CLOZARIL (clozapine)   

NDA 019758

Heritage Life Sciences (Barbados) c/o Heritage Life Sciences Therapeutics (USA) Veterans Health Administration (VHA) medical and pharmacy records  Descriptive study In FDA’s review of the effectiveness of the clozapine REMS, FDA conducted several analyses of clozapine registry patients, describing adherence to absolute neutrophil count monitoring, as specified by the clozapine REMS, and estimating the cumulative risk of severe neutropenia. The study results were included in the November 19 Joint Meeting of the Drug Safety and Risk Management and Psychopharmacologic Drugs Advisory Committee briefing package, where the committee voted to remove the clozapine REMS. Based on the advice from the Advisory Committee and the Agency’s re-evaluation, the Agency removed the clozapine REMS and issued a DSC. DSC August 27,2025  FDA Drug Safety Communication: FDA removes risk evaluation and mitigation strategy (REMS) program for the antipsychotic drug Clozapine (REMS release, labeling changes) 

Toprol-XL and Lopressor (Metoprolol), Inderal LA (propranolol), [beta blockers]   

Multiple NDAs 

Multiple sponsors Sentinel System Retrospective cohort study The results from a retrospective cohort study in Sentinel indicated an association between beta blocker use and hypoglycemia in pediatric populations. FDA approved safety labeling changes to describe the risk for hypoglycemia in pediatrics or individuals unable to communicate signs of hypoglycemia. This resulted in a labeling change. Beta Blockers Safety Communications & Labeling Changes (Sentinel Initiative), July. 25, 2025. FDA Labeling Change: Additional Language to Mitigate the Risk of Hypoglycemia Associated with Beta Blockers in Children      Beta blockers | Sentinel Initiative

Entyvio (vedolizumab)

BLA 761359

Takeda Pharmaceuticals Sentinel System Descriptive study The results from a descriptive Sentinel study did not indicate an increased risk for Interstitial lung disease (ILD) in patients treated with vedolizumab or natalizumab for inflammatory bowel disease. However, there were other data from case reports from the medical literature and FDA FAERS. This resulted in FDA adding “interstitial lung disease, pneumonitis” to the Postmarketing Experience subsection of labeling. Entyvio Safety Communications & Labeling Changes (Sentinel Initiative), April 18, 2024. FDA Labeling Change: Vedolizumab & Interstitial Lung Disease (ILD) 

Prolia (Denosumab)    

BLA 125320

Amgen Medicare claims data Retrospective cohort study  In FDA’s review of denosumab, an FDA retrospective cohort study in Medicare found an increased risk of severe hypocalcemia in patients with advanced chronic kidney disease taking this medication. This resulted in a DSC and addition of a Boxed Warning for an increased risk of severe hypocalcemia in patients with advanced chronic kidney disease. FDA added a boxed warning. DSC, January 19, 2024 (severe hypocalcemia). FDA Drug Safety Communication: FDA adds Boxed Warning for increased risk of severe hypocalcemia in patients with advanced chronic kidney disease taking osteoporosis medicine Prolia (denosumab)    Prolia label change, November 22, 2022. FDA Drug Safety Communication: FDA investigating risk of severe hypocalcemia in patients on dialysis receiving osteoporosis medicine Prolia

Anticoagulant, oral   

Multiple NDAs 

Multiple sponsors Sentinel System Retrospective cohort study FDA conducted a retrospective cohort study in the Sentinel System to examine severe uterine bleeding events requiring medical intervention in women treated with oral anticoagulants. The study found a risk of clinically significant uterine bleeding, potentially requiring gynecological surgical interventions. This finding contributed to a class-wide label change for this risk with oral anticoagulants and that this should be assessed in females of reproductive potential and those with abnormal uterine bleeding. There was also a communication via the Sentinel initiative website.  Oral Anticoagulants Safety Communications & Labeling Changes (Sentinel Initiative), January. 28, 2021. FDA Labeling Change: Oral Anticoagulants and Clinically Significant Uterine Bleeding

Methotrexate, oral   

Multiple NDAs 

Multiple sponsors Sentinel System A chart confirmed analysis was conducted in one Sentinel Data Partner An FDA medical chart review analysis conducted in a Sentinel Data Partner, found the incidence of low-dose oral methotrexate wrong frequency dosing errors to be 0.4%. This resulted in adding the risk of improper dosing to Section 5 (Warnings and Precautions), removing an option for doses given every 12 hours for 3 days each week from Section 2 (Dosage and Administration). Oral Methotrexate (Sentinel Initiative), December. 17, 2021. FDA Labeling Change: Oral Methotrexate and Wrong Frequency Dosing Errors

Singulair (montelukast)   

NDA 021409

Organon Sentinel System Retrospective cohort study Retrospective cohort studies conducted in the Sentinel system informed the re-evaluation of the benefits and risks of montelukast use. Considering the totality of evidence, including the negative Sentinel studies resulted in FDA strengthening existing warnings about serious behavior and mood-related changes with montelukast (Singulair and generics). There was also a communication via the Sentinel initiative website.  Singulair Safety Communications & Labeling Changes (Sentinel Initiative), March. 3, 2020. FDA Requires Boxed Warning about Serious Mental Health Side Effects for Asthma and Allergy Drug Montelukast (Singulair); Advises Restricting Use for Allergic Rhinitis 

Hydrochlorothiazide (HCTZ)-containing products     

Multiple NDAs     

Multiple sponsors Sentinel System Retrospective cohort study An FDA conducted retrospective cohort study in the Sentinel System assessed the risk of non-melanoma skin cancer for patients treated with HCTZ-containing products. The study identified an association with an increased risk of non-melanoma skin cancer, predominantly for squamous cell carcinoma and in white patients taking large cumulative doses. These findings informed additions to adverse reactions and patient information sections of the labeling, and a communication via the Sentinel initiative website. HCTZ Safety Communications & Labeling Changes (Sentinel Initiative), August. 20, 2020. FDA Labeling Change: Hydrochlorothiazide and Non-Melanoma Skin Cancer

Feraheme, infed, injectafer, monoferric, venofer (Parenteral Iron Products)     

Multiple NDAs 

Multiple sponsors Sentinel System Descriptive study An FDA Sentinel analysis characterized the frequency of IV iron utilization relative to live birth and stillbirth deliveries. The finding contributed to a class-wide labeling update for parenteral iron products to add new safety information to Section 8 (Use in Specific Populations, Pregnancy) of the label. This update describes the risk of severe adverse reactions to pregnant women and their fetus. There was also a communication via the Sentinel initiative website. Parenteral Iron Safety Communications & Labeling Changes (Sentinel Initiative) The class-wide labeling update regarding risks to pregnant women and their fetus was approved on September. 11, 2020.     FDA Labeling Change: Parenteral Iron Products and Risk of Severe Adverse Reactions to Pregnant Women and their Fetuses 

Comtan, Stalevo (Entacapone)

NDA 021485/ 20796

Orion Corporation VHA claims, medical records, and cancer registry Retrospective cohort study  In FDA’s review of entacapone, an FDA conducted retrospective cohort study in the VA found no clear evidence of an increased risk of prostate cancer in patients treated with entacapone versus add-on dopamine agonist or monoamine oxidase inhibitor. This resulted in a DSC. Entacapone DSC, August 13, 2019 (no increase in prostate cancer risk). FDA Drug Safety Communication: FDA review finds no increased risk of prostate cancer with Parkinson's disease medicines containing entacapone (Comtan, Stalevo) 

Pradaxa (dabigatran)

NDA 022512

Boehringer Ingelheim Pharmaceuticals, Inc Medicare claims data  Retrospective cohort study  In FDA’s review of dabigatran, an FDA conducted retrospective cohort study among Medicare patients, showed lower risks stroke and death but higher risk for gastrointestinal bleeding with PRADAXA compared to warfarin. FDA still considered Pradaxa to have a favorable benefit/risk profile and made no changes to the labeling. This resulted in a DSC. Dabigatran Drug Safety Communication, May 13, 2014 FDA Drug Safety Communication: FDA study of Medicare patients finds risks lower for stroke and death but higher for gastrointestinal bleeding with Pradaxa (dabigatran) compared to warfarin

Enbrel (etanercept)   

BLA 103795

Amgen Inc. Sentinel System Descriptive study FDA conducted a drug utilization analysis of TNF alpha inhibitors in pregnant women in the Sentinel System. The study found that among pregnant women with a chronic inflammatory condition, there was a preference to use etanercept compared to other TNF alpha inhibitors. This assessment was one source of evidence considered for the Pregnancy and Lactation Labeling Rule (PLLR) Conversion Safety Labeling Change. There was also a communication via the Sentinel initiative website. ENBREL Safety Communications & Labeling Changes (Sentinel Initiative), July. 11, 2017. FDA Labeling Change: Etanercept (Enbrel) and Use in Pregnancy 

Gadolinium-based contrast agents (GBCA)   

Multiple NDAs 

Multiple sponsors Sentinel System Descriptive study Analyses on gadolinium retention were done with FDA Sentinel data and other data streams. These analyses, in part, resulted in class-wide updates to Section 5 (Warnings and Precautions) to include the risk of gadolinium retention in tissues, including the brain, for months to years, a medication guide, required manufacturers to conduct additional safety assessments. There was also a communication via the Sentinel initiative website.     GBCAs Safety Communications & Labeling Changes (Sentinel Initiative), December. 19, 2017. FDA Warns that Gadolinium-Based Contrast Agents (GBCAs) are Retained in the Body; Requires New Class Warnings

Comtan, Stalevo (entacapone)   

NDA 021485/ 20796

Orion Corporation Medicare claims data Retrospective cohort study  FDA conducted a retrospective cohort study in Medicare to assess cardiovascular risk associated with entacapone use. FDA found no clear evidence of increased cardiovascular risk with entacapone. The study resulted in a publication and DSC. Entacapone DSC, October 26, 2015. FDA Drug Safety Communication: FDA review found no increased cardiovascular risks with Parkinson’s disease drug entacapone      Movement Disorder Society Publication, 2013. 

Benicar (olmesartan)

NDA 021286

Daiichi Sankyo Medicare claims data Retrospective cohort study  In FDA’s review of Olmesartan, an FDA conducted retrospective cohort study in Medicare found no clear evidence of increased cardiovascular risks associated with high dose use in diabetic patients.  As a result, FDA’s recommendations for use of olmesartan (BENICAR, BENICAR HCT, AZOR, TRIBENZOR, and generics) in patients with diabetes remained the same. This resulted in a DSC and the addition of the study information in the labeling. Olmesartan DSC, June 24, 2014 (Medicare study results added to labeling). FDA Drug Safety Communication: FDA review of cardiovascular risks for diabetics taking hypertension drug olmesartan not conclusive; label updates required         

Benicar, Benicar hct (Olmesartan), Azor, Tribenzor (medoxomil)

Multiple NDAs 

Daiichi Sankyo Inc. Mini-Sentinel and Medicare Retrospective cohort study In FDA’s review of Olmesartan, an FDA evaluation of the FDA Adverse Event Reporting System (FAERS) and the published literature found evidence of an association between olmesartan and sprue-like enteropathy. To evaluate an ARB class association FDA conducted a retrospective cohort study in Mini-Sentinel and Medicare. These study results did not support a class effect. This resulted in an FDA safety communication that Olmesartan-containing products can cause intestinal problems known as sprue-like enteropathy. Olmesartan Safety Communications & Labeling Changes (Sentinel Initiative), July. 3, 2013.  FDA Approves Labeling Changes to Include Intestinal Problems (Sprue-Like Enteropathy) Linked to Blood Pressure Medicine Olmesartan Medoxomil    

Pradaxa (dabigatran)

NDA 022512

Boehringer Ingelheim Pharmaceuticals, Inc Mini-Sentinel Retrospective cohort study In 2012, an FDA conducted retrospective cohort study in Mini-Sentinel evaluated new information about the risk of serious bleeding associated with use of dabigatran (PRADAXA) and warfarin (COUMADIN, JANTOVEN, and generics). The results indicated that bleeding rates associated with new use of Pradaxa did not appear to be higher than bleeding rates associated with new use of warfarin, which was consistent with observations from the large clinical trial used to approve Pradaxa. FDA issued a DSC to communicate the findings and a communication via the Sentinel initiative website.  DSC November, 02,2012  FDA Drug Safety Communication: Update on the risk for serious bleeding events with the anticoagulant Pradaxa (dabigatran)   Sentinel Initiative, October. 31, 2012. Update on the Risk for Serious Bleeding Events with the Anticoagulant Pradaxa (Dabigatran)     

Epogen, Procrit, Aranesp (Erythropoietin stimulating agents (ESA))   

BLA 103234 and BLA 103951

Amgen Medicare claims data  Retrospective cohort study In FDA’s review of the effects of a labeling change recommending lower doses of ESAs in dialysis patients, an FDA retrospective cohort study in Medicare which assessed the effects of the changes in reimbursement policy in addition to changes in the ESA’s drug labeling found that the risk of MACE and mortality was unchanged, and risk of stroke was reduced following the labeling change. In Black patients, there was a substantial reduction in MACE and mortality after the labeling change. A bundled comprehensive payment system for dialysis that includes the costs of ESAs, and a revised drug label that recommends more conservative dosing had no adverse effects on older dialysis patients covered by fee-for-service Medicare. This resulted in a publication. The labeling change regarding use in patients with chronic kidney disease (CKD) was approved on June 24,2011   JAMA Publication, 2016.   

Avandia (rosiglitazone)      

NDA 021071

GlaxoSmithKline Medicare claims data Retrospective cohort study FDA conducted a retrospective cohort study in Medicare that evaluated the risk of heart attacks in patients taking rosiglitazone. The study resulted in labeling changes and an update to the Risk Evaluation and Mitigation Strategy (REMS) to include a restricted access and distribution program for all three rosiglitazone products.  This also resulted in two Drug Safety Communications (DSC). Rosiglitazone DSC, May 18, 2011 (imposition of REMS for rosiglitazone use). FDA Drug Safety Communication: Updated Risk Evaluation and Mitigation Strategy (REMS) to Restrict Access to Rosiglitazone-containing Medicines including Avandia, Avandamet, and Avandaryl          Rosiglitazone DSC and labeling change, February 3, 2011 (Medicare results added to label). FDA Drug Safety Communication: Avandia (rosiglitazone) labeling now contains updated information about cardiovascular risks and use in certain patients 

Imitrex (sumatriptan), Treximet® (sumatriptan and naproxen sodium)   

NDA 020626/ 020080/ 020132/ 021926/  

GSK Pregnancy registry Prospective registry study The Sumatriptan/Naratriptan/Treximet Pregnancy Registry collected data on fetal malformations and birth defects from in-utero exposure to sumatriptan (January 1996 to September 2012).  A prospective study conducted by the Sponsor identified too few exposed pregnancy outcomes to support definitive conclusions about overall malformation risk or for making comparisons of the frequencies of specific birth defects.   Section 8 of the label was updated to reflect that data from the prospective pregnancy exposure registry and other epidemiological studies of pregnant women did not show an increased frequency of birth defects or a consistent pattern of birth defects among women exposed to sumatriptan compared with the general population.  Completed Pregnancy Registry Study (ClinicalTrials.gov ID NCT01059604) Sumatriptan and Naratriptan Pregnancy Registry Study IMITREX labeling update December 14, 2017: See Section: 8 USE IN SPECIFIC POPULATIONS, 8.1 Pregnancy  TREXIMET labeling update April 28,2021: TREXIMET labeling update April 28, 2021: See Section: 8 USE INSPECIFIC POPULATIONS, 8.1 Pregnancy

Amerge (naratriptan)

NDA 020763

GSK Pregnancy registry Prospective registry study The Sumatriptan/Naratriptan/Treximet Pregnancy Registry collected data on adverse fetal outcomes from in utero exposure to naratriptan. Section 8 of the AMERGE labeling was updated to reflect that no definitive conclusions could be drawn from the registry and epidemiological studies regarding the risk of birth defects following exposure to naratriptan.  AMERGE label update November 29, 2016 See Section: 8 USE IN SPECIFIC POPULATIONS, 8.1 Pregnancy

Proton pump inhibitors (PPI)  

Multiple NDAs 

Multiple sponsors Medicare claims data  Case-control study In FDA’s review of drugs repurposed for treating patients with COVID-19 or drugs being taken by patients with COVID-19, there was concern that PPI use might increase the risk of developing severe COVID-19. An FDA conducted case control study in Medicare compared new users of PPIs versus new users of histamine-2 receptor antagonists and found that PPIs were not associated with increased risk uncomplicated or complicated (ICU, mechanical ventilation, death) COVID-19 hospitalizations. This provided reassurance to FDA that regulatory action was not needed. This resulted in a publication.  Pharmacotherapy publication, 2024.  

Angiotensin-converting enzyme (ACE) Inhibitors (multiple) and angiotensin receptor blockers (ARB) (multiple)   

Multiple NDAs 

Multiple sponsors Medicare claims data Case-control study In FDA’s review of ACE inhibitors or ARBs, an FDA conducted case-control study in Medicare evaluated the effect of ACE inhibitors or ARBs on the risk of developing severe COVID-19 and found that use of these drugs was not associated with increased risk of hospitalized COVID-19 or COVID-19-related mortality. No labeling changes were warranted. This resulted in a publication. Journal of General Internal Medicine publication, 2021.  

EPOGEN, PROCRIT, ARANESP (Erythropoietin stimulating agents (ESA))  

BLA 103234 and 103951

Amgen Medicare Retrospective cohort study FDA reviewed the effect of the REMS for ESA use for chemotherapy-induced anemia, during and after the discontinuation of the REMS, and conducted a restrospective cohort study in Medicare that showed that the REMS had minimal impact on ESA use or transfusion rates and that the removal of the REMS did not affect subsequent ESA use or blood transfusions. Study results provided reassurance that FDA's removal of the REMS had not led to increased ESA use or transfusions. This resulted in a publication. Pharmacoepidemiology Drug Safety publication, 2021. 

LYBREL (ethinyl estradiol; levonorgestrel)  

NDA 021864

Pfizer Sentinel System Retrospective cohort study An FDA conducted retrospective cohort study evaluated the risk of venous thromboembolism (VTE) for extended cycle contraceptives to determine whether these posed a greater risk of VTE due to increased hormone exposure, compared to 28-day products. The study provided reassurance that VTE risk was not substantially different between traditional and extended use oral contraceptives. JAMA Publication 2018    

Januvia (sitagliptin)   

NDA 021995

Merck Pregnancy registry Prospective registry study A prospective study conducted by the Sponsor in a pregnancy registry identified too few exposed pregnancy outcomes to support definitive conclusions about overall malformation risk or for making comparisons of the frequencies of specific birth defects.  Section 8 of the labeling was updated to reflect that the data available for pregnant women exposed to sitagliptin were not sufficient to inform a drug- associated risk for major birth defects and miscarriage.  JANUVIA label update February 9, 2018. See Section: 8 USE IN SPECIFIC POPULATIONS, 8.1 Pregnancy - Risk Summary

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