2.1 Recommended Dosage

The recommended XROMI dosage in pediatric patients aged 6 months to less than 2 years is described in Table 1.

Caregivers must be able to follow directions regarding drug administration and their monitoring and care.

If a dose of XROMI is missed at the scheduled time, the patient should take the missed dose as soon as possible once it is noticed, but only on the same day. If this is not possible, the patient should skip the dose and continue with the next dose as prescribed.

The patient should not take two doses to make up for a missed dose.

Fetal hemoglobin (HbF) levels may be used to evaluate the efficacy of XROMI in clinical use. Obtain HbF levels every three to four months. Monitor for an increase in HbF of at least two-fold over the baseline value.

XROMI causes macrocytosis, which may mask the incidental development of folic acid deficiency. Prophylactic administration of folic acid is recommended.

2.2 Administration Instructions

XROMI is for oral use. See Instructions for Use for details on preparation and administration of XROMI for oral solution.

Do not shake.

Two dosing oral syringes (a red oral dosing syringe graduated to 3 mL and a white oral dosing syringe graduated to 12 mL) are provided for accurate measurement of the prescribed dose of the oral solution. It is recommended that the healthcare professional advises the caregiver which oral dosing syringe to use to ensure that the correct volume is administered.

The smaller 3 mL oral dosing syringe (red), marked from 0.5 mL to 3 mL, is for measuring doses of less than or equal to 3 mL. This oral dosing syringe should be recommended for doses less than or equal to 3 mL (each graduation of 0.1 mL contains 10 mg of hydroxyurea).

The larger 12 mL oral dosing syringe (white), marked 1 mL to 12 mL, is for measuring doses of more than 3 mL. This oral dosing syringe should be recommended for doses greater than 3 mL (each graduation of 0.25 mL contains 25 mg of hydroxyurea).

XROMI may be taken with or after meals at any time of the day but caregivers should standardize the method of administration and time of day.

XROMI is a hazardous drug. Follow applicable special handling and disposal procedures [see Reference (15)].

2.3 Dosage Modifications in Renal Impairment

Reduce the dose of XROMI by 50% in patients with 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 were obtained using 24-hour urine collections.

Monitor the hematologic parameters closely in these patients.

5.1 Myelosuppression

Hydroxyurea causes severe myelosuppression. Do not initiate treatment with XROMI in patients 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.

Some patients, treated at the recommended initial dose of 15 mg/kg/day, have experienced severe or life-threatening myelosuppression.

Evaluate hematologic status (CBC, reticulocyte count) prior to and every 2 weeks during dose-escalation period of XROMI treatment. Once a stable dose of XROMI is achieved, monitor every 4 weeks. Provide supportive care and modify dose or discontinue XROMI as needed. Recovery from myelosuppression is usually rapid when therapy is interrupted. [see Dosage and Administration (2.1)].

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 XROMI.

5.3 Malignancies

Hydroxyurea is a human carcinogen. In patients receiving long-term hydroxyurea for myeloproliferative disorders (a condition for which XROMI is not approved), secondary leukemia has been reported.

Secondary leukemia has also been reported in patients treated with long-term hydroxyurea for sickle cell anemia. Leukemia has also been reported in patients with sickle cell anemia and no prior history of treatment with hydroxyurea.

All patients using XROMI should be followed up on a long-term basis with regular blood counts to detect development of leukemia.

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 with Unapproved Use in Adolescents and Adults

Based on the mechanism of action and findings in animals, XROMI 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/m2 basis.

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 therapy. If cutaneous vasculitic ulcers occur, institute treatment and discontinue XROMI.

5.6 Live Vaccinations

Avoid use of live vaccines in patients taking XROMI. Concomitant use of XROMI with a 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 XROMI. Vaccination with live vaccines in a patient receiving XROMI may result in severe infection [see Drug Interactions (7.2)]. Patient’s antibody response to vaccines may be decreased. Consider consultation with a specialist.

5.7 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)].

5.8 Macrocytosis

XROMI 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 B12 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. Safety and effectiveness have not been established for the use of XROMI in the treatment of myeloproliferative neoplasms and the use is not approved by the FDA. Monitor patients developing pyrexia, cough, dyspnea, or other respiratory symptoms frequently, investigate and treat promptly. Discontinue XROMI 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)].

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 [see Drug Interactions (7.2)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of XROMI was evaluated in 32 pediatric patients aged 10 months -16 years with sickle cell anemia in a single-arm, open-label, prospective, multi-center, pharmacokinetic, safety and efficacy study (HUPK study). Only adverse reactions associated with the use of XROMI in pediatric patients aged 10 months to less than 2 years are presented.

The most frequently reported adverse reactions in HUPK study (>33%) were neutropenia, and thrombocytopenia [see Table 3].

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of hydroxyurea. 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
• 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 reoccurred typically within 24 hours.
• Blood and lymphatic system disorders: hemolytic anemia

7.1 Increased Toxicity with Concomitant Use of Antiretroviral Drugs

7.2 Laboratory Test Interference

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

The safety and effectiveness of XROMI have been established in pediatric patients aged 6 months to less than 2 years with sickle cell anemia with recurrent moderate to severe painful crises. Use of XROMI in these age groups is supported by evidence from a pharmacokinetic, efficacy and safety study, in which 32 pediatric patients ages 6 months to <18 years were enrolled. Among the 32 pediatric patients treated with XROMI, 6 were infants (6 months – 2years). The safety and effectiveness of XROMI have not been established in pediatric patients less than 6 months of age. Continuous follow-up of the growth of treated children is recommended.

8.6 Renal Impairment

The exposure to XROMI is higher in patients with creatinine clearance of less than 60 mL/min. Reduce dosage and closely monitor the hematologic parameters when XROMI is to be administered to these patients [see Dosage and Administration (2.2) 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.

12.1 Mechanism of Action

The precise mechanism by which hydroxyurea produces its cytotoxic and cytoreductive effects is not known. However, various studies support 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.

The mechanisms by which XROMI produces its beneficial effects in patients with sickle cell anemia are uncertain. Known pharmacologic effects of XROMI that may contribute to its beneficial effects include increasing HbF levels in red blood cells (RBCs), decreasing neutrophils, increasing the water content of RBCs, increasing deformability of sickled cells, and altering the adhesion of RBCs to endothelium.

12.2 Pharmacodynamics

In pediatric patients treated with hydroxyurea for up to 15 months, the ratio of fetal hemoglobin to total hemoglobin was 25%, at the end of the study, representing a change from baseline increase of 9% in patients aged 6 months to <2 years.

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Conventional long-term studies to evaluate the carcinogenic potential of hydroxyurea have not been performed. However, intraperitoneal administration of 125 to 250 mg/kg hydroxyurea (about 0.6-1.2 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 [see Warnings and Precautions (5.3 , 5.4)].

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 [see Use in Specific Populations (8.3)].

16.1 How Supplied

XROMI (hydroxyurea) 100 mg/mL is a colorless to pale yellow liquid supplied in an Amber type III glass bottle with tamper evident child-resistant closure (HDPE with expanded polyethylene liner) containing 150 mL of oral solution.

Each carton NDC 62484-0015-2 contains 1 bottle XROMI NDC 62484-0015-1, an LDPE bottle adaptor and 2 oral dosing syringes (a red oral dosing syringe graduated to 3 mL and a white oral dosing syringe graduated to 12 mL).

16.2 Storage

Store XROMI between 2°C to 8°C (35°F to 46°F) excursions permitted to 25°C (77°F) for up to 72 hours. Keep the bottle tightly closed to protect the integrity of the product and minimize the risk of accidental spillage. Do not freeze.

Use within 12 weeks after initially opening the bottle. Discard unused XROMI remaining after 12 weeks of first opening the bottle.

16.3 Handling and Disposal

XROMI is a hazardous drug. Follow applicable special handling and disposal procedures [see References (15)].

Anyone handling XROMI should wash their hands before and after administering a dose. To decrease the risk of exposure, parents and caregivers should wear disposable gloves when handling XROMI. To minimize air bubbles, the bottle should not be shaken prior to dosing. XROMI contact with skin or mucous membrane must be avoided. If XROMI comes into contact with skin or mucosa, it should be washed immediately and thoroughly with soap and water. Spillages must be wiped immediately with a damp disposable towel and discarded in a closed container, such as a plastic bag. The spill areas should be cleaned three times using a detergent solution followed by clean water. If contact with XROMI occurs in the eye(s), flush the eye(s) thoroughly with water or isotonic eyewash designated for that purpose for at least 15 minutes. Women who are pregnant, planning to be or breast-feeding should not handle XROMI. Parents / care givers should be advised to keep hydroxyurea out of the sight and reach of children. Accidental ingestion can be lethal for children.

Oral dosing syringes should be rinsed and washed with cold or warm water and dried completely before the next use. Store oral dosing syringes in a hygienic place with the medicine.