Droxia

1 INDICATIONS AND USAGE 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.

Initial dose: 15 mg/kg once daily. Monitor the patient's blood count every two weeks. 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. 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. 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)

2.1Dosing 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 . 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 .

2.2Dose 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) . Creatinine clearance values were obtained using 24-hour urine collections. * On dialysis days, administer DROXIA to patients with ESRD following hemodialysis. Creatinine Clearance (mL/min) Recommended DROXIA Initial Dose (mg/kg once daily) ≥60 15 <60 or ESRD*

7.5Monitor the

hematologic parameters closely in these patients.

Hemolytic anemia: Monitor blood counts throughout treatment. If hemolysis persists, discontinue DROXIA. 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 DROXIA if this occurs. Live Vaccinations: Avoid live vaccine use in a patient taking DROXIA. 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 DROXIA and implement treatment.

5.1Myelosuppression Hydroxyurea

causes severe myelosuppression. Treatment with DROXIA should not be initiated 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 prior to and during treatment with DROXIA. Provide supportive care and modify dose or discontinue DROXIA as needed. Recovery from myelosuppression is usually rapid when therapy is interrupted.

5.2Hemolytic Anemia Cases of

hemolytic anemia in patients treated with hydroxyurea for myeloproliferative diseases have been reported . 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 DROXIA.

5.3Malignancies Hydroxyurea

is a human carcinogen. In patients receiving long-term hydroxyurea for myeloproliferative disorders, secondary leukemia has been reported. Secondary leukemia has also been reported in patients treated with long-term hydroxyurea for sickle cell disease. Leukemia has also been reported in patients with sickle cell disease and no prior history of treatment with hydroxyurea.

All patients using DROXIA 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.

5.4Embryo-Fetal Toxicity Based on the

mechanism of action and findings in animals, DROXIA 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. Advise pregnant women of the potential risk to a fetus . Advise females of reproductive potential to use effective contraception during and after treatment with DROXIA for at least 6 months after therapy.

Advise males of reproductive potential to use effective contraception during and after treatment with DROXIA for at least 1 year after therapy .

5.5Vasculitic 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 DROXIA.

5.6Live Vaccinations Avoid

use of live vaccine in patients taking DROXIA. Concomitant use of DROXIA 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 DROXIA. Vaccination with live vaccines in a patient receiving DROXIA may result in severe infection. Patient's antibody response to vaccines may be decreased. Consider consultation with a specialist.

5.7Risks 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 .

5.8Macrocytosis

DROXIA 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.

5.9Pulmonary 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 DROXIA 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 DROXIA and manage with corticosteroids. .

5.10Laboratory Test Interference Interference with Uric

Acid, Urea, or Lactic Acid Assays is possible, rendering falsely elevated results of these in patients treated with hydroxyurea . 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 .

4 CONTRAINDICATIONS 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.

8.1Pregnancy Risk Summary

DROXIA can cause fetal harm based on findings from animal studies and the drug's mechanism of action . There are no data with DROXIA use in pregnant women to inform a drug-associated risk. In animal reproduction studies, administration of hydroxyurea to pregnant rats and rabbits during organogenesis produced embryotoxic and teratogenic effects at doses 0.8 times and 0.3 times, respectively, the maximum recommended human daily dose on a mg/m 2 basis . Advise women of the potential risk to a fetus and to avoid becoming pregnant while being treated with DROXIA. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%–4% and 15%–20%, respectively. Data Animal Data Hydroxyurea has been demonstrated to be a potent teratogen in a wide variety of animal models, including mice, hamsters, cats, miniature swine, dogs, and monkeys at doses within 1-fold of the human dose given on a mg/m 2 basis.

Hydroxyurea is embryotoxic and causes fetal malformations (partially ossified cranial bones, absence of eye sockets, hydrocephaly, bipartite sternebrae, missing lumbar vertebrae) at 180 mg/kg/day (about 0.8 times the maximum recommended human daily dose on a mg/m 2 basis) in rats and at 30 mg/kg/day (about 0.3 times the maximum recommended human daily dose on a mg/m 2 basis) in rabbits. Embryotoxicity was characterized by decreased fetal viability, reduced live litter sizes, and developmental delays. Hydroxyurea crosses the placenta.

Single doses of ≥375 mg/kg (about 1.7 times the maximum recommended human daily dose on a mg/m 2 basis) to rats caused growth retardation and impaired learning ability.

The following clinically significant adverse reactions are described in detail in other labeling sections: Myelosuppression Hemolytic anemia Malignancies Vasculitic toxicities Risks with concomitant use of antiretroviral drugs Macrocytosis Pulmonary Toxicity 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. To report SUSPECTED ADVERSE REACTIONS, contact CHEPLAPHARM Arzneimittel GmbH at 1-888-877-5884 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical 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.

6.2Postmarketing 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