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.

AGGRENOX (NDA-020884)

(ASPIRIN; DIPYRIDAMOLE)

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

Download Data

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05/13/2021 (SUPPL-40)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

Skin and Appendages Disorders: Rash, alopecia, angioedema, Stevens-Johnson syndrome, skin hemorrhages such as bruising, ecchymosis, and hematoma, pruritus, urticaria, and drug reaction with eosinophilia and systemic symptoms (DRESS)

12/11/2019 (SUPPL-39)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.6 Stress Testing with Intravenous Dipyridamole and Other Adenosinergic Agents

(new subsection added)

Clinical experience suggests that patients being treated with AGGRENOX capsules who also require pharmacological stress testing with intravenous dipyridamole or other adenosinergic agents (e.g. adenosine, regadenoson) should interrupt AGGRENOX capsules for 48 hours prior to stress testing .

Intake of AGGRENOX capsules within 48 hours prior to stress testing with intravenous dipyridamole or other adrenosinergic agents may increase the risk for cardiovascular side effects of these agents and may impair the sensitivity of the test.

7 Drug Interactions

7.1 Drug Interaction Study Information Obtained From Literature

(additions underlined)

Adenosinergic agents (e.g. adenosine, regadenoson)

Dipyridamole has been reported to increase the plasma levels and cardiovascular effects of adenosine. Adjustment of adenosine dosage may be necessary. Dipyridamole also increases the cardiovascular effects of regadenoson, an adenosine A2A-receptor agonist. The potential risk of cardiovascular side effects with intravenous adenosinergic agents may be increased during the testing period when dipyridamole is not held 48 hours prior to stress testing.

…

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

PATIENT COUNSELING INFORMATION

(additions underlined)

…

Stress Test

Instruct patients who are scheduled to undergo a pharmacologic stress test to tell their healthcare provider that they are taking AGGRENOX.

…

PATIENT INFORMATION

(additions underlined)

…

Tell your doctor you are taking AGGRENOX if you are scheduled to have a stress test for your heart.

…

11/09/2018 (SUPPL-37)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Risk of Bleeding

(additions underlined)

…

Intracranial Hemorrhage

In European Stroke Prevention Study-2 (ESPS2), the annualized event rate for intracranial hemorrhage was 0.39%/year in the AGGRENOX group, 0.26%/year in the extended-release dipyridamole (ER-DP) group, 0.24%/year in the aspirin (ASA) group and 0.29%/year in the placebo groups.

Gastrointestinal (GI) Side Effects

…

In ESPS2, the annualized event rate for gastrointestinal bleeding was 2.97%/year in the AGGRENOX group, 1.58%/year in the extended-release dipyridamole group, 2.06%/year in the aspirin group, and 1.40%/year in the placebo groups.

6 Adverse Reactions

6.1 Clinical Trials Experience

(additions underlined)

…

Table 1 presents the annualized event rate for adverse events that occurred in 1%/year or more of patients treated with AGGRENOX where the incidence was also at least 1%/year greater than in those patients treated with placebo. There is no clear benefit of the dipyridamole/aspirin combination over aspirin with respect to safety.

(please refer to label to view Table 1)

6.2 Post-Marketing Experience

(additions underlined)

…

Body as a Whole: Hypothermia, chest pain, allergic reaction, syncope

Cardiovascular: Angina pectoris, hypotension

Central Nervous System: Cerebral edema, dizziness, cerebral hemorrhage, intracranial hemorrhage, subarachnoid hemorrhage

Fluid and Electrolyte: Hyperkalemia, metabolic acidosis, respiratory alkalosis, hypokalemia

Gastrointestinal: Pancreatitis, Reye syndrome, hematemesis, gastritis, ulceration and perforation, hemorrhage rectum, melena, GI hemorrhage

Hearing and Vestibular Disorders: Hearing loss

Heart Rate and Rhythm Disorders: Tachycardia, palpitation

Immune System Disorders: Hypersensitivity, acute anaphylaxis, laryngeal edema

Liver and Biliary System Disorders: Hepatitis, hepatic failure, cholelithiasis, jaundice, hepatic function abnormal

Musculoskeletal: Rhabdomyolysis, myalgia

Metabolic and Nutritional Disorders: Hypoglycemia, dehydration

Platelet, Bleeding and Clotting Disorders: Prolongation of the prothrombin time, disseminated intravascular coagulation, coagulopathy, thrombocytopenia, hematoma, gingival bleeding, epistaxis, purpura

Psychiatric Disorders: Confusion, agitation

Respiratory: Tachypnea, dyspnea, hemoptysis

Skin and Appendages Disorders: Rash, alopecia, angioedema, Stevens-Johnson syndrome, skin hemorrhages such as bruising, ecchymosis, and hematoma, pruritus, urticaria

Urogenital: Interstitial nephritis, papillary necrosis, proteinuria, renal insufficiency and failure, hematuria

Vascular (Extracardiac) Disorders: Allergic vasculitis, flushing

Other Adverse Events: Anorexia, aplastic anemia, migraine, pancytopenia, thrombocytosis.

8 Use in Specific Populations

8.1 Pregnancy

(PLLR conversion, please refer to label)

8.2 Lactation

(PLLR conversion)

Risk Summary

Based on data from a clinical lactation study in breastfeeding women taking low-dose aspirin, the metabolite salicylic acid is present in human milk in low levels (see Data). Dipyridamole is also present in human milk. There is no information on the effects of AGGRENOX or dipyridamole on the breastfed infant or on milk production. There is insufficient information to determine the effects of aspirin on the breastfed infant and no information on the effects of aspirin on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for AGGRENOX and any potential adverse effects on the breastfed child from AGGRENOX or from the underlying maternal condition.

Data

A published clinical study involved six exclusively breastfeeding women at 1 to 8 months postpartum who were taking 81 mg aspirin daily. Milk samples were collected at steady state, at 0, 1, 2, 4, 8, 12, and 24 hours after taking a dose of aspirin. Aspirin was undetectable in human milk. Salicylic acid was present in milk at low levels (average concentration of 24 ng/mL). Based on an average milk consumption of 150 mL/kg/day, the calculated relative infant dose was 0.4%. No adverse effects on the breastfed infants were noted.

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

Patient Information

(additions underlined)

…

How should I store AGGRENOX?

Store AGGRENOX at room temperature 68 degrees F to 77 degrees F (20 degrees C to 25 degrees C).
Keep AGGRENOX capsules dry.
…