hydroxyurea, didanosine, and stavudine. avoid this combination. peripheral neuropathy peripheral neuropathy, which was severe in some cases, has been reported in patients with hiv infection receiving hydroxyurea in combination with antiretroviral drugs, including didanosine, with or without stavudine. 7.2 laboratory test interference interference with uric acid, urea, or lactic acid assays studies have shown that there is an analytical interference of hydroxyurea with the enzymes (urease, uricase, and lactate dehydrogenase) used in the determination of urea, uric acid, and lactic acid, rendering falsely elevated results of these in patients treated with hydroxyurea.

nd are seldom seen without a preceding leukopenia. some patients, treated at the recommended initial dose of 15 mg/kg/day, have experienced severe or life-threatening myelosuppression. evaluate hematologic status prior to and during treatment with droxia. provide supportive care and modify dose or discontinue droxia as needed. recovery from myelosuppression is usually rapid when therapy is interrupted. 5.2 hemolytic anemia cases of hemolytic anemia in patients treated with hydroxyurea for myeloproliferative diseases have been reported [ see adverse reactions (6.1) ]. patients who develop acute jaundice or hematuria in the presence of persistent or worsening of anemia should have laboratory tests evaluated for hemolysis (e.g., measurement of serum lactate dehydrogenase, haptoglobin, reticulocyte, unconjugated bilirubin levels, urinalysis, and direct and indirect antiglobulin [coombs] tests). in the setting of confirmed diagnosis of hemolytic anemia and in the absence of other causes, discontinue droxia. 5.3 malignancies hydroxyurea is a human carcinogen. in patients receiving long-term hydroxyurea for myeloproliferative disorders, secondary leukemia has been reported. secondary leukemia has also been reported in patients treated with long-term hydroxyurea for sickle cell disease. leukemia has also been reported in patients with sickle cell disease and no prior history of treatment with hydroxyurea. all patients using droxia should be followed up on a long-term basis with regular blood counts to detect development of leukemia. skin cancer has also been reported in patients receiving long-term hydroxyurea. advise protection from sun exposure and monitor for the development of secondary malignancies. 5.4 embryo-fetal toxicity based on the mechanism of action and findings in animals, droxia can cause fetal harm when administered to a pregnant woman. hydroxyurea was embryotoxic and teratogenic in rats and rabbits at doses 0.8 times and 0.3 times, respectively, the maximum recommended human daily dose on a mg/m 2 basis. advise pregnant women of the potential risk to a fetus [see use in specific populations ( 8.1 )]. advise females of reproductive potential to use effective contraception during and after treatment with droxia for at least 6 months after therapy. advise males of reproductive potential to use effective contraception during and after treatment with droxia for at least 1 year after therapy [see use in specific populations ( 8.1 , 8.3 )]. 5.5 vasculitic toxicities 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. if cutaneous vasculitic ulcers occur, institute treatment and discontinue droxia. 5.6 live vaccinations avoid use of live vaccine in patients taking droxia. concomitant use of droxia with a live virus vaccine may potentiate the replication of the virus and/or may increase the adverse reaction of the vaccine because normal defense mechanisms may be suppressed by droxia. vaccination with live vaccines in a patient receiving droxia may result in severe infection. patient’s antibody response to vaccines may be decreased. consider consultation with a specialist. 5.7 risks with concomitant use of antiretroviral drugs pancreatitis, hepatotoxicity, and peripheral neuropathy have occurred when hydroxyurea was administered concomitantly with antiretroviral drugs, including didanosine and stavudine [see drug interactions (7.1) ] . 5.8 macrocytosis droxia may cause macrocytosis, which is self-limiting, and is often seen early in the course of treatment. the morphologic change resembles pernicious anemia, but is not related to vitamin b 12 or folic acid deficiency. this may mask the diagnosis of pernicious anemia. prophylactic administration of folic acid is recommended. 5.9 pulmonary toxicity interstitial lung disease including pulmonary fibrosis, lung infiltration, pneumonitis, and alveolitis/allergic alveolitis (including fatal cases) have been reported in patients treated for myeloproliferative neoplasm. safety and effectiveness have not been established for the use of droxia in the treatment of myeloproliferative neoplasms and the use is not approved by the fda. monitor patients developing pyrexia, cough, dyspnea, or other respiratory symptoms frequently, investigate and treat promptly. discontinue droxia and manage with corticosteroids. [ see adverse reactions (6.1) ]. 5.10 laboratory test interference interference with uric acid, urea, or lactic acid assays is possible, rendering falsely elevated results of these in patients treated with hydroxyurea [see drug interactions (7.2) ] .

. monitor the patient’s blood count every 2 weeks [see warnings and precautions ( 5.1 )]. dosing based on blood counts in an acceptable range increase dose 5 mg/kg/day every 12 weeks maximal dose: 35 mg/kg/day* *maximal dose is the highest dose that does not produce toxic blood counts over 24 consecutive weeks. increase dosing only if blood counts are in an acceptable range. do not increase if myelosuppression occurs. blood counts acceptable range neutrophils ≥2500 cells/mm 3 platelets ≥95,000/mm 3 hemoglobin >5.3 g/dl reticulocytes ≥95,000/mm 3 if the hemoglobin concentration <9 g/dl between acceptable and toxic range do not increase dose. if blood counts are considered toxic , discontinue droxia until hematologic recovery. blood counts toxic range neutrophils <2000 cells/mm 3 platelets <80,000/mm 3 hemoglobin <4.5 g/dl reticulocytes <80,000/mm 3 if the hemoglobin concentration <9 g/dl dosing after hematologic recovery reduce dose by 2.5 mg/kg/day. reduce the dose from the dose associated with hematologic toxicity. may titrate up or down every 12 weeks in 2.5 mg/kg/day increments. the patient should be at a stable dose with no hematologic toxicity for 24 weeks. discontinue the treatment permanently if a patient develops hematologic toxicity twice. swallow droxia capsules whole. do not open, break, or chew capsules because droxia is a cytotoxic drug. patients must be able to follow directions regarding drug administration and their monitoring and care. fetal hemoglobin (hbf) levels may be used to evaluate the efficacy of droxia in clinical use. obtain hbf levels every three to four months. monitor for an increase in hbf of at least two-fold over the baseline value. droxia causes macrocytosis, which may mask the incidental development of folic acid deficiency. prophylactic administration of folic acid is recommended. droxia is a cytotoxic drug. follow applicable special handling and disposal procedures [see references (15) ]. 2.2 dose modifications for renal impairment reduce the dose of droxia by 50% in patients with creatinine clearance of less than 60 ml/min or with end-stage renal disease (esrd) [see use in specific populations (8.6) and clinical pharmacology (12.3) ] . creatinine clearance values were obtained using 24-hour urine collections. * on dialysis days, administer droxia to patients with esrd following hemodialysis. creatinine clearance (ml/min) recommended droxia initial dose (mg/kg once daily) ≥60 15 <60 or esrd* 7.5 monitor the hematologic parameters closely in these patients.

72 or fda at 1-800-fda-1088 or www.fda.gov/medwatch. 6.1 clinical trial experience in 299 patients treated for sickle cell anemia in the multicenter study of hydroxyurea in sickle cell anemia, 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. other adverse reactions include hair loss, macrocytosis, bleeding, and melanonychia. 6.2 postmarketing experience the following adverse reactions have been identified during post-approval use of hydroxyurea in the treatment of neoplastic diseases. because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency. reproductive system and breast disorders: azoospermia, and oligospermia gastrointestinal disorders: stomatitis, nausea, vomiting, diarrhea, and constipation metabolism and nutrition disorders: anorexia skin and subcutaneous tissue disorders: maculopapular rash, skin ulceration, cutaneous lupus erythematosus, dermatomyositis-like skin changes, peripheral and facial erythema, hyperpigmentation, nail hyperpigmentation, atrophy of skin and nails, scaling, violet papules, and alopecia renal and urinary disorders: dysuria, elevations in serum uric acid, blood urea nitrogen (bun), and creatinine levels nervous system disorders: headache, dizziness, drowsiness, disorientation, hallucinations, and convulsions general disorders: fever, chills, malaise, edema, and asthenia hepatobiliary disorders: elevation of hepatic enzymes, cholestasis, and hepatitis respiratory disorders: diffuse pulmonary infiltrates, dyspnea, and pulmonary fibrosis, interstitial lung disease, pneumonitis, alveolitis, allergic alveolitis and cough immune disorders: systemic lupus erythematosus hypersensitivity: drug-induced fever (pyrexia) (>39°c, >102°f) requiring hospitalization has been reported concurrently with gastrointestinal, pulmonary, musculoskeletal, hepatobiliary, dermatological or cardiovascular manifestations. onset typically occurred within 6 weeks of initiation and resolved upon discontinuation of hydroxyurea. upon re-administration fever re-occurred typically within 24 hours. blood and lymphatic system disorders : hemolytic anemia

hydroxyurea, didanosine, and stavudine. avoid this combination. peripheral neuropathy peripheral neuropathy, which was severe in some cases, has been reported in patients with hiv infection receiving hydroxyurea in combination with antiretroviral drugs, including didanosine, with or without stavudine. 7.2 laboratory test interference interference with uric acid, urea, or lactic acid assays studies have shown that there is an analytical interference of hydroxyurea with the enzymes (urease, uricase, and lactate dehydrogenase) used in the determination of urea, uric acid, and lactic acid, rendering falsely elevated results of these in patients treated with hydroxyurea.

y 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/m 2 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/m 2 basis) in rats and at 30 mg/kg/day (about 0.3 times the maximum recommended human daily dose on a mg/m 2 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/m 2 basis) to rats caused growth retardation and impaired learning ability. 8.2 lactation risk summary hydroxyurea is excreted in human milk. because of the potential for serious adverse reactions in a breastfed infant from hydroxyurea, including carcinogenicity, discontinue breastfeeding during treatment with droxia. 8.3 females and males of reproductive potential pregnancy testing verify the pregnancy status of females of reproductive potential prior to initiating droxia therapy. contraception females droxia can cause fetal harm when administered to a pregnant woman [see use in specific populations (8.1) ] . advise females of reproductive potential to use effective contraception during and after treatment with droxia for at least 6 months after therapy. advise females to immediately report pregnancy. males droxia may damage spermatozoa and testicular tissue, resulting in possible genetic abnormalities. males with female sexual partners of reproductive potential should use effective contraception during and after treatment with droxia for at least 1 year after therapy [see nonclinical toxicology (13.1) ] . infertility males based on findings in animals and humans, male fertility may be compromised by treatment with droxia. azoospermia or oligospermia, sometimes reversible, has been observed in men. inform male patients about the possibility of sperm conservation before the start of therapy [see adverse reactions (6) and nonclinical toxicology (13.1) ] . 8.4 pediatric use safety and effectiveness in pediatric patients have not been established. 8.5 geriatric use clinical studies of droxia did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. elderly patients may be more sensitive to the effects of hydroxyurea and may require a lower dose regimen. hydroxyurea is excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [see dosage and administration (2.2) ] . 8.6 renal impairment the exposure to hydroxyurea is higher in patients with creatinine clearance of less than 60 ml/min. reduce dosage and closely monitor the hematologic parameters when droxia is to be administered to these patients [see dosage and administration (2.2) and clinical pharmacology (12.3) ] . 8.7 hepatic impairment 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.

monkeys at doses within 1-fold of the human dose given on a mg/m 2 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/m 2 basis) in rats and at 30 mg/kg/day (about 0.3 times the maximum recommended human daily dose on a mg/m 2 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/m 2 basis) to rats caused growth retardation and impaired learning ability.

crease more than proportionally with increase of dose. there are no data on the effect of food on the absorption of hydroxyurea. distribution hydroxyurea distributes throughout the body with a volume of distribution approximating total body water. hydroxyurea concentrates in leukocytes and erythrocytes. metabolism up to 60% of an oral dose undergoes conversion through saturable hepatic metabolism and a minor pathway of degradation by urease found in intestinal bacteria. excretion in patients with sickle cell anemia, the mean cumulative urinary recovery of hydroxyurea was about 40% of the administered dose. specific populations renal impairment the effect of renal impairment on the pharmacokinetics of hydroxyurea was assessed in adult patients with sickle cell disease and renal impairment. patients 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 a single oral dose of 15 mg/kg hydroxyurea. creatinine clearance values were obtained using 24-hour urine collections. patients with 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. the exposure to hydroxyurea (mean auc) in patients with crcl <60 ml/min and those with esrd was 64% higher than in patients with normal renal function (crcl >60 ml/min). reduce the dose of droxia when it is administered to patients with creatinine clearance of <60 ml/min or with esrd following hemodialysis [see dosage and administration (2.2) and use in specific populations (8.6) ] .

l 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 a single oral dose of 15 mg/kg hydroxyurea. creatinine clearance values were obtained using 24-hour urine collections. patients with 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. the exposure to hydroxyurea (mean auc) in patients with crcl <60 ml/min and those with esrd was 64% higher than in patients with normal renal function (crcl >60 ml/min). reduce the dose of droxia when it is administered to patients with creatinine clearance of <60 ml/min or with esrd following hemodialysis [see dosage and administration (2.2) and use in specific populations (8.6) ] .

ced their ability to impregnate females.

rises. 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. table 2: results from the multicenter study of hydroxyurea in sickle cell anemia event hydroxyurea (n=152) placebo (n=147) percent change versus 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 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.

able gloves when handling droxia or bottles containing droxia. wash hands with soap and water before and after contact with the bottle or capsules when handling droxia. do not open droxia capsules. avoid exposure to crushed or opened capsules. if contact with crushed or opened capsules occurs on the skin, wash affected area immediately and thoroughly with soap and water. if contact with crushed or opened capsules occurs on the eye(s), the affected area should be flushed thoroughly with water or isotonic eyewash designated for that purpose for at least 15 minutes. if the powder from the capsule is spilled, immediately wipe it up with a damp disposable towel and discard in a closed container, such as a plastic bag; as should the empty capsules. the spill areas should then be cleaned three times using a detergent solution followed by clean water. keep the medication away from children and pets. contact your doctor for instructions on how to dispose of outdated capsules.

tions (5.6) ] . advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy. advise females and males of reproductive potential to use contraception during and after treatment with droxia [see warnings and precautions (5.4) and use in specific populations (8.1 , 8.3) ] . advise females to discontinue breastfeeding during treatment with droxia [see use in specific populations (8.2) ] . patients with hiv infection should contact their physician for signs and symptoms of pancreatitis, hepatic events, and peripheral neuropathy [see warnings and precautions (5.7) ] . advise patients of the symptoms of potential pulmonary toxicity and instruct them to seek prompt medical attention in the event of pyrexia, cough, dyspnea, or other respiratory symptoms [see warnings and precautions (5.9) ] .