April 30, 2016
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Droxia

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Droxia




Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Myelosuppression

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.

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.

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, 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/m² basis. Advise pregnant women of the potential risk to a fetus [see Use in Specific Populations]. 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 [see Use in Specific Populations].

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 DROXIA.

Live 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.

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].

Macrocytosis

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 B12 or folic acid deficiency. This may mask the diagnosis of pernicious anemia. Prophylactic administration of folic acid is recommended.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION).

  • There is a risk of myelosuppression. Monitoring blood counts every two weeks throughout the duration of therapy should be emphasized to patients taking DROXIA [see WARNINGS AND PRECAUTIONS]. 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. Advise use of sun protection [see WARNINGS AND PRECAUTIONS].
  • Advise patients to inform their healthcare provider if they have received or are planning to receive vaccinations while taking DROXIA as this may result in a severe infection [see WARNINGS AND PRECAUTIONS].
  • 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 DROXIA [see WARNINGS AND PRECAUTIONS and Use In Specific Populations].
  • Advise females to discontinue breastfeeding during treatment with DROXIA [see Use in Specific Populations].
  • Patients with HIV infection should contact their physician for signs and symptoms of pancreatitis, hepatic events, and peripheral neuropathy [see WARNINGS AND PRECAUTIONS].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Conventional long-term studies to evaluate the carcinogenic potential of DROXIA 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.

Use In Specific Populations

Pregnancy

Risk Summary

DROXIA can cause fetal harm based on findings from animal studies and the drug's mechanism of action [see CLINICAL PHARMACOLOGY]. 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/m² basis (see Data).

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 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 DROXIA.

Females And Males Of Reproductive Potential

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating DROXIA therapy.

Contraception

Females

DROXIA can cause fetal harm when administered to a pregnant woman [see Use In Specific Populations]. Advise females of reproductive potential to use effective contraception during and after treatment with DROXIA for at least 6 months after therapy. Advise females to immediately report pregnancy.

Males

DROXIA 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 DROXIA for at least 1 year after therapy [see Nonclinical Toxicology].

Infertility

Males

Based on findings in animals and humans, male fertility may be compromised by treatment with DROXIA. 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 and Nonclinical Toxicology].

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of DROXIA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

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].

Renal Impairment

The exposure to hydroxyurea is higher in patients with creatinine clearance of less than 60 mL/min. Reduce dosage and closely monitor the hematologic parameters when DROXIA is to be administered to these patients [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].

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.

This monograph has been modified to include the generic and brand name in many instances.

Last reviewed on RxList: 4/27/2016

Warnings
Precautions

Report Problems to the Food and Drug Administration

 

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.


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