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.

GIAZO (NDA-022205)

(BALSALAZIDE DISODIUM)

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

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11/01/2021 (SUPPL-5)

Approved Drug Label (PDF)

5 Warnings and Precautions

Newly added subsection:

5.5 Severe Cutaneous Adverse Reactions

Severe cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP) have been reported with the use of mesalamine, the active moiety of GIAZO [see Adverse Reactions (6.2)]. Discontinue GIAZO at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation.

6 Adverse Reactions

Newly added to the bulleted line listing:

Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.5)]

6.2 Postmarketing Experience

Additions and/or revisions underlined:

Respiratory/Pulmonary: Eosinophilic pneumonia, interstitial pneumonitis, asthma exacerbation, pleurisy/pleuritis.

Skin: Alopecia, psoriasis, pyoderma gangrenosum, dry skin, erythema nodosum, urticaria, SJS/TEN, DRESS, and AGEP [see Warnings and Precautions (5.5)].

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

PATIENT COUNSELING INFORMATION

Newly added information:

Severe Cutaneous Adverse Reactions

Inform patients of the signs and symptoms of severe cutaneous adverse reactions. Instruct patients to stop taking GIAZO and report to their healthcare provider at first appearance of a severe cutaneous adverse reaction or other sign of hypersensitivity [see Warnings and Precautions (5.5)].

10/01/2020 (SUPPL-4)

Approved Drug Label (PDF)

Boxed Warning

5.1 Renal Impairment

(Newly added section)

Renal impairment, including minimal change disease, acute and chronic interstitial nephritis and renal failure, has been reported in patients given products that release mesalamine in the gastrointestinal tract. Evaluate renal function prior to initiation of GIAZO and periodically while on therapy. Evaluate the risks and benefits of using GIAZO in patients with known renal impairment, a history of renal disease or taking nephrotoxic drugs [see Drug Interactions (7.2), Use in Specific Populations (8.6)].

5 Warnings and Precautions

5.2 Mesalamine-Induced Acute Intolerance Syndrome

(Additions and/or revisions underlined)

Monitor patients for worsening of these symptoms while on treatment. If acute intolerance syndrome is suspected, promptly discontinue treatment with GIAZO.

5.3 Hypersensitivity Reactions

(Newly added subsection)

Some patients who have experienced a hypersensitivity reaction to sulfasalazine may have a similar reaction to GIAZO or to other compounds that contain or are converted to mesalamine.

Mesalamine-induced hypersensitivity reactions may present as internal organ involvement, including myocarditis, pericarditis, nephritis, hepatitis, pneumonitis, and hematologic abnormalities. Evaluate patients immediately if signs or symptoms of a hypersensitivity reaction are present. Discontinue GIAZO if an alternative etiology for the signs and symptoms cannot be established.

5.4 Hepatic Failure

(Section title revised)

(Additions and/or revisions underlined)

There have been reports of hepatic failure in patients with pre-existing liver disease who have been administered mesalamine. Because balsalazide is converted to mesalamine, evaluate the risks and benefits of GIAZO in patients with known liver impairment.

5.6 Nephrolithiasis

(Newly added subsection)

Cases of nephrolithiasis have been reported with the use of mesalamine, the active moiety of GIAZO, including stones with 100% mesalamine content. Mesalamine-containing stones are radiotransparent and undetectable by standard radiography or computed tomography (CT). Ensure adequate fluid intake during treatment with GIAZO.

5.7 Sodium Content of GIAZO

(Newly added subsection)

Each 1.1 g tablet of GIAZO contains 126 mg of sodium. The recommended dosage of GIAZO (6.6 g/day) provides about 756 mg of sodium per day. Take the sodium content of GIAZO into consideration when administering to patients on a sodium-restricted diet or those at risk for developing congestive heart failure.

5.8 Interference with Laboratory Tests

(Newly added subsection)

Use of GIAZO, which is converted to mesalamine, may lead to spuriously elevated test results when measuring urinary normetanephrine by liquid chromatography with electrochemical detection because of the similarity in the chromatograms of normetanephrine and mesalamine’s main metabolite, N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA). Consider an alternative, selective assay for normetanephrine.

6 Adverse Reactions

(Newly added information)

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

Renal Impairment [see Warnings and Precautions (5.1)]
Mesalamine-Induced Acute Intolerance Syndrome [see Warnings and Precautions (5.2)]
Hypersensitivity Reactions [see Warnings and Precautions (5.3)]
Hepatic Failure [see Warnings and Precautions (5.4)]
Photosensitivity [see Warnings and Precautions (5.5)]
Nephrolithiasis [see Warnings and Precautions (5.6)]

6.2 Postmarketing Experience

(Additions and/or revisions underlined)

The following adverse reactions have been identified during postapproval use of balsalazide, or other products which contain or are metabolized to mesalamine. 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.

Cardiovascular and Vascular: myocarditis, pericarditis, vasculitis [see Warnings and Precautions (5.3)]

Respiratory: alveolitis, pleural effusion, pneumonia (with and without eosinophilia)

Gastrointestinal: pancreatitis

Renal: interstitial nephritis, renal failure, nephrolithiasis [see Warnings and Precautions (5.1, 5.6)].

Hepatobiliary Disorders: elevated liver enzymes (AST, ALT, GGT, LDH, alkaline phosphatase), elevated bilirubin, jaundice, cholestatic jaundice, cirrhosis, hepatocellular damage including liver necrosis and liver failure, Kawasaki-like syndrome including hepatic dysfunction. Some of these cases were fatal [see Warnings and Precautions (5.4)].

7 Drug Interactions

7.1 Nephrotoxic Agents, Including Non-Steroidal Anti-Inflammatory Drugs

(Newly added section)

The concurrent use of mesalamine with known nephrotoxic agents, including non-steroidal anti-inflammatory drugs (NSAIDs), may increase the risk of renal reactions. Monitor patients taking nephrotoxic drugs for changes in renal function and mesalamine-related adverse reactions [see Warnings and Precautions (5.1)].

7.2 Azathioprine or 6-Mercaptopurine

(Newly added section)

The concurrent use of mesalamine with azathioprine or 6-mercaptopurine and/or any other drugs known to cause myelotoxicity may increase the risk for blood disorders, bone marrow failure, and associated complications. If concomitant use of GIAZO and azathioprine or 6-mercaptopurine cannot be avoided, monitor blood tests, including complete blood cell counts and platelet counts.

7.3 Interference With Urinary Normetanephrine Measurements

(Newly added section)

Consider an alternative, selective assay for normetanephrine.

8 Use in Specific Populations

8.5 Geriatric Use

(Additions and/or revisions underlined)

Clinical trials of GIAZO did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently than younger subjects. Reports from uncontrolled clinical studies and postmarketing reporting systems suggested a higher incidence of blood dyscrasias, i.e., neutropenia and pancytopenia, in patients who were 65 years or older compare to younger patients taking mesalamine-containing products. GIAZO is converted into mesalamine in the colon. Monitor complete blood cell counts and platelet counts in elderly patients during treatment with GIAZO. In general, consider the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in elderly patients when prescribing GIAZO [see Use in Specific Populations (8.6)].

8.6 Renal Impairment

(Newly added section)

Mesalamine is known to be substantially excreted by the kidney, and the risk of adverse reactions to GIAZO, which is converted to mesalamine, may be greater in patients with impaired renal function. Evaluate renal function in all patients prior to initiation and periodically while on GIAZO therapy. Monitor patients with known renal impairment or history of renal disease or taking nephrotoxic drugs for decreased renal function and mesalamine-related adverse reactions [see Warnings and Precautions (5.1), Adverse Reactions (6.2), Drug Interactions (7.1)].

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

Patient Counseling Information

(Newly added information)

Renal Impairment

Inform patients that GIAZO may decrease their renal function, especially if they have known renal impairment or are taking nephrotoxic drugs, including NSAIDs, and periodic monitoring of renal function will be performed while they are on therapy. Advise patients to complete all blood tests ordered by their healthcare provider [see Warnings and Precautions (5.1), Drug Interactions (7.1)].

Mesalamine-Induced Acute Intolerance Syndrome and Other Hypersensitivity Reactions

Inform patients of the signs and symptoms of hypersensitivity reactions. Instruct patients to stop taking GIAZO and report to their healthcare provider if they experience new or worsening symptoms of Acute Intolerance Syndrome (cramping, abdominal pain, bloody diarrhea, fever, headache, and rash) or other symptoms suggestive of mesalamine-induced hypersensitivity [see Warnings and Precautions (5.2, 5.3)].

Hepatic Failure

Inform patients with known liver disease of the signs and symptoms of worsening liver function and advise them to report to their healthcare provider if they experience such signs or symptoms [see Warnings and Precautions (5.4)].

Photosensitivity

Advise patients with pre-existing skin conditions to avoid sun exposure, wear protective clothing, and use a broad-spectrum sunscreen when outdoors [see Warnings and Precautions (5.5)].

Nephrolithiasis

Instruct patients to drink an adequate amount of fluids during treatment in order to minimize the risk of kidney stone formation and to contact their healthcare provider if they experience signs or symptoms of a kidney stone (e.g., severe side or back pain, blood in the urine) [see Warnings and Precautions (5.6)].

Sodium Content of GIAZO

Inform patients on a sodium-restricted diet or patients at risk of developing congestive heart failure of the sodium content of GIAZO tablets (126 mg per tablet) [see Warnings and Precautions (5.7)].

Blood Disorders

Inform elderly patients and those taking azathioprine or 6-mercaptopurine of the risk for blood disorders and the need for periodic monitoring of complete blood cell counts and platelet counts while on therapy. Advise patients to complete all blood tests ordered by their healthcare provider [see Drug Interactions (7.2), Use in Specific Populations (8.5)].

Administration Instruct patients:

GIAZO tablets can be taken with or without food [see Dosage and Administration (2)].
Drink an adequate amount of fluids.

01/07/2020 (SUPPL-3)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

PLLR conversion, additions and/or revisions underlined:

Risk Summary

Published data from meta-analyses, cohort studies and case series on the use of mesalamine, the active moiety of GIAZO, during pregnancy have not reliably informed an association with mesalamine and major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data). There are adverse effects on maternal and fetal outcomes associated with ulcerative colitis in pregnancy (see Clinical Considerations). In animal reproduction studies, there were no adverse developmental effects observed after oral administration of balsalazide disodium in pregnant rats and rabbits during organogenesis at doses up to 2.4 and 4.7 times, respectively, the maximum recommended human dose (MRHD) (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Disease-associated maternal and embryo/fetal risk

Published data suggest that increased disease activity is associated with the risk of developing adverse pregnancy outcomes in women with ulcerative colitis. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) infants, and small for gestational age at birth.

Data

Human Data

Published data from meta-analyses, cohort studies and case series on the use of mesalamine, the active moiety of GIAZO, during early pregnancy (first trimester) and throughout pregnancy have not reliably informed an association of mesalamine and major birth defects, miscarriage, or adverse maternal or fetal outcomes. There is no clear evidence that mesalamine exposure in early pregnancy is associated with an increase risk in major congenital malformations, including cardiac malformations. Published epidemiologic studies have important methodological limitations which hinder interpretation of the data, including inability to control for confounders, such as underlying maternal disease, and maternal use of concomitant medications, and missing information on the dose and duration of use for mesalamine products.

Animal Data

Reproduction studies in rats and rabbits following administration of balsalazide disodium during organogenesis at oral doses up to 2 g/kg/day, equivalent to 2.5 and 4.9 times the recommended human dose, respectively, based on body surface area, revealed no evidence of no adverse embryofetal developmental effects due to balsalazide disodium.

8.2 Lactation

PLLR conversion, additions and/or revisions underlined:

Risk Summary

Data from published literature report the presence of mesalamine and its metabolite, N acetyl-5 aminosalicylic acid, in human milk in small amounts with relative infant doses (RID) of 0.1% or less for mesalamine (see Data). There are case reports of diarrhea in breastfed infants exposed to mesalamine (see Clinical Considerations). There is no information on the effects of the drug on milk production. The lack of clinical data during lactation precludes a clear determination of the risk of GIAZO to an infant during lactation; therefore, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for GIAZO and any potential adverse effects on the breastfed child from GIAZO or from the underlying maternal condition.

Clinical Considerations

Advise the caregiver to monitor breastfed infants for diarrhea.

Data

In published lactation studies, maternal mesalamine doses from various oral and rectal mesalamine formulations and products ranged from 500 mg to 4.8 g daily. The average concentration of mesalamine in milk ranged from non-detectable to 0.5 mg/L. The average concentration of N-acetyl-5-aminosalicylic acid in milk ranged from 0.2 to 9.3 mg/L. Based on these concentrations, estimated infant daily dosages for an exclusively breastfed infant are 0 to 0.075 mg/kg/day (RID 0 to 0.1%) of mesalamine and 0.03 to 1.4 mg/kg/day of N-acetyl-5-aminosalicylic acid.

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Instruct patients to take GIAZO with or without food.