks. (See WARNINGS .) If blood counts are in an acceptable range*, the dose may be increased by 5 mg/kg/day every 12 weeks until a maximum tolerated dose (the highest dose that does not produce toxic** blood counts over 24 consecutive weeks), or 35 mg/kg/day, is reached. If blood counts are between the acceptable range* and toxic**, the dose is not increased. If blood counts are considered toxic**, DROXIA should be discontinued until hematologic recovery. Treatment may then be resumed after reducing the dose by 2.5 mg/kg/day from the dose associated with hematologic toxicity. DROXIA may then be titrated up or down, every 12 weeks in 2.5 mg/kg/day increments, until the patient is at a stable dose that does not result in hematologic toxicity for 24 weeks. Any dosage on which a patient develops hematologic toxicity twice should not be tried again.           *acceptable range =                     neutrophils ≥2500 cells/mm3,                     platelets ≥95,000/mm3,                     hemoglobin >5.3 g/dL and                     reticulocytes ≥95,000/mm3 if the hemoglobin concentration <9 g/dL.           **toxic =                     neutrophils <2000 cells/mm3,                     platelets <80,000/mm3,                     hemoglobin <4.5 g/dL and                     reticulocytes <80,000/mm3 if the hemoglobin concentration <9 g/dL. Renal Insufficiency As renal excretion is a pathway of elimination, consideration should be given to decreasing the dosage of DROXIA in patients with renal impairment. The results of a single-dose study of the influence of renal function on the pharmacokinetics of hydroxyurea in adults with sickle cell disease suggest that the initial dose of hydroxyurea should be reduced by 50%, to 7.5 mg/kg/day, when used to treat patients with renal impairment. (See PRECAUTIONS and CLINICAL PHARMACOLOGY .) Close monitoring of hematologic parameters is advised in these patients. *On dialysis days, hydroxyurea should be administered to patients with ESRD following hemodialysis. Creatinine Clearance (mL/min) Recommended DROXIA Initial Dose (mg/kg daily) ≥60 15 <60 or ESRD* 7.5 Hepatic Insufficiency There are no data that support specific guidance for dosage adjustment in patients with hepatic impairment. Close monitoring of hematologic parameters is advised in these patients. HOW SUPPLIED DROXIA® (hydroxyurea capsules, USP). 200 mg capsules packaged in HDPE bottles of 60 with a plastic safety screw cap. (NDC 0003-6335-17). The cap and body are opaque blue-green. The capsule is marked in black ink on both the cap and body with “DROXIA” and “6335”. 300 mg capsules packaged in HDPE bottles of 60 with a plastic safety screw cap. (NDC 0003-6336-17). The cap and body are opaque purple. The capsule is marked in black ink on both the cap and body with “DROXIA” and “6336”. 400 mg capsules packaged in HDPE bottles of 60 with a plastic safety screw cap. (NDC 0003-6337-17). The cap and body are opaque reddish-orange. The capsule is marked in black ink on both the cap and body with “DROXIA” and “6337”. Storage Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Keep tightly closed.