ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following clinically significant adverse reactions are described in detail in other labeling sections:oMyelosuppression [see Warnings and Precautions (5.1)] oMalignancies [see Warnings and Precautions (5.2)] oVasculitic toxicities [see Warnings and Precautions (5.4 )] oRisks with concomitant use of antiretroviral drugs [see Warnings and Precautions (5.6)] oRadiation recall [see Warnings and Precautions (5.7)] oMacrocytosis [see Warnings and Precautions (5.8)] oPulmonary Toxicity [see Warnings and Precautions (5.9)] oMyelosuppression [see Warnings and Precautions (5.1)] oMalignancies [see Warnings and Precautions (5.2)] oVasculitic toxicities [see Warnings and Precautions (5.4 )] oRisks with concomitant use of antiretroviral drugs [see Warnings and Precautions (5.6)] oRadiation recall [see Warnings and Precautions (5.7)] oMacrocytosis [see Warnings and Precautions (5.8)] oPulmonary Toxicity [see Warnings and Precautions (5.9)] Most common adverse reactions (>=30%) are hematological, gastrointestinal symptoms, and anorexia. 6) To report SUSPECTED ADVERSE REACTIONS, contact Par Pharmaceutical at 1-800-828-9393 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Postmarketing Experience. The following adverse reactions have been identified during post-approval use of hydroxyurea capsules. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency.oReproductive System and Breast disorders: azoospermia, and oligospermia oGastrointestinal disorders: stomatitis, nausea, vomiting, diarrhea, and constipation oMetabolism and Nutrition disorders: anorexia, tumor lysis syndrome oSkin 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 oRenal and urinary disorders: dysuria, elevations in serum uric acid, blood urea nitrogen (BUN), and creatinine levels oNervous system disorders: headache, dizziness, drowsiness, disorientation, hallucinations, and convulsions oGeneral Disorders: fever, chills, malaise, edema, and asthenia oHepatobiliary disorders: elevation of hepatic enzymes, cholestasis, and hepatitis oRespiratory disorders: diffuse pulmonary infiltrates, dyspnea, and pulmonary fibrosis, interstitial lung disease, pneumonitis, alveolitis, allergic alveolitis and cough oImmune disorders: systemic lupus erythematosus oHypersensitivity: Drug-induced fever (pyrexia) (>39C, >102F) requiring hospitalization has been reported concurrently with gastrointestinal, pulmonary, musculoskeletal, hepatobiliary, dermatological or cardiovascular manifestations. Onset typically occurred within weeks of initiation and resolved upon discontinuation of hydroxyurea. Upon re-administration fever re-occurred typically within 24 hours. Adverse reactions observed with combined hydroxyurea and irradiation therapy are similar to those reported with the use of hydroxyurea or radiation treatment alone. These effects primarily include bone marrow depression (anemia and leukopenia), gastric irritation, and mucositis. Almost all patients receiving an adequate course of combined hydroxyurea and irradiation therapy will demonstrate concurrent leukopenia. Platelet depression (<100,000 cells/mm 3) has occurred in the presence of marked leukopenia. Hydroxyurea capsules may potentiate some adverse reactions usually seen with irradiation alone, such as gastric distress and mucositis. oReproductive System and Breast disorders: azoospermia, and oligospermia oGastrointestinal disorders: stomatitis, nausea, vomiting, diarrhea, and constipation oMetabolism and Nutrition disorders: anorexia, tumor lysis syndrome oSkin 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 oRenal and urinary disorders: dysuria, elevations in serum uric acid, blood urea nitrogen (BUN), and creatinine levels oNervous system disorders: headache, dizziness, drowsiness, disorientation, hallucinations, and convulsions oGeneral Disorders: fever, chills, malaise, edema, and asthenia oHepatobiliary disorders: elevation of hepatic enzymes, cholestasis, and hepatitis oRespiratory disorders: diffuse pulmonary infiltrates, dyspnea, and pulmonary fibrosis, interstitial lung disease, pneumonitis, alveolitis, allergic alveolitis and cough oImmune disorders: systemic lupus erythematosus oHypersensitivity: Drug-induced fever (pyrexia) (>39C, >102F) requiring hospitalization has been reported concurrently with gastrointestinal, pulmonary, musculoskeletal, hepatobiliary, dermatological or cardiovascular manifestations. Onset typically occurred within weeks of initiation and resolved upon discontinuation of hydroxyurea. Upon re-administration fever re-occurred typically within 24 hours.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. The precise mechanism by which hydroxyurea produces its antineoplastic effects cannot, at present, be described. However, the reports of various studies in tissue culture in rats and humans lend support to the hypothesis that hydroxyurea causes an immediate inhibition of DNA synthesis by acting as ribonucleotide reductase inhibitor, without interfering with the synthesis of ribonucleic acid or of protein. This hypothesis explains why, under certain conditions, hydroxyurea may induce teratogenic effects.Three mechanisms of action have been postulated for the increased effectiveness of concomitant use of hydroxyurea therapy with irradiation on squamous cell (epidermoid) carcinomas of the head and neck. In vitro studies utilizing Chinese hamster cells suggest that hydroxyurea (1) is lethal to normally radioresistant S-stage cells, and (2) holds other cells of the cell cycle in the G1 or pre-DNA synthesis stage where they are most susceptible to the effects of irradiation. The third mechanism of action has been theorized on the basis of in vitro studies of HeLa cells. It appears that hydroxyurea, by inhibition of DNA synthesis, hinders the normal repair process of cells damaged but not killed by irradiation, thereby decreasing their survival rate; RNA and protein synthesis have shown no alteration. 12.3 Pharmacokinetics. Absorption Following oral administration of hydroxyurea capsules, hydroxyurea reaches peak plasma concentrations in to hours. Mean peak plasma concentrations and AUCs increase 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 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 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 to 80 mL/min), moderate (CrCl =30 to <50 mL/min), or severe (<30 mL/min) renal impairment received single oral dose of 15 mg/kg hydroxyurea. Patients with ESRD received two doses of 15 mg/kg separated by days; the first was given following 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 hydroxyurea capsules when it is administered to patients with creatinine clearance of <60 mL/min or with ESRD following hemodialysis [see Dosage and Administration (2.3) and Use in Specific Populations (8.6)].

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. oIndividualize treatment based on tumor type, disease state, response to treatment, patient risk factors, and current clinical practice standards. 2.1) oRenal impairment: Reduce the dose of hydroxyurea by 50% in patients with creatinine clearance less than 60 mL/min. 2.3, 8.6, 12.3) oIndividualize treatment based on tumor type, disease state, response to treatment, patient risk factors, and current clinical practice standards. 2.1) oRenal impairment: Reduce the dose of hydroxyurea by 50% in patients with creatinine clearance less than 60 mL/min. 2.3, 8.6, 12.3) 2.1 Dosing Information. Hydroxyurea is used alone or in conjunction with other antitumor agents or radiation therapy to treat neoplastic diseases. Individualize treatment based on tumor type, disease state, response to treatment, patient risk factors, and current clinical practice standards.Base all dosage on the patients actual or ideal weight, whichever is less.Hydroxyurea is cytotoxic drug. Follow applicable special handling and disposal procedures [see References (15)]. Swallow hydroxyurea capsules whole. Do NOT open, break, or chew capsules because hydroxyurea is cytotoxic drug.Prophylactic administration of folic acid is recommended [see Warnings and Precautions (5.8)]. Monitor blood counts at least once week during Hydroxyurea capsules therapy. Severe anemia must be corrected before initiating therapy with Hydroxyurea capsules.. 2.2 Dose Modifications for Toxicity. Monitor for the following and reduce the dose or discontinue hydroxyurea accordingly:oMyelosuppression [see Warnings and Precautions (5.1)]. oCutaneous vasculitis [see Warnings and Precautions (5.4)] Consider dose modifications for other toxicities.. oMyelosuppression [see Warnings and Precautions (5.1)]. oCutaneous vasculitis [see Warnings and Precautions (5.4)] 2.3 Dose Modifications for Renal Impairment. Reduce the dose of hydroxyurea capsules by 50% in patients with measured 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(mL/min)Recommended Hydroxyurea capsules Initial Dose(mg/kg once daily)>=6015<60 or ESRD On dialysis days, administer hydroxyurea capsules to patients following hemodialysis. 7.5Close monitoring of hematologic parameters is advised in these patients.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. oAntiretroviral drugs 7.1) oLaboratory Test Interference. 7.2) oAntiretroviral drugs 7.1) oLaboratory Test Interference. 7.2) 7.1 Increased Toxicity with Concomitant Use of Antiretroviral Drugs. Pancreatitis In patients with HIV infection during therapy with hydroxyurea and didanosine, with or without stavudine, fatal and nonfatal pancreatitis have occurred. Hydroxyurea is not indicated for the treatment of HIV infection; however, if patients with HIV infection are treated with hydroxyurea, and in particular, in combination with didanosine and/or stavudine, close monitoring for signs and symptoms of pancreatitis is recommended. Permanently discontinue therapy with hydroxyurea in patients who develop signs and symptoms of pancreatitis. Hepatotoxicity Hepatotoxicity and hepatic failure resulting in death have been reported during postmarketing surveillance in patients with HIV infection treated with hydroxyurea and other antiretroviral drugs. Fatal hepatic events were reported most often in patients treated with the combination of 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.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. 16.1 How Supplied. Hydroxyurea capsules, USP 500 mg are dark green opaque (cap) printed 724 in white ink/ pink opaque (body) printed par in black ink capsules. Available:Overbagged with 10 capsules per bag, NDC 55154-7143-0 16.2 Storage. Store at 20 to 25C (68 to 77F); excursions permitted to 15 to 30C (59 to 86F) [see USP Controlled Room Temperature].FOR YOUR PROTECTION: Do not use if blister is torn or broken. 16.3 Handling and Disposal. Hydroxyurea capsules is cytotoxic drug. Follow applicable special handling and disposal procedures [see References (15)]. To decrease the risk of contact, advise caregivers to wear disposable gloves when handling hydroxyurea capsules or bottles containing hydroxyurea capsules. Wash hands with soap and water before and after contact with the bottle or capsules when handling hydroxyurea capsules. Do not open hydroxyurea 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 damp disposable towel and discard in closed container, such as plastic bag; as should the empty capsules. The spill areas should then be cleaned three times using 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.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. oThere is risk of myelosuppression. Monitoring blood counts weekly throughout the duration of therapy should be emphasized to patients taking hydroxyurea capsules [see Warnings and Precautions (5.1)]. Advise patients to report signs and symptoms of infection or bleeding immediately. oAdvise patients that there is risk of cutaneous vasculitic toxicities and secondary malignancies including leukemia and skin cancers [see Warnings and Precautions (5.2, 5.4)]. oAdvise females of reproductive potential of the potential risk to fetus and to inform their healthcare provider of known or suspected pregnancy. Advise females and males of reproductive potential to use contraception during and after treatment with hydroxyurea capsules [see Warnings and Precautions (5.3) and Use in Specific Populations (8.1, 8.3)]. oAdvise patients to inform their healthcare provider if they have received or are planning to receive vaccinations while taking hydroxyurea capsules as this may result in severe infection [see Warnings and Precautions (5.5)]. oAdvise females to discontinue breastfeeding during treatment with hydroxyurea capsules [see Use in Specific Populations (8.3)]. oPatients with HIV infection should contact their physician for signs and symptoms of pancreatitis, hepatic events, and peripheral neuropathy [see Warnings and Precautions (5.6)]. oPost-irradiation erythema can occur in patients who have received previous irradiation therapy [see Warnings and Precautions (5.7)]. For more information about the drug product, go to www.parpharm.com or call 1-800-828-9393. oThere is risk of myelosuppression. Monitoring blood counts weekly throughout the duration of therapy should be emphasized to patients taking hydroxyurea capsules [see Warnings and Precautions (5.1)]. Advise patients to report signs and symptoms of infection or bleeding immediately. oAdvise patients that there is risk of cutaneous vasculitic toxicities and secondary malignancies including leukemia and skin cancers [see Warnings and Precautions (5.2, 5.4)]. oAdvise females of reproductive potential of the potential risk to fetus and to inform their healthcare provider of known or suspected pregnancy. Advise females and males of reproductive potential to use contraception during and after treatment with hydroxyurea capsules [see Warnings and Precautions (5.3) and Use in Specific Populations (8.1, 8.3)]. oAdvise patients to inform their healthcare provider if they have received or are planning to receive vaccinations while taking hydroxyurea capsules as this may result in severe infection [see Warnings and Precautions (5.5)]. oAdvise females to discontinue breastfeeding during treatment with hydroxyurea capsules [see Use in Specific Populations (8.3)]. oPatients with HIV infection should contact their physician for signs and symptoms of pancreatitis, hepatic events, and peripheral neuropathy [see Warnings and Precautions (5.6)]. oPost-irradiation erythema can occur in patients who have received previous irradiation therapy [see Warnings and Precautions (5.7)].

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. The precise mechanism by which hydroxyurea produces its antineoplastic effects cannot, at present, be described. However, the reports of various studies in tissue culture in rats and humans lend support to the hypothesis that hydroxyurea causes an immediate inhibition of DNA synthesis by acting as ribonucleotide reductase inhibitor, without interfering with the synthesis of ribonucleic acid or of protein. This hypothesis explains why, under certain conditions, hydroxyurea may induce teratogenic effects.Three mechanisms of action have been postulated for the increased effectiveness of concomitant use of hydroxyurea therapy with irradiation on squamous cell (epidermoid) carcinomas of the head and neck. In vitro studies utilizing Chinese hamster cells suggest that hydroxyurea (1) is lethal to normally radioresistant S-stage cells, and (2) holds other cells of the cell cycle in the G1 or pre-DNA synthesis stage where they are most susceptible to the effects of irradiation. The third mechanism of action has been theorized on the basis of in vitro studies of HeLa cells. It appears that hydroxyurea, by inhibition of DNA synthesis, hinders the normal repair process of cells damaged but not killed by irradiation, thereby decreasing their survival rate; RNA and protein synthesis have shown no alteration.

NURSING MOTHERS SECTION.

8.3 Females and Males of Reproductive Potential. Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating hydroxyurea capsules therapy. ContraceptionFemales Hydroxyurea capsules can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during and after treatment with hydroxyurea capsules for at least months after therapy. Advise females to immediately report pregnancy. Males Hydroxyurea capsules 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 hydroxyurea capsules for at least year after therapy [see Nonclinical Toxicology (13.1)]. InfertilityMales Based on findings in animals and humans, male fertility may be compromised by treatment with hydroxyurea capsules. 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)].

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Absorption Following oral administration of hydroxyurea capsules, hydroxyurea reaches peak plasma concentrations in to hours. Mean peak plasma concentrations and AUCs increase 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 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 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 to 80 mL/min), moderate (CrCl =30 to <50 mL/min), or severe (<30 mL/min) renal impairment received single oral dose of 15 mg/kg hydroxyurea. Patients with ESRD received two doses of 15 mg/kg separated by days; the first was given following 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 hydroxyurea capsules when it is administered to patients with creatinine clearance of <60 mL/min or with ESRD following hemodialysis [see Dosage and Administration (2.3) and Use in Specific Populations (8.6)].

PREGNANCY SECTION.

8.1 Pregnancy. Risk Summary Hydroxyurea capsules can cause fetal harm based on findings from animal studies and the drugs mechanism of action [see Clinical Pharmacology (12.1)]. There are no data with hydroxyurea capsules use in pregnant women to inform drug-associated risk. In animal reproduction studies, administration of hydroxyurea to pregnant rats and rabbits during organogenesis produced embryotoxic and teratogenic effects at doses 0.8 times and 0.3 times, respectively, the maximum recommended human daily dose on mg/m basis (see Data). Advise women of the potential risk to fetus and to avoid becoming pregnant while being treated with hydroxyurea capsules. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.DataAnimal Data Hydroxyurea has been demonstrated to be potent teratogen in 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 mg/m 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 mg/m basis) in rats and at 30 mg/kg/day (about 0.3 times the maximum recommended human daily dose on mg/m 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 mg/m basis) to rats caused growth retardation and impaired learning ability.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. oLactation: Advise women not to breastfeed. 8.2) oGeriatric Use: Care should be taken in dose selection and may require lower dose regimen and monitoring of renal function. 8.5) oLactation: Advise women not to breastfeed. 8.2) oGeriatric Use: Care should be taken in dose selection and may require lower dose regimen and monitoring of renal function. 8.5) 8.1 Pregnancy. Risk Summary Hydroxyurea capsules can cause fetal harm based on findings from animal studies and the drugs mechanism of action [see Clinical Pharmacology (12.1)]. There are no data with hydroxyurea capsules use in pregnant women to inform drug-associated risk. In animal reproduction studies, administration of hydroxyurea to pregnant rats and rabbits during organogenesis produced embryotoxic and teratogenic effects at doses 0.8 times and 0.3 times, respectively, the maximum recommended human daily dose on mg/m basis (see Data). Advise women of the potential risk to fetus and to avoid becoming pregnant while being treated with hydroxyurea capsules. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.DataAnimal Data Hydroxyurea has been demonstrated to be potent teratogen in 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 mg/m 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 mg/m basis) in rats and at 30 mg/kg/day (about 0.3 times the maximum recommended human daily dose on mg/m 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 mg/m 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 breastfed infant from hydroxyurea, including carcinogenicity, discontinue breastfeeding during treatment with hydroxyurea capsules. 8.3 Females and Males of Reproductive Potential. Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating hydroxyurea capsules therapy. ContraceptionFemales Hydroxyurea capsules can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during and after treatment with hydroxyurea capsules for at least months after therapy. Advise females to immediately report pregnancy. Males Hydroxyurea capsules 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 hydroxyurea capsules for at least year after therapy [see Nonclinical Toxicology (13.1)]. InfertilityMales Based on findings in animals and humans, male fertility may be compromised by treatment with hydroxyurea capsules. 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. Elderly patients may be more sensitive to the effects of hydroxyurea, and may require 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 (2.3)]. 8.6 Renal Impairment. The exposure to hydroxyurea is higher in patients with creatinine clearance of less than 60 mL/min or in patients with end-stage renal disease (ESRD). Reduce dosage and closely monitor the hematologic parameters when hydroxyurea capsules is to be administered to these patients [see Dosage and Administration (2.3) 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.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. oMyelosuppression: Do not give if bone marrow function is markedly depressed. Monitor hematology labs and interrupt, reduce dose as appropriate. 5.1) oMalignancies: Advise protection from sun exposure and monitor for secondary malignancies. 5.2) oEmbryo-Fetal toxicity: Can cause fetal harm. Advise of potential risk to fetus and use of effective contraception. 5.3, 8.1, 8.3) oVasculitic toxicities: Discontinue hydroxyurea and initiate treatment if this occurs. 5.4) oLive Vaccinations: Avoid live vaccine use in patient taking hydroxyurea capsules. 5.5) oRisks with concomitant use of antiretroviral drugs: Pancreatitis, hepatotoxicity, and neuropathy have occurred. Monitor for signs and symptoms in patients with HIV infection using antiretroviral drugs; discontinue hydroxyurea capsules, and implement treatment. 5.6) oRadiation recall: Monitor for skin erythema in patients who previously received radiation and manage symptomatically. 5.7) oMyelosuppression: Do not give if bone marrow function is markedly depressed. Monitor hematology labs and interrupt, reduce dose as appropriate. 5.1) oMalignancies: Advise protection from sun exposure and monitor for secondary malignancies. 5.2) oEmbryo-Fetal toxicity: Can cause fetal harm. Advise of potential risk to fetus and use of effective contraception. 5.3, 8.1, 8.3) oVasculitic toxicities: Discontinue hydroxyurea and initiate treatment if this occurs. 5.4) oLive Vaccinations: Avoid live vaccine use in patient taking hydroxyurea capsules. 5.5) oRisks with concomitant use of antiretroviral drugs: Pancreatitis, hepatotoxicity, and neuropathy have occurred. Monitor for signs and symptoms in patients with HIV infection using antiretroviral drugs; discontinue hydroxyurea capsules, and implement treatment. 5.6) oRadiation recall: Monitor for skin erythema in patients who previously received radiation and manage symptomatically. 5.7) 5.1 Myelosuppression. Hydroxyurea causes severe myelosuppression. Treatment with hydroxyurea should not be initiated if bone marrow function is markedly depressed. Bone marrow suppression may occur, and leukopenia is generally its first and most common manifestation. Thrombocytopenia and anemia occur less often and are seldom seen without preceding leukopenia. Bone marrow depression is more likely in patients who have previously received radiotherapy or cytotoxic cancer chemotherapeutic agents; use hydroxyurea cautiously in such patients.Evaluate hematologic status prior to and during treatment with hydroxyurea capsules. Provide supportive care and modify dose or discontinue hydroxyurea as needed. Recovery from myelosuppression is usually rapid when therapy is interrupted.. 5.2 Malignancies. Hydroxyurea is human carcinogen. In patients receiving long-term hydroxyurea for myeloproliferative disorders, secondary leukemia has been reported. 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.. 5.3 Embryo-Fetal Toxicity. Based on the mechanism of action and findings in animals, hydroxyurea can cause fetal harm when administered to 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 mg/m basis. Advise pregnant women of the potential risk to fetus [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during and after treatment with hydroxyurea capsules for at least months after therapy. Advise males of reproductive potential to use effective contraception during and after treatment with hydroxyurea capsules for at least year after therapy [see Use in Specific Populations (8.1, 8.3)]. 5.4 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 history of, or currently receiving, interferon therapy. If cutaneous vasculitic ulcers occur, institute treatment and discontinue hydroxyurea capsules.. 5.5 Live Vaccinations. Avoid use of live vaccine in patients taking hydroxyurea capsules. Concomitant use of hydroxyurea capsules with 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 hydroxyurea capsules. Vaccination with live vaccines in patient receiving hydroxyurea capsules may result in severe infection. Patients antibody response to vaccines may be decreased. Consider consultation with specialist.. 5.6 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)]. 5.7 Radiation Recall. Patients who have received irradiation therapy in the past may have an exacerbation of post-irradiation erythema. Monitor for skin erythema in patients who previously received radiation and manage symptomatically.. 5.8 Macrocytosis. Hydroxyurea capsules 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 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. Monitor patients developing pyrexia, cough, dyspnea, or other respiratory symptoms frequently, investigate and treat promptly. Discontinue Hydroxyurea capsules 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)].