Hydrea
Generic Name: hydroxyurea
Dosage Form: capsule
Indications and Usage for Hydrea
Hydrea is indicated for the
treatment of:
•
Resistant chronic myeloid
leukemia.
•
Locally advanced squamous cell
carcinomas of the head and neck (excluding the lip) in combination with
chemoradiation.
Hydrea Dosage and
AdministrationDosing Information
Hydrea
is used alone or in conjunction with other antitumor agents or radiation
therapy to treat neoplastic diseases. Individualize treatment based on tumor
type, disease state, response to treatment, patient risk factors, and current
clinical practice standards.
Base
all dosage on the patient’s actual or ideal weight, whichever is less.
Hydrea
is a cytotoxic drug. Follow applicable special handling and disposal
procedures [see References
(15)].
Prophylactic
administration of folic acid is recommended [see Warnings
and Precautions (5.7)].
Dose Modifications for Toxicity
Monitor
for the following and reduce the dose or discontinue Hydrea accordingly:
•
Myelosuppression [see Warnings
and Precautions(5.1)]
• Cutaneous vasculitis [see Warnings
and Precautions (5.4)]
Monitor
blood counts at least once a week during Hydrea therapy. Severe anemia must be
corrected before initiating therapy with Hydrea. Consider dose modifications
for other toxicities.
Dose Modifications for Renal Impairment
Reduce
the dose of Hydrea by 50% in patients with measured 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
(mL/min)
|
Recommended Hydrea Initial Dose
(mg/kg daily)
|
|
≥60
|
15
|
|
<60 or
ESRD*
|
7.5
|
* On
dialysis days, administer Hydrea to patients following hemodialysis.
Close
monitoring of hematologic parameters is advised in these patients.
Dosage Forms and
Strengths
Capsules:
500 mg opaque green cap and opaque pink body imprinted with “Hydrea” and “830.”
Contraindications
Hydrea
is contraindicated in patients who have demonstrated a previous
hypersensitivity to hydroxyurea or any other component of the formulation.
Warnings and
PrecautionsMyelosuppression
Hydroxyurea
causes severe myelosuppression. Treatment with hydroxyurea 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. Bone marrow depression is more likely in
patients who have previously received radiotherapy or cytotoxic cancer
chemotherapeutic agents; use hydroxyurea cautiously in such patients.
Evaluate
hematologic status prior to and during treatment with Hydrea. Provide
supportive care and modify dose or discontinue Hydrea as needed. Recovery from
myelosuppression is usually rapid when therapy is interrupted.
Malignancies
Hydroxyurea
is a human carcinogen. In patients receiving long-term hydroxyurea for
myeloproliferative disorders, secondary leukemia has been reported. 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.
Embryo-Fetal Toxicity
Based
on the mechanism of action and findings in animals, Hydrea 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/m2 basis. Advise pregnant
women of the potential risk to a fetus [see Use in
Specific Populations(8.1)].
Advise
females of reproductive potential to use effective contraception during and
after treatment with Hydrea for at least 6 months after therapy. Advise males
of reproductive potential to use effective contraception during and after
treatment with Hydrea for at least 1 year after therapy [see Use in
Specific Populations (8.1, 8.3)].
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 Hydrea.
Live Vaccinations
Avoid
use of live vaccine in patients taking Hydrea. Concomitant use of Hydrea 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 Hydrea. Vaccination with live vaccines in a patient
receiving Hydrea may result in severe infection. Patient’s antibody response to
vaccines may be decreased. Consider consultation with a specialist.
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)].
Radiation Recall
Patients
who have received irradiation therapy in the past may have an exacerbation of
post irradiation erythema. Monitor for skin erythema in patients who previously
received radiation and manage symptomatically.
Macrocytosis
Hydrea
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 B12 or folic acid deficiency. This may mask the diagnosis of
pernicious anemia. Prophylactic administration of folic acid is recommended.
Adverse Reactions
The
following adverse reactions are described in detail in other labeling sections:
•
Myelosuppression [see Warnings
and Precautions (5.1)]
•
Malignancies [see Warnings
and Precautions (5.2)]
•
Embryo-fetal toxicity [see Warnings
and Precautions (5.3)]
•
Vasculitic toxicities [see Warnings
and Precautions (5.4)]
•
Risks with concomitant use of
antiretroviral drugs [see Warnings
and Precautions (5.6)]
•
Radiation recall [see Warnings
and Precautions (5.7)]
•
Macrocytosis [see Warnings
and Precautions (5.8)]
Postmarketing Experience
The
following adverse reactions have been identified during post approval use of
Hydrea. 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, tumor lysis syndrome
• Skin and subcutaneous tissue disorders: maculopapular rash, skin
ulceration,dermatomyositis-like skin changes, peripheral and facial
erythema,hyperpigmentation,nail pigmentation,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
• Hypersensitivity: Drug-induced Fever : High fever (> 39°C, >102°F)
requiring hospitalization in some cases has been reported concurrently with
gastrointestinal, pulmonary, musculoskeletal, hepatobiliary, dermatological or
cardiovascular manifestations. Onset typically occurred within 6 weeks of
initiation and resolved promptly after discontinuation of hydroxyurea. Upon
re-administration fever re-occurred within 24 hours.
Adverse
reactions observed with combined hydroxyurea and irradiation therapy are
similar to those reported with the use of hydroxyurea or radiation treatment
alone. These effects primarily include bone marrow depression (anemia and
leukopenia), gastric irritation, and mucositis. Almost all patients receiving
an adequate course of combined hydroxyurea and irradiation therapy will
demonstrate concurrent leukopenia. Platelet depression (<100,000 cells/mm3) has occurred in the presence
of marked leukopenia. Hydrea may potentiate some adverse reactions usually seen
with irradiation alone, such as gastric distress and mucositis.
Drug InteractionsIncreased 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
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.
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.
USE IN SPECIFIC
POPULATIONSPregnancy
Risk Summary
Hydrea
can cause fetal harm based on findings from animal studies and the drug’s
mechanism of action [see Clinical
Pharmacology (12.1)]. There are no data with
Hydrea 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/m2 basis (see Data). Advise women of the
potential risk to a fetus and to avoid becoming pregnant while being treated
with Hydrea.
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/m2 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/m2 basis) in rats and at 30 mg/kg/day (about 0.3 times the
maximum recommended human daily dose on a mg/m2 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/m2 basis) to rats caused growth retardation and impaired
learning ability.
Lactation
Risk Summary
Hydroxyurea
is excreted in human milk. Because of the potential for serious adverse
reactions in a breastfed infant from hydroxyurea, including carcinogenicity,
discontinue breastfeeding during treatment with Hydrea.
Females and Males of Reproductive Potential
Pregnancy Testing
Verify
the pregnancy status of females of reproductive potential prior to initiating
Hydrea therapy.
Contraception
Females
Hydrea
can cause fetal harm when administered to a pregnant woman [see Use in
Specific Populations (8.1)]. Advise females of
reproductive potential to use effective contraception during and after
treatment with Hydrea for at least 6 months after therapy. Advise females to
immediately report pregnancy.
Males
Hydrea
may damage spermatozoa and testicular tissue, resulting in possible genetic
abnormalities. Males with female sexual partners of reproductive potential
should use effective contraception during and after treatment with Hydrea for
at least 1 year after therapy [see Nonclinical
Toxicology (13.1)].
Infertility
Males
Based
on findings in animals and humans, male fertility may be compromised by
treatment with Hydrea. Azoospermia or oligospermia, sometimes reversible, has
been observed in men. Inform male patients about the possibility of sperm
conservation before the start of therapy [see Adverse
Reactions (6) and Nonclinical
Toxicology (13.1)].
Pediatric Use
Safety
and effectiveness in pediatric patients have not been established.
Geriatric Use
Elderly
patients may be more sensitive to the effects of hydroxyurea, and may require a
lower dose regimen. Hydroxyurea is excreted by the kidney, and the risk of
adverse reactions to this drug may be greater in patients with impaired renal
function. Because elderly patients are more likely to have decreased renal
function, care should be taken in dose selection, and it may be useful to
monitor renal function [see Dosage
and Administration (2.3)].
Renal Impairment
The
exposure to hydroxyurea is higher in patients with creatinine clearance of less
than 60 mL/min or in patients with end-stage renal disease (ESRD). Reduce
dosage and closely monitor the hematologic parameters when Hydrea is to be
administered to these patients [see Dosage
and Administration (2.3)and Clinical
Pharmacology (12.3)].
Hepatic Impairment
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.
Overdosage
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 also been observed.
Hydrea Description
Hydrea
(hydroxyurea capsules, USP) is an antimetabolite available for oral use as
capsules containing 500 mg hydroxyurea. Inactive ingredients include citric
acid, colorants (D&C Yellow No. 10, FD&C Blue No. 1, FD&C Red No.
40, and D&C Red No. 28), gelatin, lactose, magnesium stearate, sodium phosphate,
and titanium dioxide.
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 CH4N2O2 and it has a molecular weight of 76.05. Its structural
formula is:
Hydrea - Clinical
Pharmacology
Mechanism of Action
The
precise mechanism by which hydroxyurea produces its antineoplastic effects
cannot, at present, be described. However, the reports of various studies in
tissue culture in rats and humans lend support to 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. This hypothesis explains why, under certain
conditions, hydroxyurea may induce teratogenic effects.
Three
mechanisms of action have been postulated for the increased effectiveness of
concomitant use of hydroxyurea therapy with irradiation on squamous cell
(epidermoid) carcinomas of the head and neck. In vitro studies
utilizing Chinese hamster cells suggest that hydroxyurea (1) is lethal to
normally radioresistant S-stage cells, and (2) holds other cells of the cell
cycle in the G1 or pre-DNA synthesis stage where they are most susceptible to
the effects of irradiation. The third mechanism of action has been theorized on
the basis of in vitro studies of
HeLa cells. It appears that hydroxyurea, by inhibition of DNA synthesis,
hinders the normal repair process of cells damaged but not killed by
irradiation, thereby decreasing their survival rate; RNA and protein syntheses
have shown no alteration.
Pharmacokinetics
Absorption
Following
oral administration of Hydrea, hydroxyurea reaches peak plasma concentrations
in 1 to 4 hours. Mean peak plasma concentrations and AUCs increase more than
proportionally with increase of dose.
There
are no data on the effect of food on the absorption of hydroxyurea.
Distribution
Hydroxyurea
distributes throughout the body with a volume of distribution approximating
total body water.
Hydroxyurea
concentrates in leukocytes and erythrocytes.
Metabolism
Up to
60% of an oral dose undergoes conversion through saturable hepatic metabolism
and a minor pathway of degradation by urease found in intestinal bacteria.
Excretion
In
patients with sickle cell anemia, the mean cumulative urinary recovery of
hydroxyurea was about 40% of the administered dose.
Specific Populations
Renal Impairment
The
effect of renal impairment on the pharmacokinetics of hydroxyurea was assessed
in adult patients with sickle cell disease and renal impairment. Patients 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 a single oral dose of
15 mg/kg hydroxyurea. Patients with 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. The exposure to
hydroxyurea (mean AUC) in patients with CrCl <60 mL/min and those with
ESRD was 64% higher than in patients with normal renal function (CrCl >60
mL/min). Reduce the dose of Hydrea when it is administered to patients with
creatinine clearance of <60 mL/min or with ESRD following hemodialysis [see Dosage
and Administration (2.3) and Use in
Specific Populations (8.6)].
Nonclinical ToxicologyCarcinogenesis, Mutagenesis, Impairment of Fertility
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/m2 basis) thrice weekly for 6 months to female rats increased
the incidence of mammary tumors in rats surviving to 18 months compared to
control. Hydroxyurea is mutagenic in vitro to
bacteria, fungi, protozoa, and mammalian cells. Hydroxyurea is
clastogenic in vitro (hamster
cells, human lymphoblasts) and in vivo (SCE
assay in rodents, mouse micronucleus assay). Hydroxyurea causes the transformation
of rodent embryo cells to a tumorigenic phenotype.
Hydroxyurea
administered to male rats at 60 mg/kg/day (about 0.3 times the maximum
recommended human daily dose on a mg/m2 basis) produced testicular atrophy, decreased
spermatogenesis, and significantly reduced their ability to impregnate females.
REFERENCES
OSHA.
http://www.osha.gov/SLTC/hazardousdrugs/index.html.
How Supplied/Storage
and HandlingHow Supplied
Hydrea® (hydroxyurea capsules,
USP) is supplied as 500 mg capsules in HDPE bottles with a plastic safety screw
cap. Each bottle contains 100 capsules. The cap is opaque green and the body is
opaque pink. The capsules are imprinted on both sections with “Hydrea” and
“830” in black ink (NDC 0003-0830-50).
Storage
Store
at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F) [see USP
Controlled Room Temperature]. Keep tightly closed.
Handling and Disposal
Hydrea
is a cytotoxic drug. Follow applicable special handling and disposal
procedures [see References
(15)].
To
decrease the risk of contact, advise caregivers to wear disposable gloves when
handling Hydrea or bottles containing Hydrea. Wash hands with soap and water
before and after contact with the bottle or capsules when handling Hydrea. Do
not open Hydrea capsules. Avoid exposure to crushed or opened capsules. If
contact with crushed or opened capsules occurs on the skin, wash affected area
immediately and thoroughly with soap and water. If contact with crushed or
opened capsules occurs on the eye(s), the affected area should be flushed
thoroughly with water or isotonic eyewash designated for that purpose for at
least 15 minutes. If the powder from the capsule is spilled, immediately wipe
it up with a damp disposable towel and discard in a closed container, such as a
plastic bag; as should the empty capsules. The spill areas should then be
cleaned three times using a detergent solution followed by clean water. Keep
the medication away from children and pets. Contact your doctor for
instructions on how to dispose of outdated capsules.
Patient Counseling
Information
•
There is a risk of myelosuppression. Monitoring blood counts weekly throughout
the duration of therapy should be emphasized to patients taking Hydrea
[see Warnings
and Precautions(5.1)]. Advise patients to report signs and symptoms of infection or
bleeding immediately.
• Advise patients that there is a risk of cutaneous vasculitic toxicities and
secondary malignancies including leukemia and skin cancers [see Warnings
and Precautions(5.2, 5.4)].
• Advise females of reproductive potential of the potential risk to a fetus and
to inform their healthcare provider of a known or suspected pregnancy. Advise
females and males of reproductive potential to use contraception during and
after treatment with Hydrea [see Warnings
and Precautions(5.3) and Use in
Specific Populations (8.1, 8.3)].
• Advise patients to inform their healthcare provider if they have received or
are planning to receive vaccinations while taking Hydrea as this may result in
a severe infection [see Warnings
and Precautions(5.5)].
• Advise females to discontinue breastfeeding during treatment with Hydrea
[see Use in
Specific Populations (8.2)].
• Patients with HIV infection should contact their physician for signs and
symptoms of pancreatitis, hepatic events, and peripheral neuropathy [see Warnings
and Precautions(5.6)].
• Post irradiation erythema can occur in patients who have received previous
irradiation therapy [see Warnings
and Precautions(5.7)].
Manufactured
for:
Bristol-Myers Squibb Company
Princeton, New Jersey 08543 USA
[Print
code]
Revised:
June 2017
Hydrea 500 mg capsules
Representative Packaging
See
HOW SUPPLIED section for a complete list of available packages of Hydrea.
100
CAPSULES
NDC 0003-0830-50
Hydrea®
(hydroxyurea capsules, USP)
500 mg per capsule
Rx only
Bristol-Myers Squibb
|
Hydrea hydroxyurea capsule
|
|
Product
Information
|
|
Product Type
|
HUMAN
PRESCRIPTION DRUG LABEL
|
Item Code
(Source)
|
NDC:0003-0830
|
|
Route of Administration
|
ORAL
|
DEA Schedule
|
|
|
|
Active
Ingredient/Active Moiety
|
|
Ingredient
Name
|
Basis of
Strength
|
Strength
|
|
hydroxyurea (hydroxyurea)
|
hydroxyurea
|
500 mg
|
|
|
Inactive
Ingredients
|
|
Ingredient
Name
|
Strength
|
|
citric acid monohydrate
|
|
|
D&C Yellow No. 10
|
|
|
FD&C Blue No. 1
|
|
|
FD&C Red No. 40
|
|
|
D&C Red No. 28
|
|
|
gelatin
|
|
|
LACTOSE, UNSPECIFIED FORM
|
|
|
magnesium stearate
|
|
|
sodium phosphate
|
|
|
titanium dioxide
|
|
|
|
Product
Characteristics
|
|
Color
|
GREEN, PINK
|
Score
|
no score
|
|
Shape
|
CAPSULE
|
Size
|
22mm
|
|
Flavor
|
|
Imprint Code
|
Hydrea;830;Hydrea;830
|
|
Contains
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package
Description
|
|
|
1
|
NDC:0003-0830-50
|
100 CAPSULE in
1 BOTTLE
|
|
|
|
|
|
Marketing Information
|
|
Marketing
Category
|
Application
Number or Monograph Citation
|
Marketing
Start Date
|
Marketing
End Date
|
|
NDA
|
NDA016295
|
06/01/2009
|
|
|
|
Labeler - E.R. Squibb & Sons, L.L.C. (011550092)
|
Revised: 06/2017
E.R. Squibb & Sons, L.L.C.
