HYDREA

HYDREA 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. Warnings and Precautions, Laboratory Test Interference ( 5.11 ) 11/2023 Drug Interactions, Laboratory Test Interference ( 7.2 ) 11/2023

1 INDICATIONS AND USAGE HYDREA 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. HYDREA 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)

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 HYDREA by 50% in patients with creatinine clearance less than 60 mL/min. (2.3 , 8.6 , 12.3) 2.1 Dosing Information HYDREA 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. HYDREA is a cytotoxic drug. Follow applicable special handling and disposal procedures [see References (15) ]. Swallow HYDREA capsules whole. Do NOT open, break, or chew capsules because HYDREA 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 HYDREA therapy. Severe anemia must be corrected before initiating therapy with HYDREA. 2.2 Dose Modifications for Toxicity Monitor for the following and reduce the dose or discontinue HYDREA accordingly: Myelosuppression [ see Warnings and Precautions ( 5.1 ) ] Cutaneous vasculitis [ see Warnings and Precautions (5.5) ] Consider dose modifications for other toxicities. 2.3 Dose Modifications for Renal Impairment Reduce the dose of HYDREA 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 HYDREA Initial Dose (mg/kg once daily) ≥60 15 <60 or ESRD* 7.5 * On dialysis days, administer HYDREA to patients following hemodialysis. Close monitoring of hematologic parameters is advised in these patients.

3 DOSAGE FORMS AND STRENGTHS Capsules: 500 mg opaque green cap and opaque pink body imprinted with "HYDREA" and "500". Capsules: 500 mg ( 3 )

4 CONTRAINDICATIONS HYDREA 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 )

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described in detail in other labeling sections: 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 CHEPLAPHARM Arzneimittel GmbH at 1-888-877-5884 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 HYDREA. 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/mm 3 ) has occurred in the presence of marked leukopenia. HYDREA may potentiate some adverse reactions usually seen with irradiation alone, such as gastric distress and mucositis.

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 HYDREA 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. Interference with Continuous Glucose Monitoring Systems Hydroxyurea may falsely elevate sensor glucose results from certain continuous glucose monitoring (CGM) systems and may lead to hypoglycemia if sensor glucose results are relied upon to dose insulin. If a patient using a CGM is to be prescribed hydroxyurea, consult with the CGM prescriber about alternative glucose monitoring methods.

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 HYDREA 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 HYDREA 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 HYDREA. 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 HYDREA. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating HYDREA therapy. Contraception Females HYDREA 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 HYDREA for at least 6 months after therapy. Advise females to immediately report pregnancy. Males HYDREA 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 HYDREA 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 HYDREA. 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 h …

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.

11 DESCRIPTION HYDREA (hydroxyurea capsules, USP) is an antimetabolite available for oral use as capsules containing 500 mg hydroxyurea. Inactive ingredients include citric acid, colorants (D&C Yellow No. 10, FD&C Blue No. 1, FD&C Red No. 40, and D&C Red No. 28), gelatin, lactose, magnesium stearate, sodium phosphate, and titanium dioxide. Hydroxyurea is a white to off-white crystalline powder. It is hygroscopic and freely 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: Hydroxyurea Chemical Structure

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.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied HYDREA ® (hydroxyurea capsules, USP) is supplied as 500 mg capsules in HDPE bottles with a plastic safety screw cap. Each bottle contains 100 capsules. The cap is opaque green and the body is opaque pink. The capsules are imprinted on both sections with "HYDREA" and "500" in black ink (NDC 61269-835-10). 16.2 Storage Store at 20°C-25°C (68°F -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 HYDREA 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 HYDREA or bottles containing HYDREA. Wash hands with soap and water before and after contact with the bottle or capsules when handling HYDREA. Do not open HYDREA 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.