XROMI_- hydroxyurea_solution

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. In pediatric patients treated with hydroxyurea for up to 15 months, the ratio of fetal hemoglobin to total hemoglobin was 25%, 23. 2% at the end of the study, representing a change from baseline increase of 9%, 148% and 167% in patients aged 6 months to <2 years, 2 to <6 years and 6 to <18 years, respectively. Absorption Effect of Food Distribution Elimination Metabolism Excretion Specific Populations Renal Impairment [see Dosage and Administration (2. 2) Use in Specific Populations (8. 6) Pediatric Patients.

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.

Initial dose: 15 mg/kg orally once daily. Monitor the patient’s blood count every two weeks. 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. 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. 1) Renal impairment: Reduce the dose of XROMI by 50% in patients with creatinine clearance less than 60 mL/min. 3) The recommended XROMI dosage in pediatric patients aged 6 months and older is described in 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. Increase dose only if blood counts are in an acceptable range. Target Blood Counts 9 9 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 Platelets less than 80 x 10 9 Hemoglobin 20% decrease from baseline or hemoglobin less than 4. 5 g/dL Reticulocytes less than 80 x10 9 Dosing after Hematologic Recovery If hematologic toxicity resolved within 1 week, restart at the same XROMI dose. 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. XROMI is for oral use. See Instructions for Use for details on preparation and administration of XROMI for oral solution. [see Reference (15) 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) Clinical Pharmacology (12. 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.

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 www. gov/medwatch. 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]. Adverse Reactions Reported in Pediatric Patients Aged 10 Months and Older Enrolled in HUPK 10 Monthsen dash<2 Years 2 en dash<6 Years 6 en dash<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) 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.

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.

Risk Summary Clinical Pharmacology (12. 1) 2 Data Data Animal Data 2 2 2 2 Risk Summary Pregnancy Testing Contraception Females Use in Specific Populations (8. 1) Males Nonclinical Toxicology (13. 1) Infertility Males Nonclinical Toxicology (13. 1) The safety and effectiveness of XROMI have been established in pediatric patients aged 6 months and older 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 en dash 2 years), 16 children (2-6 years) and 10 were adolescents (6-18 years) [see Clinical Studies (14) 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) Clinical Pharmacology (12. 3) 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.

Antiretroviral drug. 1) Laboratory Test Interference. 2) Pancreatitis Hepatotoxicity Peripheral Neuropathy 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 If a patient using a CGM is to be prescribed hydroxyurea, consult with the CGM prescriber about alternative glucose monitoring methods.

OVERDOSAGE
Acute mucocutaneous toxicity and neutropenia has been reported in patients receiving hydroxyurea at doses several times above the therapeutic dose. Soreness, violet erythema, oedema on palms and soles followed by scaling of hand and feet, severe generalized hyperpigmentation of the skin and stomatitis have been observed.
NONCLINICAL TOXICOLOGY
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/m 2 in vitro in vitro in vivo [see Warnings and Precautions (5.3 , 5.4) 2 [see Use in Specific Populations (8.3)
CLINICAL STUDIES
The effectiveness of XROMI has been established for the indication, “to reduce the frequency of painful crises and to reduce the need for blood transfusions in pediatric patients aged 6 months and older with sickle cell anemia with recurrent moderate to severe painful crises” based on an adequate and well-controlled study of hydroxyurea capsules in adult patients with sickle cell anemia with recurrent moderate to severe pain crises and additional pharmacokinetic data from a single-arm, open-label study of XROMI in pediatric patients aged 10 months to less than 18 years with sickle cell anemia, who were treatment naïve or had not received hydroxyurea in the 6 months prior to enrollment: HUPK study [see Adverse Reactions (6.1)
REFERENCES
OSHA Hazardous Drugs. OSHA.

Nova Laboratories, Ltd.

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