Hydroxyurea

1 INDICATIONS AND USAGE Hydroxyurea capsules, USP is indicated for the treatment of: Resistant chronic myeloid leukemia. Locally advanced squamous cell carcinomas of the head and neck (excluding the lip) in combination with chemoradiation. Hydroxyurea capsules, USP is an antimetabolite indicated for the treatment of: • Resistant chronic myeloid leukemia. (1) • Locally advanced squamous cell carcinomas of the head and neck, (excluding lip) in combination with concurrent chemoradiation. (1)

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 a 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 syntheses have shown no alteration. 12.3 Pharmacokinetics Absorption Following oral administration of hydroxyurea capsules, hydroxyurea reaches peak plasma concentrations in 1 to 4 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 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 to 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. 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 hydroxyurea capsules when it is administered to

2 DOSAGE AND ADMINISTRATION Individualize treatment based on tumor type, disease state, response to treatment, patient risk factors, and current clinical practice standards. (2.1) Renal 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 patient’s actual or ideal weight, whichever is less. Hydroxyurea is a cytotoxic drug. Follow applicable special handling and disposal procedures [ see References (15) ]. Swallow hydroxyurea capsule whole. Do NOT open, break, or chew capsules because hydroxyurea is a cytotoxic drug. Prophylactic administration of folic acid is recommended [ see Warnings and Precautions (5.8) ]. Monitor blood counts at least once a week during hydroxyurea therapy. Severe anemia must be corrected before initiating therapy with hydroxyurea. 2.2 Dose Modifications for Toxicity Monitor for the following and reduce the dose or discontinue hydroxyurea accordingly: Myelosuppression [see Warnings and Precautions (5.1) ] Cutaneous vasculitis [see Warnings and Precautions (5.5) ] 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) ≥60 15 <60 or ESRD On dialysis days, administer hydroxyurea capsules to patients following hemodialysis. 7.5 Close monitoring of hematologic parameters is advised in these patients.

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 patient’s actual or ideal weight, whichever is less. Hydroxyurea is a cytotoxic drug. Follow applicable special handling and disposal procedures [ see References (15) ]. Swallow hydroxyurea capsule whole. Do NOT open, break, or chew capsules because hydroxyurea is a cytotoxic drug. Prophylactic administration of folic acid is recommended [ see Warnings and Precautions (5.8) ]. Monitor blood counts at least once a week during hydroxyurea therapy. Severe anemia must be corrected before initiating therapy with hydroxyurea.

2.2 Dose Modifications for Toxicity Monitor for the following and reduce the dose or discontinue hydroxyurea accordingly: Myelosuppression [see Warnings and Precautions (5.1) ] Cutaneous vasculitis [see Warnings and Precautions (5.5) ]

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) ≥60 15 <60 or ESRD On dialysis days, administer hydroxyurea capsules to patients following hemodialysis. 7.5 Close monitoring of hematologic parameters is advised in these patients.

6 ADVERSE REACTIONS • Myelosuppression [see Warnings and Precautions (5.1) ] • Hemolytic anemia [see Warnings and Precautions (5.2) ] • Malignancies [see Warnings and Precautions (5.3) ] • Vasculitic toxicities [see Warnings and Precautions (5.5) ] • Risks with concomitant use of antiretroviral drugs [see Warnings and Precautions (5.7) ] • Radiation recall [see Warnings and Precautions (5.8) ] • Macrocytosis [see Warnings and Precautions (5.9) ] • Pulmonary Toxicity [see Warnings and Precautions (5.10) ] Most common adverse reactions (≥30%) are hematological, gastrointestinal symptoms, and anorexia. (6) To report SUSPECTED ADVERSE REACTIONS, contact Leading Pharma, LLC at 1-844-740-7500 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 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, tumor lysis syndrome 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 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/mm3) 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.

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 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, tumor lysis syndrome 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 pa

5 WARNINGS AND PRECAUTIONS Myelosuppression: Do not give if bone marrow function is markedly depressed. Monitor blood counts at baseline and throughout treatment. Interrupt treatment and reduce dose as necessary. (5.1) Hemolytic anemia: Monitor blood counts throughout treatment. If hemolysis persists, discontinue Hydroxyurea. (5.2) Malignancies: Advise protection from sun exposure and monitor for secondary malignancies. ( 5.3) Embryo-Fetal toxicity: Can cause fetal harm. Advise of potential risk to a fetus and use of effective contraception. ( 5.4 , 8.1 , 8.3 ) Vasculitic toxicities: Discontinue hydroxyurea and initiate treatment if this occurs. (5.5) Live Vaccinations: Avoid live vaccine use in a patient taking hydroxyurea capsules. (5.6) Risks 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. (5.7) Radiation recall: Monitor for skin erythema in patients who previously received radiation and manage symptomatically. (5.8) 5.1 Myelosuppression s ion 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 a 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 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 hydroxyurea. 5.3 Malignancies Hydroxyurea is a 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. 5.4 Embryo-Fetal Toxicity Based on the mechanism of action and findings in animals, hydroxyurea 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 hydroxyurea capsules for at least 6 months after therapy. Advise males of reproductive potential to use effective contraception during and after treatment with hydroxyurea capsules 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

4 CONTRAINDICATIONS Hydroxyurea capsules is contraindicated in patients who have demonstrated a previous hypersensitivity to hydroxyurea or any other component of the formulation. • In patients who have demonstrated a previous hypersensitivity to hydroxyurea or any other component of its formulation. (4)

10 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 also been observed.