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.

SIKLOS (NDA-208843)

(HYDROXYUREA)

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

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11/28/2023 (SUPPL-4)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.8 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 (7.3)].

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 (7.3)].

7 Drug Interactions

7.3 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 SIKLOS 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 SIKLOS.

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 SIKLOS, tell your healthcare provider about all of your medical conditions, including if you:

have kidney problems or are receiving hemodialysis
have liver problems
have human immunodeficiency virus (HIV) or take HIV medicines. Taking SIKLOS with certain HIV medicines can cause serious reactions and may lead to death.
have increased levels of uric acid in your blood (hyperuricemia)
have a history of receiving interferon therapy or are currently receiving interferon therapy
have leg wounds or ulcers
plan to receive any vaccinations. You should not receive “live vaccines” during treatment with SIKLOS.
are pregnant or plan to become pregnant. See “What is the most important information I should know about SIKLOS?”
are breastfeeding or plan to breastfeed. It is not known if SIKLOS can pass into your breast milk. Do not breastfeed during treatment with SIKLOS.
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 SIKLOS.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

…

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Advise the patient or caregiver to read the FDA-approved patient labeling (Instructions for Use and Medication Guide).

…

Advise patients to notify their healthcare provider if they are using a continuous glucose monitoring system while taking SIKLOS [see Warnings and Precautions (5.8)].

…

12/07/2021 (SUPPL-3)

Approved Drug Label (PDF)

5 Warnings and Precautions

Additions and/or revisions underlined:

5.1 Myelosuppression

Hydroxyurea causes severe myelosuppression … 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 in adults or 20 mg/kg/day in children, have experienced severe or life-threatening myelosuppression.

5.2 Malignancies

Hydroxyurea is a human carcinogen. In patients receiving long-term hydroxyurea for myeloproliferative disorders (a condition for which Siklos is not approved), secondary leukemia has been reported.

Leukemia secondary to long-term hydroxyurea has also been reported in patients with sickle cell disease. Leukemia has also been reported in patients with sickle cell disease and no prior history of treatment with hydroxyurea.

Newly added subsection:

5.9 Hemolytic Anemia

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 not related to the disease and in the absence of other causes, discontinue SIKLOS.

6 Adverse Reactions

The following clinically significant adverse reactions are described elsewhere in the labeling:

Newly added to the bulleted line listing:

Hemolytic Anemia [see Warnings and Precautions (5.9)]

6.1 Clinical Trial Experience

Additions and/or revisions underlined:

… The safety of SIKLOS has been assessed in 405 pediatric patients with sickle cell disease from 2-18 years of age and 1077 adults in the European Sickle Cell Disease prospective Cohort study ESCORT-HU …

At least one serious adverse reaction was reported in 33% of the 405 pediatric patients and 32% of the 1077 adults with sickle cell disease in ESCORT-HU. The most frequent serious adverse reactions were infections (18%), and blood and lymphatic system disorders (9%) in children, including serious neutropenia (3.2%), thrombocytopenia (3%) and anemia (3%). Other reported serious adverse reactions were gastrointestinal disorders (3.2 %), fever (2.5 %) and nervous system disorders (4%), including headache (2.7%). Among adults, the most frequent serious adverse reactions were infections (12.9%), respiratory, thoracic and mediastinal disorders (5.8%), blood and lymphatic disorders (4.8%), nervous system disorders (3.6%), and general disorders and administration site disorders (3.1%).

Table 3: Most frequent (greater than or equal to 3%) adverse reactions reported in adult patients enrolled in ESCORT-HU Newly added table; please refer to label for complete information.

6.2 Postmarketing Experience

Additions and/or revisions underlined:

… Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and lymphatic system disorders: macrocytosis, hemolytic anemia in patients who are treated with hydroxyurea for myeloproliferative disorders.

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

MEDICATION GUIDE

What are the possible side effects of SIKLOS? SIKLOS may cause serious side effects, including:

See “What is the most important information I should know about SIKLOS?”

Additions and/or revisions underlined:

Hemolytic Anemia, the fast breakdown of red blood cells, has happened in people who take SIKLOS. 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 not related to sickle cell anemia.
The most common side effects of SIKLOS in children include:

infections
low white blood cells

The most common side effects of SIKLOS in adults include:

infections
headache
dry skin

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Advise male patients of potential risk to fertility [see Use in Specific Populations (8.3)].
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 not related to sickle cell anemia [see Warnings and Precautions (5.9)].

05/22/2019 (SUPPL-2)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Myelosuppression

(addition underlined)

…

Evaluate hematologic status prior to and every two weeks during treatment with SIKLOS. Provide supportive care and modify dose or discontinue SIKLOS as needed. Recovery from myelosuppression is usually observed within 15 days when therapy is interrupted. Resume therapy after interruption at a lower dose.

6 Adverse Reactions

6.1 Clinical Trials Experience

(additions and revisions underlined)

…

At least one serious adverse reaction was reported in 33% of the 405 pediatric patients with sickle cell disease in ESCORT-HU. The most frequent serious adverse reactions were infections (18%), and blood and lymphatic system disorders (9%). This included serious neutropenia (3.2%), thrombocytopenia (3%) and anemia (3%). Other reported serious adverse reactions were gastrointestinal disorders (3.2 %), fever (2.5 %) and nervous system disorders (4%), including headache (2.7%).

…

8 Use in Specific Populations

8.7 Hepatic impairment

(addition underlined)

Monitor hematologic parameters more frequently in patients with hepatic impairment receiving SIKLOS.