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.

AVALIDE (NDA-020758)

(HYDROCHLOROTHIAZIDE; IRBESARTAN)

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

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08/01/2025 (SUPPL-87)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

Blood and lymphatic system: Thrombocytopenia

Hepatobiliary: Hepatitis, Jaundice

Renal and urinary: Impaired renal function including renal failure

Skin and subcutaneous tissue: Urticaria

Irbesartan

Blood and lymphatic system: Anemia Ear and labyrinth: Tinnitus Gastrointestinal: Intestinal angioedema

Skin and subcutaneous tissue: Angioedema (involving swelling of the face, lips, pharynx, and/or tongue)

Immune system: Anaphylactic reaction including anaphylactic shock

Investigations: Increased CPK (Creatine Phosphokinase)

Metabolism and nutrition: Hyperkalemia, Hypoglycemia in diabetic patients

Hydrochlorothiazide

Eye: acute angle-closure glaucoma, acute myopia, and choroidal effusion

. . .

09/10/2021 (SUPPL-80)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.8 Acute Angle-Closure Glaucoma, Acute Myopia, and Choroidal Effusion

(Additions and/or revisions are underlined)

Hydrochlorothiazide

Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction resulting in acute angle- closure glaucoma and elevated intraocular pressure with or without a noticeable acute myopic shift and/or choroidal effusions. Cases of acute angle-closure glaucoma have been reported with hydrochlorothiazide. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma may result in permanent vision loss. The primary treatment is to discontinue drug intake as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

6 Adverse Reactions

6.2 Postmarketing Experience

(Additions and/or revisions are underlined)

The following adverse reactions have been identified during postapproval use of AVALIDE. 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. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to AVALIDE.

The following have been very rarely reported with irbesartan and hydrochlorothiazide monotherapies: urticaria, jaundice, hepatitis, thrombocytopenia, and impaired renal function including renal failure.

The following have been reported with irbesartan monotherapy: tinnitus, hyperkalemia, angioedema (involving swelling of the face, lips, pharynx, and/or tongue), anaphylactic reaction including anaphylactic shock, increased CPK, anemia, and hypoglycemia in diabetic patients.

The following have been reported with hydrochlorothiazide monotherapy: acute angle-closure glaucoma, acute myopia, and choroidal effusion.

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Acute Angle-Closure Glaucoma, Acute Myopia, and Choroidal Effusion

Advise patients to discontinue AVALIDE and seek immediate medical attention if they experience symptoms of acute angle-closure glaucoma, acute myopia, and choroidal effusion [see Warnings and Precautions (5.8)].

05/11/2021 (SUPPL-81)

Approved Drug Label (PDF)

5 Warnings and Precautions

Additions and/or revisions underlined:

5.8 Acute Angle-Closure Glaucoma, Acute Myopia, and Choroidal Effusion

Hydrochlorothiazide

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

… The following have been reported with irbesartan monotherapy: tinnitus, hyperkalemia, angioedema (involving swelling of the face, lips, pharynx, and/or tongue), anaphylactic reaction including anaphylactic shock, increased CPK, and anemia.

The following have been reported with hydrochlorothiazide monotherapy: acute angle-closure glaucoma, acute myopia and choroidal effusion.

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Acute Angle-Closure Glaucoma, Acute Myopia, and Choroidal Effusion

12/15/2020 (SUPPL-76)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Fetal Toxicity

(Additions and/or revisions underlined)

AVALIDE can cause fetal harm when administered to a pregnant woman. Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue AVALIDE as soon as possible [see Use in Specific Populations (8.1)].

Thiazides cross the placenta, and use of thiazides during pregnancy is associated with a risk of fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in adults.

8 Use in Specific Populations

8.1 Pregnancy

(PLLR conversion; please refer to label)

8.2 Lactation

(PLLR conversion)

There are no available data on the presence of irbesartan in human milk, effects on milk production, or the breastfed infant. Irbesartan or some metabolite of irbesartan is secreted in the milk of lactating rats. Thiazides appear in human milk [see Clinical Pharmacology (12.3)]. Because of the potential for adverse effects on the nursing infant, the use of AVALIDE in breastfeeding women is not recommended.

08/20/2020 (SUPPL-79)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Newly added information underlined:

… The following have been reported with hydrochlorothiazide monotherapy: secondary acute angle-closure glaucoma and/or acute myopia.

Non-melanoma Skin Cancer

Hydrochlorothiazide is associated with an increased risk of non-melanoma skin cancer. In a study conducted in the Sentinel System, increased risk was predominantly for squamous cell carcinoma (SCC) and in white patients taking large cumulative doses. The increased risk for SCC in the overall population was approximately 1 additional case per 16,000 patients per year, and for white patients taking a cumulative dose of greater than or equal to 50,000 mg the risk increase was approximately 1 additional SCC case for every 6,700 patients per year.

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

PATIENT COUNSELING INFORMATION

Newly added information:

Non-melanoma Skin Cancer

Instruct patients taking hydrochlorothiazide to protect skin from the sun and undergo regular skin cancer screening.

07/20/2018 (SUPPL-73)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.8 Secondary Acute Angle-Closure Glaucoma and/or Acute Myopia

(additions underlined)

Hydrochlorothiazide

Sulfonamide or sulfonamide derivative drugs, such as hydrochlorothiazide, can cause an idiosyncratic reaction, resulting in transient myopia and/or acute angle-closure glaucoma. Cases of acute angle-closure glaucoma have been reported with hydrochlorothiazide. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue drug intake as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing

6 Adverse Reactions

6.2 Postmarketing Experience

(additions underlined)

…

The following have been reported with hydrochlorothiazide monotherapy: secondary acute angle-closure glaucoma and/or acute myopia.

07/10/2017 (SUPPL-72)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Post-Marketing Experience

(Additions and/or revisions are underlined)

The following have been reported with irbesartan and with hydrochlorothiazide monotherapies: urticaria, jaundice, hepatitis, thrombocytopenia, impaired renal function including renal failure.

The following have been reported with irbesartan monotherapy: tinnitus, hyperkalemia, angioedema (involving swelling of the face, lips, pharynx, and/or tongue), increased CPK

The following have been reported with hydrochlorothiazide monotherapy: secondary acute angle closure glaucoma and/or acute myopia.

02/05/2016 (SUPPL-70)

Approved Drug Label (PDF)

5 Warnings and Precautions

Electrolyte and Metabolic Imbalances

Coadministration of AVALIDE with potassium sparing diuretics, potassium supplements, potassium-containing salt substitutes or other drugs that raise serum potassium levels may result hyperkalemia, sometimes severe. Monitor serum potassium in such patients.

6 Adverse Reactions

Post-Marketing Experience

tinnitus.

7 Drug Interactions

Non-Steroidal Anti-Inflammatory Agents Including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors)

Irbesartan

The antihypertensive effect of ARBs may be attenuated by NSAIDs.

Hydrochlorothiazide

Administration of a non-steroidal anti-inflammatory agent, including a selective COX-2 inhibitor can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing, and thiazide diuretics. Therefore, when AVALIDE (irbesartanhydrochlorothiazide) Tablets and non-steroidal anti-inflammatory agents are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained

Agents Increasing Serum Potassium

Coadministration of AVALIDE with other drugs that raise serum potassium levels may result in hyperkalemia, sometimes severe. Monitor serum potassium in such patients
Cholestyramine and Colestipol Resins: Stagger the dosage of hydrochlorothiazide and the resin such that AVALIDE is administered at least 4 hours before or 4 to 6 hours after the administration of the resin.