Drug Facts
Composition & Profile
Identifiers & Packaging
16 HOW SUPPLIED/STORAGE AND HANDLING 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 148 mL of oral solution. Each carton NDC 62484-0015-5 contains 1 bottle XROMI NDC 62484-0015-4, an LDPE bottle adaptor and 2 oral dosing syringes (one oral dosing syringe graduated to 3 mL and one oral dosing syringe graduated to 10 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. 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.; PACKAGE LABEL XROMI Carton Label XROMI Bottle label XROMI Carton Label XROMI Bottle Label Picture of bottle and oral dispensing syringes Figure A Figure B Figure C Figure D Figure E Figure F Figure G Figure H Figure I Figure J
- 16 HOW SUPPLIED/STORAGE AND HANDLING 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 148 mL of oral solution. Each carton NDC 62484-0015-5 contains 1 bottle XROMI NDC 62484-0015-4, an LDPE bottle adaptor and 2 oral dosing syringes (one oral dosing syringe graduated to 3 mL and one oral dosing syringe graduated to 10 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. 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.
- PACKAGE LABEL XROMI Carton Label XROMI Bottle label XROMI Carton Label XROMI Bottle Label Picture of bottle and oral dispensing syringes Figure A Figure B Figure C Figure D Figure E Figure F Figure G Figure H Figure I Figure J
Overview
XROMI (hydroxyurea) is available for oral use as oral solution containing 100 mg/mL hydroxyurea. Inactive ingredients include methyl parahydroxybenzoate, purified water, sodium hydroxide, strawberry flavor, sucralose and xanthan gum. 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: Chemical Structure
Indications & Usage
XROMI is indicated to reduce the frequency of painful crises and reduce the need for blood transfusions in pediatric patients aged 6 months of age and older with sickle cell anemia with recurrent moderate to severe painful crises. XROMI is an antimetabolite indicated to reduce the frequency of painful crises and reduce the need for blood transfusions in pediatric patients aged 6 months of age and older with sickle cell anemia with recurrent moderate to severe painful crises. (1)
Dosage & Administration
Initial dose: 15 mg/kg orally once daily. Monitor the patient’s blood count every two weeks. (2.1) The dose may be increased by 5 mg/kg/day every 8 to 12 weeks until a maximum tolerated dose or 35 mg/kg/day is reached if blood counts are in an acceptable range. (2.1) The dose is not increased if blood counts are below the acceptable range and toxic. Discontinue XROMI until hematologic recovery if blood counts are considered toxic. Treatment may be resumed after reducing the dose by 2.5mg/kg/day to 5mg/kg/day from the dose associated with hematological toxicity. (2.1) Renal impairment: Reduce the dose of XROMI by 50% in patients with creatinine clearance less than 60 mL/min. (2.2 , 8.6 , 12.3) 2.1 Recommended Dosage The recommended XROMI dosage in pediatric patients aged 6 months and older is described in Table 1. Table 1. Dosing Recommendation Based on Blood Count Dosing Regimen Dose Dose modification criteria Monitoring parameters Initial Recommended dosing 15 mg/kg/day (rounded to nearest 10 mg) orally as a single dose once daily based on the patient’s actual body weight. Monitor the patient’s complete blood count (CBC) with differential and reticulocyte count every 2 weeks while adjusting dosage [see Warnings and Precautions (5.1) ] . Dosing Adjustment Based on Blood Counts in the acceptable range Increase dose 5 mg/kg/day every 8 to 12 weeks. Maximal dose: 35 mg/kg/day.* *Maximal dose is the highest dose that does not produce toxic blood counts over 24 consecutive weeks. Increase dose only if blood counts are in an acceptable range. Do not increase if myelosuppression occurs. Target Blood Counts Absolute neutrophil count (ANC) 1 to 3 x 10 9 /L and platelets at least 80 x 10 9 /L Dosing Adjustment Based on Blood Counts below acceptable range Do not increase dose. If blood counts are considered toxic, discontinue XROMI until hematologic recovery. Blood Counts Toxic Range ANC less than 1 x 10 9 /L Platelets less than 80 x 10 9 /L Hemoglobin 20% decrease from baseline or hemoglobin less than 4.5 g/dL Reticulocytes less than 80 x10 9 /L if the hemoglobin concentration is less than 9 g/dL. Dosing after Hematologic Recovery If hematologic toxicity resolved within 1 week, restart at the same XROMI dose. If hematologic toxicity persisted for more than 1 week or occurred twice in a 3 month period, reduce dose by 5 mg/kg/day. Once a stable dose is established, monitor CBC with differential and reticulocyte count every 4 weeks for 2 months and then as clinically indicated. 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 oral dosing syringes (one oral dosing syringe graduated to 3 mL and one oral dosing syringe graduated to 10 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, 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 10 mL oral dosing syringe, marked 1 mL to 10 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 collection. Table 2. Creatinine Clearance Creatinine Clearance (mL/min) Recommended XROMI Initial Dose Greater than or equal to 60 15 mg/kg once daily Less than 60 or ESRD* 7.5 mg/kg once daily * On dialysis days, administer XROMI to patients with ESRD following hemodialysis Monitor the hematologic parameters closely in these patients.
Warnings & Precautions
Hemolytic anemia: Monitor blood counts throughout treatment. If hemolysis persists, discontinue XROMI. ( 5.2 ) 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: Institute treatment and discontinue XROMI if this occurs. (5.5) Live Vaccinations: Avoid live vaccine use in a patient taking XROMI. (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 XROMI and implement treatment. (5.7) 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/m 2 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 B 12 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) ] .
Boxed Warning
MYELOSUPPRESSION and MALIGNANCIES Myelosuppression: XROMI may cause severe 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 [see Warnings and Precautions(5.1) ] . Malignancies: Hydroxyurea is carcinogenic. Advise sun protection and monitor patients for malignancies [see Warnings and Precautions (5.3) ] . WARNING: MYELOSUPPRESSION and MALIGNANCIES See full prescribing information for complete boxed warning. Myelosuppression: XROMI may cause severe 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 ) . Malignancies Hydroxyurea is carcinogenic. Advise sun protection and monitor patients for malignancies ( 5.3 ).
Contraindications
XROMI is contraindicated in patients: who have demonstrated a previous hypersensitivity to hydroxyurea or any other component of its formulation. [see Adverse Reactions (6) ] . In patients who have demonstrated a previous hypersensitivity to hydroxyurea or any other component of its formulation. (4)
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) ] Live vaccinations [see Warnings and Precautions (5.6) Risks with concomitant use of antiretroviral drugs [see Warnings and Precautions (5.7) ] Macrocytosis [see Warnings and Precautions (5.8) ] Pulmonary toxicity [see Warnings and Precautions (5.9) ] Most common adverse reactions (incidence > 5%) are neutropenia and thrombocytopenia, and popular rash. (6) To report SUSPECTED ADVERSE REACTIONS, contact Rare Disease Therapeutics, Inc. at 844-472-7389 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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]. Table 3. Adverse Reactions Reported in Pediatric Patients Aged 10 Months and Older Enrolled in HUPK 10 Months–<2 Years 2 –<6 Years 6 –<18 Years Overall Body System Adverse Reactions (n=6)% (n=16)% (n=10)% (n=32)% Neutropenia 3 (50) 1 (6) 0 4 (13) Thrombocytopenia 2 (33) 1 (6) 0 3 (9) Diarrhea 1 (17) 0 0 1 (3) GGT Increased 0 0 1(10) 1 (3) Absolute Reticulocyte Count Decreased 1 (17) 0 0 1 (3) Alopecia 0 1 (6) 0 1 (3) Nail Discolouration 0 0 1 (10) 1 (3) Rash 0 0 1 (10) 1 (3) Rash Popular 0 1 (6) 1 (10) 2 (6) 6.2 Post marketing 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
Drug Interactions
Antiretroviral drug. (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 cases of 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. 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.
Storage & Handling
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.
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