Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/1796
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DROXIA (Capsule)
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To minimize the risk of dermal exposure, always wear impervious
gloves when handling bottles containing DROXIA capsules. This includes all
handling activities in clinical settings, pharmacies, storerooms, and home
healthcare settings, including during unpacking and inspection, transport
within a facility, and dose preparation and administration. Procedures for proper handling and disposal of cytotoxic drugs
should be considered. Several guidelines on this subject have been published.There
is no general agreement that all of the procedures recommended in the guidelines
are necessary or appropriate. Dosage should be based on the patient's actual or ideal weight,
whichever is less. The initial dose of DROXIA is 15 mg/kg/day as a single
dose. The patient's blood count must be monitored every two weeks. If blood counts are in an acceptable range*, the dose
may be increased by 5 mg/kg/day every 12 weeks until a maximum tolerated dose
(the highest dose that does not produce toxic** blood counts
over 24 consecutive weeks), or 35 mg/kg/day, is reached. If blood counts are between the acceptable range* and toxic**,
the dose is not increased. If blood counts are considered toxic**, DROXIA should
be discontinued until hematologic recovery. Treatment may then be resumed
after reducing the dose by 2.5 mg/kg/day from the dose associated with hematologic
toxicity. DROXIA may then be titrated up or down, every 12 weeks in 2.5 mg/kg/day
increments, until the patient is at a stable dose that does not result in
hematologic toxicity for 24 weeks. Any dosage on which a patient develops
hematologic toxicity twice should not be tried again. *acceptable
range =neutrophils���2500 cells/mm,platelets���95,000/mm,hemoglobin>5.3 g/dL andreticulocytes���95,000/mmif the hemoglobin concentration<9
g/dL. **toxic =neutrophils<2000 cells/mm,platelets<80,000/mm,hemoglobin<4.5 g/dL andreticulocytes<80,000/mmif the hemoglobin concentration<9 g/dL.<br/>Renal Insufficiency: As renal excretion is a pathway of elimination, consideration should
be given to decreasing the dosage of DROXIA in patients with renal impairment.
The results of a single-dose study of the influence of renal function on the
pharmacokinetics of hydroxyurea in adults with sickle cell disease suggest
that the initial dose of hydroxyurea should be reduced by 50%, to 7.5 mg/kg/day,
when used to treat patients with renal impairment. Close monitoring of
hematologic parameters is advised in these patients.<br/>Hepatic Insufficiency: 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.
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DROXIA (hydroxyurea capsules,
USP) is available for oral use as capsules providing 200 mg, 300 mg, and 400
mg hydroxyurea. Inactive ingredients: citric acid, gelatin, lactose, magnesium
stearate, sodium phosphate, titanium dioxide, and capsule colorants; FD&C
Blue #1 and FD&C Green #3 (200 mg capsules); D&C Red #28, D&C
Red #33, and FD&C Blue #1 (300 mg capsules); D&C Red #28, D&C
Red #33, and D&C Yellow #10 (400 mg capsules). Hydroxyurea is an essentially tasteless, white crystalline powder.
Its structural formula is:
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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 DROXIA (hydroxyurea capsules, USP) produces
its beneficial effects in patients with sickle cell anemia (SCA) are uncertain.
Known pharmacologic effects of DROXIA that may contribute to its beneficial
effects include increasing hemoglobin F levels in RBCs, decreasing neutrophils,
increasing the water content of RBCs, increasing deformability of sickled
cells, and altering the adhesion of RBCs to endothelium.<br/>Pharmacokinetics:<br/>Absorption: Hydroxyurea is readily absorbed after oral administration. Peak
plasma levels are reached in 1 to 4 hours after an oral dose. With increasing
doses, disproportionately greater mean peak plasma concentrations and AUCs
are observed. There are no data on the effect of food on the absorption of hydroxyurea.<br/>Distribution: Hydroxyurea distributes rapidly and widely in the body with an
estimated volume of distribution approximating total body water. Plasma to ascites fluid ratios range from 2:1 to 7.5:1. Hydroxyurea
concentrates in leukocytes and erythrocytes.<br/>Metabolism: Up to 60% of an oral dose undergoes conversion through metabolic
pathways that are not fully characterized. One pathway is probably saturable
hepatic metabolism. Another minor pathway may be degradation by urease found
in intestinal bacteria. Acetohydroxamic acid was found in the serum of three
leukemic patients receiving hydroxyurea and may be formed from hydroxylamine
resulting from action of urease on hydroxyurea.<br/>Excretion: Excretion of hydroxyurea in humans is likely a linear first-order
renal process. In adults with SCA, mean cumulative urinary recovery of hydroxyurea
was about 40% of the administered dose.<br/>Special Populations:<br/>Geriatric, Gender, Race: No information is available regarding pharmacokinetic differences
due to age, gender or race.<br/>Pediatric: No pharmacokinetic data are available in pediatric patients treated
with hydroxyurea for SCA.<br/>Renal Insufficiency: As renal excretion is a pathway of elimination, consideration should
be given to decreasing the dosage of hydroxyurea in patients with renal impairment.
In adult patients with sickle cell disease, an open-label, non-randomized,
single-dose, multicenter study was conducted to assess the influence of renal
function on the pharmacokinetics of hydroxyurea. Patients in the study with
normal renal function (creatinine clearance [CrCl]>80 mL/min), mild (CrCl
50���80 mL/min), moderate (CrCl = 30���<50 mL/min), or severe (<30 mL/min)
renal impairment received hydroxyurea as a single oral dose of 15 mg/kg, achieved
by using combinations of the 200 mg, 300 mg, or 400 mg capsules. Patients
with end-stage renal disease (ESRD) received two doses of 15 mg/kg separated
by 7 days, the first was given following a 4-hour hemodialysis session, the
second prior to hemodialysis. In this study the mean exposure (AUC) in patients
whose creatinine clearance was<60 mL/min (or ESRD) was approximately 64%
higher than in patients with normal renal function. The results suggest that
the initial dose of hydroxyurea should be reduced when used to treat patients
with renal impairment. The table below
describes the recommended dosage modification. Close monitoring of hematologic parameters is advised in these
patients.<br/>Hepatic Insufficiency: 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.<br/>Drug Interactions: There are no data on concomitant use of hydroxyurea with other
drugs in humans.<br/>Clinical Studies: The efficacy of hydroxyurea in sickle cell anemia was assessed
in a large clinical study (Multicenter Study of Hydroxyurea in Sickle Cell
Anemia). The study was a randomized, double-blind, placebo-controlled trial
that evaluated 299 adult patients (���18 years) with moderate to severe disease
(���3 painful crises yearly). The trial was stopped by the Data Safety Monitoring
Committee, after accrual was completed but before the scheduled 24 months
of follow-up was completed in all patients, based on observations of fewer
painful crises among patients receiving hydroxyurea. Compared to placebo treatment, treatment with hydroxyurea resulted
in a significant decrease in the yearly rate of painful crises, the yearly
rate of painful crises requiring hospitalization, the incidence of chest syndrome,
the number of patients transfused, and units of blood transfused. Hydroxyurea
treatment significantly increased the median time to both first and second
painful crises. Although patients with 3 or more painful crises during the preceding
12 months were eligible for the study, most of the benefit in crisis reduction
was seen in the patients with 6 or more painful crises during the preceding
12 months. No deaths were attributed to treatment with hydroxyurea, and none
of the patients developed neoplastic disorders during the study. Treatment
was permanently stopped for medical reasons in 14 hydroxyurea-treated (2 patients
with myelotoxicity) and 6 placebo-treated patients. (See ADVERSE
REACTIONS.)<br/>Fetal Hemoglobin: In patients with SCA treated with hydroxyurea, fetal hemoglobin
(HbF) increases 4 to 12 weeks after initiation of treatment. In general, average
HbF levels correlate with dose and plasma level with possible plateauing at
higher dosages. A clear relation between reduction in crisis frequency and increased
HbF or F-cell levels has not been demonstrated. The dose-related cytoreductive
effects of hydroxyurea, particularly on neutrophils, was the factor most strongly
correlated with reduced crisis frequency.
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DROXIA is contraindicated in patients who have demonstrated a previous
hypersensitivity to hydroxyurea or any other component of its formulation.
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DROXIA (hydroxyurea capsules,
USP). 200 mg capsules packaged in HDPE bottles of 60 with
a plastic safety screw cap. (NDC 0003-6335-17). The cap and body are opaque
blue-green. The capsule is marked in black ink on both the cap and body with���DROXIA���and���6335.��� 300 mg capsules packaged in HDPE bottles of 60 with
a plastic safety screw cap. (NDC 0003-6336-17). The cap and body are opaque
purple. The capsule is marked in black ink on both the cap and body with���DROXIA���and���6336.��� 400 mg capsules packaged in HDPE bottles of 60 with
a plastic safety screw cap. (NDC 0003-6337-17). The cap and body are opaque
reddish-orange. The capsule is marked in black ink on both the cap and body
with���DROXIA���and���6337.���<br/>Storage: Store at 25��C (77��F); excursions permitted to 15���30��C (59���86��F) [see USP Controlled Room Temperature]. Keep tightly closed.
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WARNING: Treatment of patients with DROXIA may be complicated by severe,
sometimes life-threatening, adverse effects. DROXIA should be administered
under the supervision of a physician experienced in the use of this medication
for the treatment of sickle cell anemia. Hydroxyurea is mutagenic and clastogenic, and causes cellular transformation
to a tumorigenic phenotype. Hydroxyurea is thus unequivocally genotoxic and
a presumed transspecies carcinogen which implies a carcinogenic risk to humans.
In patients receiving long-term hydroxyurea for myeloproliferative disorders,
such as polycythemia vera and thrombocythemia, secondary leukemias have been
reported. It is unknown whether this leukemogenic effect is secondary to hydroxyurea
or is associated with the patient's underlying disease. The physician
and patient must very carefully consider the potential benefits of DROXIA
relative to the undefined risk of developing secondary malignancies.
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General: Therapy with DROXIA requires close supervision. Some patients treated
at the recommended initial dose of 15 mg/kg/day have experienced severe or
life-threatening myelosuppression, requiring interruption of treatment and
dose reduction. The hematologic status of the patient, as well as kidney and
liver function should be determined prior to, and repeatedly during treatment.
Treatment should be interrupted if neutrophil levels fall to<2000/mm;
platelets fall to<80,000/mm; hemoglobin declines
to less than 4.5 g/dL; or if reticulocytes fall below 80,000/mmwhen
the hemoglobin concentration is below 9 g/dL. Following recovery, treatment
may be resumed at lower doses (see DOSAGE AND
ADMINISTRATION). Hydroxyurea should be used with caution in patients with renal
dysfunction. Data from a single-dose study of the pharmacokinetics of hydroxyurea
in patients with sickle cell anemia suggest that the initial dose of hydroxyurea
should be reduced in patients with renal impairment. (See CLINICAL
PHARMACOLOGY: Special Populations and DOSAGE
AND ADMINISTRATION.) Patients must be able to follow directions regarding drug administration
and their monitoring and care. Hydroxyurea is not indicated for the treatment of HIV infection;
however, if HIV-infected patients are treated with hydroxyurea, and in particular,
in combination with didanosine and/or stavudine, close monitoring for signs
and symptoms of pancreatitis is recommended. Patients who develop signs and
symptoms of pancreatitis should permanently discontinue therapy with hydroxyurea.
(See WARNINGS and ADVERSE
REACTIONS.) An increased risk of hepatotoxicity, which may be fatal, may occur
in patients treated with hydroxyurea, and in particular, in combination with
didanosine and stavudine. This combination should be avoided.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: See WARNINGS and Boxed WARNING for Carcinogenesis and Mutagenesis information. Impairment of Fertility: Hydroxyurea administered to male rats
at 60 mg/kg/day (about 0.3 times the maximum recommended human daily dose
on an mg/mbasis) produced testicular atrophy,
decreased spermatogenesis, and significantly reduced their ability to impregnate
females.<br/>Pregnancy: Pregnancy Category D.<br/>Nursing Mothers: Hydroxyurea is excreted in human milk. Because of the potential
for serious adverse reactions with hydroxyurea, a decision should be made
either to discontinue nursing or to discontinue the drug, taking into account
the importance of the drug to the mother.<br/>Pediatric Use: Safety and effectiveness in pediatric patients have not been established.<br/>Drug Interactions: Prospective studies on the potential for hydroxyurea to interact
with other drugs have not been performed.<br/>Information for Patients: (See Patient Information at
end of labeling.) Patients should be reminded that this medication must be
handled with care. People who are not taking DROXIA should not be exposed
to it. To decrease the risk of exposure, wear disposable gloves when handling
DROXIA or bottles containing DROXIA. Anyone handling DROXIA should wash their
hands before and after contact with the bottle or capsules. If the powder
from the capsule is spilled, it should be wiped up immediately with a damp
disposable towel and discarded in a closed container, such as a plastic bag.
The medication should be kept away from children and pets. Contact your doctor
for instructions on how to dispose of outdated capsules. The necessity of monitoring blood counts every two weeks, throughout
the duration of therapy, should be emphasized. For additional information,
see the accompanying Patient Information leaflet.
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Acute mucocutaneous toxicity has been reported in patients receiving
hydroxyurea at dosages several times the therapeutic dose. Soreness, violet
erythema, edema on palms and soles followed by scaling of hands and feet,
severe generalized hyperpigmentation of the skin, and stomatitis have been
observed.
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HYDROXYUREA
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DROXIA (Capsule)
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Sickle Cell Anemia: In 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. Non-hematologic events that possibly were associated with treatment
include hair loss, skin rash, fever, gastrointestinal disturbances, weight
gain, bleeding, and parvovirus B-19 infection; however, these non-hematologic
events occurred with similar frequencies in the hydroxyurea and placebo treatment
groups. Melanonychia has also been reported in patients receiving DROXIA (hydroxyurea
capsules, USP) for SCA.<br/>Other: Adverse events associated with the use of hydroxyurea in the treatment
of neoplastic diseases, in addition to hematologic effects include: gastrointestinal
symptoms (stomatitis, anorexia, nausea, vomiting, diarrhea, and constipation),
and dermatological reactions such as maculopapular rash, skin ulceration,
dermatomyositis-like skin changes, peripheral erythema, and facial erythema.
Hyperpigmentation, atrophy of skin and nails, scaling, and violet papules
have been observed in some patients after several years of long-term daily
maintenance therapy with hydroxyurea. Skin cancer has been reported. Cutaneous
vasculitic toxicities, including vasculitic ulcerations and gangrene, have
occurred in patients with myeloproliferative disorders duringtherapy with
hydroxyurea. These vasculitic toxicities were reported most often in patients
with a history of, or currently receiving, interferon therapy . Dysuria and alopecia occur very
rarely. Large doses may produce moderate drowsiness. Neurological disturbances
have occurred extremely rarely and were limited to headache, dizziness, disorientation,
hallucinations, and convulsions. Hydroxyurea occasionally may cause temporary
impairment of renal tubular function accompanied by elevations in serum uric
acid, BUN, and creatinine levels. Abnormal BSP retention has been reported.
Fever, chills, malaise, edema, asthenia, and elevation of hepatic enzymes
have also been reported. The association of hydroxyurea with the development of acute pulmonary
reactions consisting of diffuse pulmonary infiltrates, fever, and dyspnea
has been rarely reported. Pulmonary fibrosis also has been reported rarely. Fatal and nonfatal pancreatitis and hepatotoxicity, and severe
peripheral neuropathy have been reported in HIV-infected patients who received
hydroxyurea in combination with antiretroviral agents, in particular, didanosine
plus stavudine. Patients treated with hydroxyurea in combination with didanosine,
stavudine, and indinavir in Study ACTG 5025 showed a median decline in CD4
cells of approximately 100/mm.
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DROXIA (hydroxyurea capsules, USP) is indicated to reduce the frequency
of painful crises and to reduce the need for blood transfusions in adult patients
with sickle cell anemia with recurrent moderate to severe painful crises (generally
at least 3 during the preceding 12 months).
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DROXIA
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