Drug Safety-related Labeling Changes (SrLC)

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Drug Safety-related Labeling Changes (SrLC) Database

ANDA	Abbreviated New Drug Application
BLA	Biologics License Application
CDER	Center for Drug Evaluation and Research
MG	Medication Guide
NDA	New Drug Application
PCI	Patient Counseling Information
PI	Patient Information
PLR	Physician Labeling Rule
PLLR	Pregnancy and Lactation Labeling Rule
Italics	For the most part, italics indicate an FDA comment such as: Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section.
Underlines	Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text.

Sections

BW	Box Warning
WP	Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format)
AR	Adverse Reactions (in pre-PLR format, this may be a subheading under precautions).
DI	Drug Interactions (in pre-PLR format, this may be a subheading under precautions).
USP	Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format.
PCI/PI/MG	Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.

Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.

DROXIA (NDA-016295)

(HYDROXYUREA)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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11/28/2023 (SUPPL-58)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.10 Laboratory Test Interference

Additions and/or revisions underlined:

Interference with Uric Acid, Urea, or Lactic Acid Assays is possible, rendering falsely elevated results of these in patients treated with hydroxyurea [see Drug Interactions (7.2)].

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 [see Drug Interactions (7.2)].

7 Drug Interactions

7.2 Laboratory Test Interference

Additions and/or revisions underlined:

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.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined:

…

Before taking DROXIA, tell your healthcare provider about all of your medical conditions, including if you:

are using a continuous glucose monitor (CGM) to test your blood glucose. Hydroxyurea may affect your sensor glucose results and may lead to low blood sugar (hypoglycemia). Talk to the healthcare provider that prescribed your CGM about whether it is safe to use while you are taking DROXIA.

…

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

…

Advise patients to notify their healthcare provider if they are using a continuous glucose monitoring system while taking DROXIA [see Warnings and Precautions (5.10)].

…

06/07/2023 (SUPPL-57)

Approved Drug Label (PDF)

Boxed Warning

Additions and/or revisions underlined:

WARNING: MYELOSUPPRESSION AND MALIGNANCIES Myelosuppression: DROXIA may cause severe myelosuppression. Do not give if bone marrow function is markedly depressed. Monitor blood counts at baseline and throughout treatment. Interrupt treatment and reduce dose as necessary [see Warnings and Precautions (5.1)].
Malignancies: DROXIA is carcinogenic. Advise sun protection and monitor patients for malignancies [see Warnings and Precautions (5.3)].

01/13/2022 (SUPPL-56)

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

What are the possible side effects of DROXIA?

DROXIA may cause serious side effects, including:

Newly added information:

Hemolytic Anemia, the fast breakdown of red blood cells, has happened in people who take DROXIA. Tell your healthcare provider if you develop yellowing of your skin (jaundice) or blood in your urine. Your healthcare provider may do blood tests if you have persistent or worsening anemia.

08/05/2021 (SUPPL-55)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Hemolytic Anemia

(Newly Added Subsection)

Cases of hemolytic anemia in patients treated with hydroxyurea for myeloproliferative diseases have been reported [see Adverse Reactions (6.1)]. 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.

6 Adverse Reactions

(Additions and/or revisions underlined)

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)]

6.2 Postmarketing Experience

(Additions and/or revisions underlined)

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.

Blood and lymphatic system disorders: hemolytic anemia

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

There is a risk of myelosuppression. Monitoring blood counts every two weeks throughout the duration of therapy should be emphasized to patients taking DROXIA. Advise patients to report signs and symptoms of infection or bleeding immediately. [see Warnings and Precautions (5.1)].
Advise patients of the risk of hemolytic anemia. Advise patients that they will have blood tests to evaluate for this if they develop persistent anemia. [see Warnings and Precautions (5.2)].

02/09/2021 (SUPPL-54)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Malignancies

(Additions and/or revisions underlined)

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 hydroxyurea 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.

07/22/2019 (SUPPL-51)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.8 Pulmonary Toxicity

(newly added subsection)

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.

6 Adverse Reactions

(additions are underlined)

The following clinically significant adverse reactions are described in detail in other labeling sections:

Myelosuppression
Malignancies
Vasculitic toxicities
Risks with concomitant use of antiretroviral drugs

Macrocytosis
Pulmonary Toxicity

6.2 Postmarketing Experience

(additions are underlined)

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.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

(extensive revisions; please refer to labeling)

PATIENT COUNSELING INFORMATION

(additions are underlined)

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

There is a risk of myelosuppression. Monitoring blood counts every two weeks throughout the duration of therapy should be emphasized to patients taking DROXIA. 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.
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.
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
Advise females to discontinue breastfeeding during treatment with DROXIA.
Patients with HIV infection should contact their physician for signs and symptoms of pancreatitis, hepatic events, and peripheral neuropathy.
Advise patients of the symptoms of potential pulmonary toxicity and instruct them to seek prompt medical attention in the event of pyrexia, cough, dyspnea, or other respiratory symptoms.

12/18/2017 (SUPPL-49)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.8 Laboratory Test Interference

(Newly added subsection)

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

6 Adverse Reactions

6.2 Postmarketing Experience

(Additions and/or revisions are underlined)

Skin and subcutaneous tissue disorders: maculopapular rash, skin ulceration, dermatomyositis-like skin changes, peripheral and facial erythema, hyperpigmentation, nail hyperpigmentation...

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.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Medication Guide DROXIA (drock-SEE-yuh) (hydroxyurea) capsules

(Extensive changes; please refer to label)

03/23/2016 (SUPPL-47)

Approved Drug Label (PDF)

5 Warnings and Precautions

Embryo-Fetal Toxicity

Based on the mechanism of action and findings in animals, HYDREA/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
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.

Live Vaccinations

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

6 Adverse Reactions

Postmarketing Experience

Reproductive System and Breast disorders: azoospermia, and oligospermia

Metabolism and Nutrition disorders: anorexia, tumor lysis syndrome

Hepatobiliary disorders: cholestasis, and hepatitis

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.