HYDROXYUREA

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.

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)

11 DESCRIPTION Hydroxyurea Capsules USP is an antimetabolite available for oral use as capsules containing 500 mg hydroxyurea, USP. Inactive ingredients include Colorants (D&C Yellow No. 10, FD&C Red No.3, FD&C Blue No.1), gelatin, lactose anhydrous, magnesium stearate and silicon dioxide and titanium dioxide. Hydroxyurea is a White or almost white, crystalline powder. It is hygroscopic and soluble in water, but practically insoluble in alcohol. The empirical formula is CH 4 N 2 O 2 and it has a molecular weight of 76.05. Its structural formula is: image description

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 capsule 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.

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)

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.

7 DRUG INTERACTIONS Antiretroviral drugs (7.1) Laboratory 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.

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 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) ].

20230908

9

3 DOSAGE FORMS AND STRENGTHS Capsules: 500 mg, green opaque cap imprinted in black with “LP 164” and light pink opaque body imprinted in black with “LP 164” • Capsules: 500 mg

HYDROXYUREA HYDROXYUREA HYDROXYUREA HYDROXYUREA D&C YELLOW NO. 10 FD&C RED NO. 3 FD&C BLUE NO. 1 GELATIN ANHYDROUS LACTOSE MAGNESIUM STEARATE SILICON DIOXIDE TITANIUM DIOXIDE cap-opaque green body-opaque light pink LP;164

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Conventional long-term studies to evaluate the carcinogenic potential of hydroxyurea capsules have not been performed. However, intraperitoneal administration of 125 to 250 mg/kg hydroxyurea (about 0.6 to 1.2 times the maximum recommended human oral daily dose on a mg/m 2 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. Hydroxyurea administered to male rats at 60 mg/kg/day (about 0.3 times the maximum recommended human daily dose on a mg/m 2 basis) produced testicular atrophy, decreased spermatogenesis, and significantly reduced their ability to impregnate females.

ANDA213438

HYDROXYUREA

HYDROXYUREA

69315-164

HUMAN PRESCRIPTION DRUG

ORAL

Hydroxyurea capsules, USP container label image description

RECENT MAJOR CHANGES Warnings and Precautions, Hemolytic Anemia (5.2) 7/2021

17 PATIENT COUNSELING INFORMATION There is a risk of myelosuppression. Monitoring blood counts weekly throughout the duration of therapy should be emphasized to patients taking hydroxyurea capsules . Advise patients to report signs and symptoms of infection or bleeding immediately. [see Warnings and Precautions (5.1) ]. Advise patients of the risk of hemolytic anemia. Advise patients that they will have blood tests to evaluate for this if they develop persistent anemia [see Warnings and Precautions (5.2) ]. Advise patients that there is a risk of cutaneous vasculitic toxicities and secondary malignancies including leukemia and skin cancers [see Warnings and Precautions (5.3, 5.5) ]. 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 hydroxyurea capsules [see Warnings and Precautions (5.4) and Use in Specific Populations (8.1 , 8.3) ]. Advise 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 a severe infection [see Warnings and Precautions (5.6) ]. Advise females to discontinue breastfeeding during treatment with hydroxyurea capsules [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) ]. Post-irradiation erythema can occur in patients who have received previous irradiation therapy [see Warnings and Precautions (5.8) ]. 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 (5.10) ]. Rx only Manufactured by: Halo Pharmaceutical Inc 30 North Jefferson Road, Whippany, NJ 07981 Distributed by: Leading Pharma, LLC Fairfield, NJ 07004 Rev.05 02/23

15 REFERENCES OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html.

8 USE IN SPECIFIC POPULATIONS Lactation: Advise women not to breastfeed. (8.2) Geriatric Use: Care should be taken in dose selection and may require a 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 drug’s mechanism of action [see Clinical Pharmacology (12.1) ]. There are no data with hydroxyurea capsules use in pregnant women to inform a 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 a mg/m 2 basis (see Data). Advise women of the potential risk to a 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%–4% and 15%–20%, respectively. Data Animal Data 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/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 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 therapy. Contraception Females Hydroxyurea capsules 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 hydroxyurea capsules for at least 6 months after therapy. Advise females to immediately report pregnancy. Males Hydroxyurea 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 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 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 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 (2.3) ]. 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.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Hydroxyurea capsules, USP is supplied as 500 mg capsules in HDPE bottles with heat induction Child Resistant Closures. Each bottle contains 100 capsules. The cap is opaque green, and the body is opaque light pink. The capsules are imprinted on both sections with “LP 164” in black ink (NDC 69315-164-01). 16.2 Storage Store at 20-25°C (68-77°F); excursions permitted to 15°C-30°C (59°F-86°F) [see USP Controlled Room Temperature]. Keep tightly closed. 16.3 Handling and Disposal Hydroxyurea capsules is a 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 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.