DROXIA

DROXIA ® (hydroxyurea capsules, USP) is available for oral use as capsules containing 200 mg, 300 mg, and 400 mg hydroxyurea. Inactive ingredients include citric acid, gelatin, lactose, magnesium stearate, sodium phosphate, titanium dioxide, and capsule colorants: FD&C Blue No. 1 and FD&C Green No. 3 (200 mg capsules); D&C Red No. 28, D&C Red No. 33, and FD&C Blue No. 1 (300 mg capsules); D&C Red No. 28, D&C Red No. 33, and D&C Yellow No. 10 (400 mg capsules). 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

DROXIA is indicated to reduce the frequency of painful crises and to reduce the need for blood transfusions in patients with sickle cell anemia with recurrent moderate to severe painful crises. DROXIA is an antimetabolite indicated to reduce the frequency of painful crises and to reduce the need for blood transfusions in patients with sickle cell anemia with recurrent moderate to severe painful crises. ( 1 )

Initial dose: 15 mg/kg once daily. Monitor the patient's blood count every two weeks. ( 2.1 ) The dose may be increased by 5 mg/kg/day every 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 between the acceptable range and toxic. Discontinue DROXIA until hematologic recovery if blood counts are considered toxic. Treatment may then be resumed after reducing the dose by 2.5 mg/kg/day from the dose associated with hematological toxicity. ( 2.1 ) Renal impairment: Reduce the dose of DROXIA by 50% in patients with creatinine clearance less than 60 mL/min. ( 2.2 , 8.6 , 12.3 ) 2.1 Dosing Information Table 1: Dosing Recommendation Based on Blood Count Dosing Regimen Dose Dose Modification Criteria Monitoring Parameters Initial Recommended Dosing 15 mg/kg/day as a single dose once daily based on the patient's actual or ideal weight, whichever is less. Monitor the patient's blood count every 2 weeks [see Warnings and Precautions (5.1) ] . Dosing Based on Blood Counts In an acceptable range Increase dose 5 mg/kg/day every 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 dosing only if blood counts are in an acceptable range. Do not increase if myelosuppression occurs. Blood Counts Acceptable Range neutrophils ≥2500 cells/mm 3 platelets ≥95,000/mm 3 hemoglobin >5.3 g/dL reticulocytes ≥95,000/mm 3 if the hemoglobin concentration <9 g/dL Between acceptable and toxic range Do not increase dose. If blood counts are considered toxic , discontinue DROXIA until hematologic recovery. Blood Counts Toxic Range neutrophils <2000 cells/mm 3 platelets <80,000/mm 3 hemoglobin <4.5 g/dL reticulocytes <80,000/mm 3 if the hemoglobin concentration <9 g/dL Dosing After Hematologic Recovery Reduce dose by 2.5 mg/kg/day. Reduce the dose from the dose associated with hematologic toxicity. May titrate up or down every 12 weeks in 2.5 mg/kg/day increments. The patient should be at a stable dose with no hematologic toxicity for 24 weeks. Discontinue the treatment permanently if a patient develops hematologic toxicity twice. Swallow DROXIA capsules whole. Do NOT open, break, or chew capsules because DROXIA is a cytotoxic drug. Patients must be able to follow directions regarding drug administration and their monitoring and care. Fetal hemoglobin (HbF) levels may be used to evaluate the efficacy of DROXIA 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. DROXIA causes macrocytosis, which may mask the incidental development of folic acid deficiency. Prophylactic administration of folic acid is recommended. DROXIA is a cytotoxic drug. Follow applicable special handling and disposal procedures [see References (15) ]. 2.2 Dose Modifications for Renal Impairment Reduce the dose of DROXIA 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 values were obtained using 24-hour urine collections. Creatinine Clearance (mL/min) Recommended DROXIA Initial Dose (mg/kg once daily) ≥60 <60 or ESRD On dialysis days, administer DROXIA to patients with ESRD following hemodialysis. 15 7.5 Monitor the hematologic parameters closely in these patients.

DROXIA is contraindicated in patients who have demonstrated a previous hypersensitivity to hydroxyurea or any other component of its formulation. In patients who have demonstrated a previous hypersensitivity to hydroxyurea or any other component of its formulation. ( 4 )

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) ] Macrocytosis [see Warnings and Precautions (5.8) ] Pulmonary Toxicity [see Warnings and Precautions (5.9) ] 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. Most common adverse reactions (≥30%) are hematological, gastrointestinal symptoms, and anorexia. (6) To report SUSPECTED ADVERSE REACTIONS, contact Waylis Therapeutics LLC at 1-844-200-7910 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trial Experience In 299 patients treated for sickle cell anemia in the Multicenter Study of Hydroxyurea in Sickle Cell Anemia, the most common adverse reactions were hematologic, with neutropenia, and low reticulocyte and platelet levels necessitating temporary cessation in almost all patients. Hematologic recovery usually occurred in two weeks. Other adverse reactions include hair loss, macrocytosis, bleeding, and melanonychia. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of hydroxyurea in the treatment of neoplastic diseases. 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 re-occurred typically within 24 hours. Blood and lymphatic system disorders: hemolytic anemia

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 DROXIA 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.

16.2 Storage Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Keep tightly closed.