Hydrea

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.

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)].

Close monitoring of hematologic parameters is advised in these patients.

Capsules: 500 mg, green opaque cap imprinted in black with “LP 164” and light pink opaque body imprinted in black with “LP 164”

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.

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)].

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.

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.

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 CH4N2O2 and it has a molecular weight of 76.05. Its structural formula is:

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)].

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/m2 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/m2 basis) produced testicular atrophy, decreased spermatogenesis, and significantly reduced their ability to impregnate females.

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.