Possible Drug Risks Buried in Delayed FDA 'Watch Lists'

March 29, 2016

The US Food and Drug Administration (FDA) has an early warning system to help catch safety problems with drugs after they reach the market. In the second quarter of 2015, a class of diabetes drugs called SGLT-2 inhibitors showed up on its radar screen.

The public didn't know about this blip until about 7 months later. By law, it should have known months earlier. FDA critics say the agency's early warning system needs fixing.

The regulatory radar is built on the FDA Adverse Event Reporting System (FAERS), which receives reports of problems from physicians, nurses, pharmacists, patients and their family members, and attorneys as well as drug manufacturers who pass on complaints they get from the public. Based on FAERS reports received during the second quarter of 2015, the agency identified stroke and thromboembolic events as a "potential signal of a serious risk" for seven SGLT-2 inhibitors.

The seven drugs cited are canagliflozin (Invokana, Janssen Pharmaceuticals), canagliflozin/metformin (Invokamet, Janssen Pharmaceuticals), dapagliflozin (Farxiga, AstraZeneca), dapagliflozin/metformin (Xigduo XR, AstraZeneca), empagliflozin (Jardiance, Boehringer Ingelheim/Eli Lilly), empagliflozin/metformin (Synjardy, Boehringer Ingelheim/Eli Lilly), and empagliflozin/linagliptin (Glyxambi, Boehringer Ingelheim/Eli Lilly). Thromboembolisms and stroke do not appear as possible adverse events on the latest FDA- approved labels for any of these drugs.

A 2007 law requires the FDA to publish quarterly lists of drugs with reported adverse events that qualify as a potential signal of a serious risk. These quarterly lists, sometimes called FDA watch lists, are supposed to appear sometime in the following 3 months. The idea is to alert physicians and patients alike that regulators have questions about a drug, such as SGLT-2 inhibitors.

In flagging these diabetes drugs and any others on a watch list, the agency stresses that it is not alleging a causal relationship between the adverse event and the drug. Nor does a drug's appearance on the list mean that clinicians should stop prescribing it, or patients stop taking it.

What flagging does mean is that the FDA intends to investigate the radar blip. Sometimes the agency concludes that it's a false alarm — a flock of geese instead of a missile. However, the investigation may trigger a regulatory response that ranges from adding a warning to a drug's label to, in rare cases, pulling it from the market — shooting it out of the sky, as it were.

The potential-signals list for the second quarter of 2015, the one that flagged SGLT-2 inhibitors for stroke and thromboembolic events, should have been posted on the FDA's website before September 30, 2015. Instead, it quietly appeared there on February 5, 2016, without any public notice. Concerning the issue with SGLT-2 inhibitors, the report said in its usual formulaic manner that "FDA is evaluating the need for regulatory action."

That same day, the agency posted the FAERS watch lists for the first and third quarters of 2015 as well. In total, the lists for the first 9 months of the year covered potential problems with 39 drugs or drug classes.

On March 22, the FDA finally caught up on its publication schedule when it posted the FAERS watch list for the last 3 months of 2015, which cited an additional six drugs or drug classes. SGLT-2 inhibitors popped up again, this time for acute renal injury. The refrain was the same: "FDA is evaluating the need for regulatory action."

All four quarterly watch lists for 2015 appear at the end of this article.

FDA Points to "Competing Priorities and Understaffing"

In late December of 2015, Medscape Medical News asked the FDA why it had fallen behind in publishing its quarterly watch lists, and why the number of drugs or drug classes listed in the quarterly reports sharply declined from 2011 through 2014.

The answers underscore the byzantine nature of the FDA's postmarket surveillance machinery.


Table 1. Drugs Appearing in FAERS Watch Lists
2008 2009 2010 2011 2012 2013 2014 2015
42 20 14 34 20 6 6 46*

*A drug or drug class may be counted more than once in a given year or even in a given quarterly watch list on account of multiple adverse events. In the list for the fourth quarter of 2015, for example, four drugs or drug classes showed up twice.

Not every problem reported to FAERS makes it into a FAERS watch list. Instead, the staff of the FDA's Center for Drug Evaluation and Research (CDER) pulls out the significant adverse events — dubbed tracked safety issues (TSIs) — and enters them into a second computer system for monitoring drugs after their approval. It's called the Document Archiving, Reporting, and Regulatory Tracking System (DARRTS). CDER then develops a watch list from the TSIs in DARRTS.

FDA spokesperson Angela Stark said in a written statement that month that the agency had entered some — but not all — of the TSIs originally reported to FAERS from January 2012 through April 2015 into DARRTS.

CDER "is currently taking steps to enter tracked safety issues that were not previously entered," according to Stark.

This catch-up campaign suggests that as more TSIs from FAERS find their way into DARRTS for the period beginning in 2012 through 2014, the more drugs will be flagged for potential- risk signals in the watch lists already posted for that period, increasing the totals. But these revisions haven't happened yet.

Medscape Medical News did not receive an explanation on why the FDA was not entering TSIs into DARRTS in a timely manneruntil January 4. Stark wrote that the retroactive data entry under way "reflects challenges with balancing the important work of timely evaluation and action of identified post-market safety issues with the data entry process for tracking post-market safety issues.

"Due to multiple competing priorities and understaffing, CDER staff have prioritized the work of fully addressing and resolving important public health issues over completely adhering to the time-consuming data entry procedures of tracking safety issues," Stark said.

She also noted that although there have been delays in entering TSIs in DARRTS over the past several years, the FDA has nevertheless evaluated and addressed the majority of them, which in some cases has led to safety communications to the public and label changes.

Government Watchdog Barks at Late FDA Reports

The FDA gave a similar explanation to investigators from the federal watchdog agency called the Government Accountability Office (GAO).

Rep. Rosa DeLauro (D-CT) had asked GAO to assess how well the FDA tracks reported safety issues for drugs that receive some kind of expedited approval. That happens, for example, to drugs designated as a "breakthrough therapy" because preliminary studies indicate they will treat serious or life-threatening illnesses much more effectively than existing drugs. Such expedited approvals may entail fewer, smaller, or shorter clinical trials, which may not establish a drug's safety profile as well as more extensive trials might.

Along the same lines, DeLauro asked GAO to investigate how well the FDA keeps tabs on postmarket studies that drug manufacturers are asked to perform after an expedited approval.

In a report released on January 14, GAO rendered a harsh verdict. "[The] FDA lacks reliable, readily accessible data on tracked safety issues and post-market studies," GAO said. That deficiency, in turn, limits the agency's ability to fulfill its reporting and oversight responsibilities. A CDER evaluation of its database revealed "problems with the completeness, timeliness and accuracy of the data," that, combined with other problems "have prevented FDA from publishing statutorily required reports on certain potential safety issues and post-market studies in a timely manner."

The report quoted FDA officials as saying that staff attrition and recruiting difficulties had left CDER's review staff shorthanded and that the Office of New Drugs in CDER was at 90% of its authorized staffing ceiling. These FDA officials also said that reviewing postmarket studies on approved drugs took a back seat to competing priorities such as reviewing new-drug applications in a timely manner.

In the FDA's defense, the US Department of Health and Human Services (HHS) told GAO that given the high workload of staff and limited resources, CDER has focused more on identifying, evaluating, and addressing TSIs and less on "entering information…into our tracking system." That said, HHS agreed with GAO that the FDA should correct its problems with postmarket safety reports and studies, and make that data more easily accessible for the FDA to do its job.

GAO noted that although the FDA has taken some remedial steps, it lacks a comprehensive plan with goals and time frames to get its data management act together.

The FDA, however, expresses confidence that its postmarket surveillance of drug safety issues will improve. In a statement issued to Medscape Medical News, the agency said it was implementing new processes and procedures to "address the gaps and correct…its data." This remedial effort extends to feeding significant adverse events classified as TSIs into its DARRTS tracking system.

"These efforts," said the FDA, "are expected to improve the timeliness of the quarterly FAERS reports."

Faster Approvals Trump Faster Public Reporting?

To one public health expert, publication delays for the FAERS watch lists

Illustrate how the FDA caters more to drug manufacturers than patients.

"The FDA has many requirements, and Congress keeps passing legislation that adds more mandates without adding funds for staff," said Diana Zuckerman, PhD, president of the National Center for Health Research, a think tank focused on children and adults. "In the last year, it has become more obvious that the requirements that FDA has as its first priority are the ones that benefit industry — faster approvals."

The FDA is beholden to pharmaceutical companies, said Dr Zuckerman, because they pay user fees that partially fund the agency. These same companies lobby a Republican Congress for a quicker, less onerous review process, and Congress in turn pressures the FDA to speed things up.

The agency felt a different kind of pressure when GAO issued its report on January 14, and Congresswoman DeLauro immediately called the FDA's data problems "a severe safety risk for American consumers." Dr Zuckerman said it was no coincidence that roughly 3 weeks later, the FDA posted its FAERS watch lists for the first three quarters of 2015, followed by the fourth-quarter report on March 22.

The watch lists play an important role in patient care, she said.

"Doctors who know there is a possible adverse risk for a drug might be likely to report it themselves if they see it in their patients," she said. "And they'd be more likely to consider alternatives."

Likewise, said Dr Zuckerman, some patients may balk at taking a drug appearing on a watch list.

"It's not that these safety signals mean 'Never use this drug,' " she said. "But they're warning signals. That's the whole point."

And often, where there is smoke, there is fire. Of the seven drugs or drug classes flagged in the watch list for the first quarter of 2015, four later underwent label changes to reflect the adverse event captured in FAERS. For example, the FDA revised the label of metreleptin injection (Myalept, Amylin Pharmaceuticals), approved in 2014 to treat complications of leptin deficiency, to include the risk for anaphylaxis.

And reports of cardiac arrhythmia and bradycardia for a group of three hepatitis C drugs eventually prompted label changes warning of these side effects when amiodarone is given with either ledipasvir/sofosbuvir (Harvoni, Gilead Sciences) or sofosbuvir (Sovaldi, Gilead Sciences) in combination with another direct-acting antiviral drug such as simeprevir (Olysio, Janssen Pharmaceuticals).

Potential Signals, Crossed Signals

The appearance of a drug on an FDA watch list shouldn't make anyone jump to conclusions about cause and effect. That caution applies to SGLT-2 inhibitors in the second-quarter 2015 report, particularly because other evidence doesn't point to stroke and thromboembolic events as a risk for at least one of these drugs.

A landmark study published in the New England Journal of Medicine last year demonstrated that empagliflozin offered cardiac benefits besides reducing blood glucose. In the study, called Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG), patients taking the drug had a lower relative risk for both cardiovascular mortality and all-cause mortality.

EMPA-REG, paid for by the drug's manufacturers, did not find, however, that the drug had an effect one way or the other on fatal or nonfatal strokes. Patients on empagliflozin had an overall stroke rate of 3.5% compared with 3.0% for patients receiving a placebo. The study authors said that difference was not significant.

One leading endocrinologist told Medscape Medical News that she doesn't know what to make of the stroke signal reported by the FDA in its watch list.

"The problem with these [FDA] databases is that there is no true denominator [of drug use to adverse events]," said Anne Peters, MD, a professor of medicine at the Keck School of Medicine of the University of Southern California in Los Angeles and director of its clinical diabetes program. "So we have no idea of the rates of events."

Dr Peters said it is "hard to ascertain causality" in the FDA watch list report. She noted that randomized controlled trials (RCT) for SGLT-2 inhibitors have not found an increase in strokes.

"I tend to go with RCT data in these cases, but (it's) hard to know. I have used SGLT-2 inhibitors in many, many people and never seen any of these side effects."

Dr Peters, who also writes a column for Medscape Diabetes & Endocrinology, has served as a speaker or consultant with Eli Lilly, Boehringer Ingelheim Pharmaceuticals, and AstraZeneca Pharmaceuticals, which make SGLT-2 inhibitors.

Eli Lilly, the comanufacturer of empagliflozin, told Medscape Medical News that it and Boehringer Ingelheim are aware that the FDA added the potential safety issues of stroke and thromboembolic events for SGLT-2 inhibitors to its DARRTS tracking system in 2015.

"The safety of patients is of utmost importance to us and we actively monitor the safety of our products on an ongoing basis through clinical trials, observational studies and spontaneous reporting in everyday use," Eli Lilly said in an emailed statement. "[Boehringer Ingelheim] and Lilly are continuously working with regulatory authorities to determine if any safety precautions associated with our products should be taken."

FAERS Watch Lists for 2015

Table 2. Potential Signals of Serious Risks/New Safety Information Identified by FAERS, October–December 2015
Product Name: Active Ingredient (Trade) or Product Class Potential Signal of a Serious Risk/New Safety Information Additional Information (As of March 31, 2016)
Calcium gluconate injection Potential for wrong drug error The container labels for calcium gluconate were revised to better differentiate the product from sterile water for injection.
Epinephrine auto-injectors Clostridium perfringens infection FDA is evaluating the need for regulatory action.
Epipen (epinephrine) injection Epipen Jr (epinephrine) injection Lacerations and embedded needles FDA is evaluating the need for regulatory action.
Harvoni (ledipasvir/sofosbuvir) tablet Olysio (simeprevir) capsule Sovaldi (sofosbuvir) tablet Rhabdomyolysis FDA is evaluating the need for regulatory action.
Iodinated contrast agents (numerous products) Myasthenia gravis exacerbation FDA is evaluating the need for regulatory action.
Keppra (levetiracetam) tablet, oral solution, injection Spritam (levetiracetam) tablet (for suspension) Angioedema Anaphylaxis FDA is evaluating the need for regulatory action.
SGLT-2 inhibitors:
  • Farxiga (dapagliflozin) tablet

  • Glyxambi (empagliflozin/linagliptin) tablet

  • Jardiance (empagliflozin) tablet

  • Invokamet (canagliflozin/metformin HCl) tablet

  • Invokana (canagliflozin) tablet

  • Synjardy (empagliflozin/metformin HCl) tablets

  • Xigduo XR (dapagliflozin/metformin HCl) extended release tablet

Acute kidney injury FDA is evaluating the need for regulatory action.
Somatostatin analogues:
  • Sandostatin (octreotide acetate) injection

  • Sandostatin LAR Depot (octreotide acetate) for injectable suspension

  • Somatuline Depot (lanreotide) injection

  • Signifor (pasireotide) injection

  • Signifor LAR (pasireotide) injection

Cholecystitis FDA is evaluating the need for regulatory action.
TachoSil (fibrin sealant patch) Intestinal obstruction in patients undergoing abdominal and/or pelvic surgery. FDA is evaluating the need for regulatory action.
Visipaque (iodixanol) injection Hypersensitivity FDA decided that no action is necessary at this time.

 


Table 3. Potential Signals of Serious Risks/New Safety Information Identified by FAERS, July–September 2015
Product Name: Active Ingredient (Trade) or Product Class Potential Signal of a Serious Risk/New Safety Information Additional Information (As of January 13, 2016)
  • Articaine hydrochloride (HCl)/epinephrine bitartrate injection

  • Orabloc (articaine HCl/epinephrine bitartrate) injection

  • Septocaine (articaine HCl/epinephrine bitartrate) injection, solution

Paresthesia and taste disturbances FDA is evaluating the need for regulatory action.
Diabeta (glyburide) tablet Cardiovascular mortality FDA decided that no action is necessary at this time.
Dipeptidyl peptidase IV (DPP-IV) inhibitor:
  • Glyxambi (empagliflozin/linagliptin) tablet

  • Janumet XR (sitagliptin/metformin HCl) extended release tablet

  • Janumet (sitagliptin/metformin HCl) tablet

  • Januvia (sitagliptin) tablet

  • Jentadueto (linagliptin/metformin HCl) tablet

  • Kazano (alogliptin/metformin HCl) tablet

  • Kombiglyze XR (saxagliptin/metformin HCl) extended-release tablet

  • Nesina (alogliptin) tablet

  • Onglyza (saxagliptin) tablet

  • Oseni (alogliptin/pioglitazone) tablet

  • Tradjenta (linagliptin) tablet

Renal failure FDA is evaluating the need for regulatory action.
Dipeptidyl peptidase IV (DPP-IV) inhibitors:
  • Glyxambi (empagliflozin/linagliptin) tablet

  • Janumet XR (sitagliptin/metformin HCl) extended release tablet

  • Janumet (sitagliptin/metformin HCl) tablet

  • Januvia (sitagliptin) tablet

  • Jentadueto (linagliptin/metformin HCl) tablet

  • Kazano (alogliptin/metformin HCl) tablet

  • Kombiglyze XR (saxagliptin/metformin HCl) extended-release tablet

  • Nesina (alogliptin) tablet

  • Onglyza (saxagliptin) tablet

  • Oseni (alogliptin/pioglitazone) tablet

  • Tradjenta (linagliptin) tablet

Mouth ulcerations and stomatitis The "Postmarketing Experience" section of the labeling for products containing linagliptin was updated to include mouth ulcerations and stomatitis.





FDA is evaluating the need for regulatory action for products containing sitagliptin, alogliptin, and saxagliptin.
Honest sunscreen lotion SPF 30 Sunburn FDA is evaluating the need for regulatory action.
Mirvaso (brimonidine tartrate) gel Hypersensitivity, local vascular effects, and systemic effects consistent with pharmacologic action of alpha-2 agonists FDA is evaluating the need for regulatory action.
Nicotine replacement therapy:
  • Habitrol (nicotine) patch (transdermal system)

  • Nicoderm (nicotine) patch (transdermal system)

  • Nicotrol (nicotine) inhaler

  • Nicotrol NS (nicotine) spray

  • Nicorette & Nicorette DS (nicotine polacrilex) gum

  • Nicorette (nicotine polacrilex) lozenge

Seizures The "Ask a doctor before use if you have" section of the labeling for Nicorette and Nicoderm was updated to include a "history of seizures."



FDA continues to evaluate the need for regulatory action for other nicotine replacement products.
Proton pump inhibitors:
  • Aciphex (rabeprazole sodium) tablet, sprinkle

  • Dexilant (dexlansoprazole) capsule

  • Esomeprazole magnesium capsule, oral suspension, injection

  • Esomeprazole sodium injection

  • Esomeprazole strontium capsule

  • Lansoprazole capsule

  • Naproxen/esomeprazole magnesium tablet

  • Nexium (esomeprazole magnesium) capsule, granule

  • Omeclamox-Pak (omeprazole delayed-release capsules, clarithromycin tablets, and amoxicillin capsules)

  • Omeprazole capsule, granules for oral suspension

  • Pantoprazole sodium tablet

  • Prevacid (lansoprazole) capsule

  • Prevpac (lansoprazole/amoxicillin/clarithromycin) capsule/capsule/tablet

  • Prilosec (omeprazole magnesium) capsule, tablet, granule

  • Protonix (pantoprazole sodium) tablet, injection, oral suspension

  • Rabeprazole sodium tablet

  • Vimovo (naproxen/esomeprazole magnesium) tablet

  • Zegerid (omeprazole/sodium bicarbonate) capsule, powder for oral suspension

Systemic Lupus Erythematosus (SLE) FDA is evaluating the need for regulatory action.
Pseudoephedrine-containing products (numerous) Ischemic colitis FDA decided that no action is necessary at this time.
Recombinant human growth hormones:
  • Genotropin (somatropin) injection

  • Humatrope [somatropin (rDNA origin)] injection

  • Norditropin cartridges [somatropin (rDNA origin)] injection

  • Nutropin AQ [somatropin (rDNA origin)] injection

  • Omnitrope [somatropin (rDNA origin)] injection

  • Saizen (somatropin recombinant [rDNA origin]) injection

  • Serostim [somatropin (rDNA origin)] injection

  • Tev-Tropin [somatropin (rDNA origin)] injection

Hypersensitivity FDA is evaluating the need for regulatory action.
SGLT-2 inhibitors:
  • Farxiga (dapagliflozin) tablet

  • Glyxambi (empagliflozin/linagliptin) tablet

  • Invokamet (canagliflozin/metformin HCl) tablet

  • Invokana (canagliflozin) tablet

  • Jardiance (empagliflozin) tablet

  • Synjardy (empagliflozin/metformin HCl) tablet

  • Xigduo XR (dapagliflozin/metformin HCl) extended release tablet

Urosepsis "Warnings and Precautions," "Adverse Reactions," and "Patient Counseling" sections of the labeling and patient labeling were updated to include urosepsis.
Tecfidera (dimethyl fumarate) delayed-release capsule Acute pancreatitis FDA decided that no action is necessary at this time.
Viekira PAK (dasabuvir/ombitasvir/paritaprevir/ritonavir) tablets Technivie (ombitasvir/paritaprevir/ ritonavir) tablets Hepatic decompensation and hepatic failure The "Contraindications" and "Warnings and Precautions" sections along with numerous other sections of the labeling were updated to include information about risk of hepatic decompensation and hepatic failure in patients with cirrhosis.
Viekira PAK (dasabuvir/ombitasvir/paritaprevir/ritonavir) tablets Technivie (ombitasvir/paritaprevir/ ritonavir) tablets Renal adverse events including renal failure FDA is evaluating the need for regulatory action.
Votrient (pazopanib HCl) tablet Interstitial lung disease (ILD)/pneumonitis The "Warnings and Precautions" and "Patient Counseling Information" sections of the labeling were updated to include ILD and pneumonitis.
Zonegran (zonisamide) capsule Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) FDA is evaluating the need for regulatory action.

 


Table 4. Potential Signals of Serious Risks/New Safety Information Identified by FAERS, April–June 2015
Product Name: Active Ingredient (Trade) or Product Class Potential Signal of a Serious Risk/New Safety Information Additional Information (As of January 13, 2016)
Acetaminophen Pediatric ingestion errors Pediatric Oral Liquid Drug Products Containing Acetaminophen_Final Guidance (8/4/15)
Bloxiverz (neostigmine methylsulfate) injection Vazculep (phenylephrine HCl) injection Potential product selection errors Carton and vial labeling designs were revised to better differentiate Vazculep from Bloxiverz.
Brintellix (vortioxetine) tablet Brilinta (ticagrelor) tablet Brand name confusion

FDA is evaluating the need for regulatory action

Brintellix & Brilinta Drug Safety Communication (7/30/15)
Calcium carbonate Milk-alkali syndrome (hypercalcemia) FDA is evaluating the need for regulatory action.
Daliresp (roflumilast) tablet Gynecomastia "Postmarketing Experience" section updated to include gynecomastia.
Daytrana (methylphenidate) patch Chemical leukoderma The "Warnings and Precautions" section of the labeling was updated to include chemical leukoderma.
Iodinated Contrast Media:
  • Cholografin meglumine (iodipamide meglumine, 52%) injection

  • Conray 43 (iothalamate meglumine, 43%) injection

  • Conray 30 (iothalamate meglumine, 30%) injection

  • Cystografin dilute (diatrizoate meglumine, 18%) injection

  • Isovue (iopamidol) injection (several strengths)

  • Omnipaque (iohexol) injection

  • Optiray (ioversol) injection (several strengths)

  • Oxilan (ioxilan) injection

  • Ultravist (iopromide) injection (several strengths)

  • Visipaque (iodixanol) injection (several strengths)

Severe cutaneous adverse reactions including:
  • Stevens-Johnson Syndrome (SJS)

  • Toxic Epidermal Necrolysis (TEN)

  • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)

  • Acute Generalized Exanthematous Pustulosis (AGEP) associated with iodinated contrast media

FDA is evaluating the need for regulatory action.
Over-the-counter chlorhexidine gluconate topical products:
  • Bactoshield sponge

  • BD E-Z scrub solution

  • Chloraprep One-Step (with alcohol) solution

  • Chlorhexidine gluconate cloth Dyna-Hex 75 antiseptic handwash solution

  • Hibiclens solution

  • Hibistat (with alcohol) solution

  • Exidine solution

  • Exidine aerosol, metered, topical

  • Prevantics Maxi Swabstick (with alcohol) solution

  • Scrub Care Exidine-2-CHG solution

  • Scrub Care solution

  • Scrub-Stat solution

Hypersensitivity/anaphylaxis FDA is evaluating the need for regulatory action.
Proglycem (diazoxide) capsules, suspension Pulmonary hypertension The "Warnings," "Precautions," and "Adverse Reaction" sections of the labeling were updated to include pulmonary hypertension.
SGLT-2 inhibitors:
  • Farxiga (dapagliflozin) tablet

  • Glyxambi (empagliflozin/linagliptin) tablet

  • Jardiance (empagliflozin) tablet

  • Invokamet (canagliflozin/metformin HCl) tablet

  • Invokana (canagliflozin) tablet

  • Synjardy (empagliflozin/metformin HCl) tablets

  • Xigduo XR (dapagliflozin/metformin HCl) extended release tablet

Stroke and thromboembolic events FDA is evaluating the need for regulatory action.
Tramadol hydrochloride (HCl) products:
  • Conzip (tramadol HCl) extended-release capsule

  • Ultracet (tramadol HCl/acetaminophen) tablet

  • Ultram (tramadol HCl) tablet

  • Ultram ER (tramadol HCl) extended-release tablet

Respiratory depression and CYP2D6 ultra-rapid metabolism FDA continues to evaluate the need for regulatory action.

Tramadol Drug Safety Communication (9/21/15)
Tumor necrosis factor (TNF) blockers:
  • Cimzia (certolizumab pegol) injection

  • Enbrel (etanercept) injection

  • Humira (adalimumab) injection

  • Remicade (infliximab) solution

  • Simponi & Simponi Aria (golimumab) injection

Psychiatric and nervous system disorders FDA is evaluating the need for regulatory action.
Zerbaxa (ceftolozane and tazobactam) injection Drug dosing issues The "Drug and Administration" section of the labeling and the vial and carton labeling were updated regarding the drug strength.

 


Table 5. Potential Signals of Serious Risks/New Safety Information Identified by FAERS, January–March 2015
Product Name: Active Ingredient (Trade) or Product Class Potential Signal of a Serious Risk/New Safety Information Additional Information (As of January 13, 2016)
Harvoni (ledipasvir/sofosbuvir) tablet Olysio (simeprevir) capsule Sovaldi (sofosbuvir) tablet Cardiac arrhythmia, bradycardia "Warning and Precautions," "Adverse Reactions," and "Drug Interactions" sections of the labeling and the patient package insert were updated to include information on the occurrence of serious symptomatic bradycardia when the antiarrhythmic drug amiodarone is taken with hepatitis C treatments containing ledipasvir/sofosbuvir (Harvoni) or with sofosbuvir (Sovaldi) taken in combination with another direct-acting antiviral.

Harvoni and Sovaldi Drug Safety Communication (3/24/15)
Juxtapid (lomitapide mesylate) capsule Ineffectiveness of the REMS FDA is evaluating the need for regulatory action.
Juxtapid (lomitapide mesylate) capsule Severe diarrhea FDA is evaluating the need for regulatory action.
Myalept (metreleptin) injection Anaphylaxis The "Warnings and Precautions" and "Contraindications" sections of the labeling were updated to include anaphylaxis.
Noxafil (posaconazole) delayed-release tablet, oral suspension, and injection Dosing and administration errors associated with product labeling (only oral product formulations) The "Dosage and Administration" section of the labeling was updated to include information that the delayed-release tablet and oral suspension are not interchangeable due to the differences in the dosing of each formulation. Also, the outer carton/container now includes an "attention" statement.
Pomalyst (pomalidomide) capsule Hepatotoxicity The "Warnings and Precautions" section of the labeling was updated to include hepatotoxicity.
Tyvaso (treprostinil) inhalation solution Nebulizer battery overheating Starting in April 2013, the battery pack was redesigned and included on all new nebulizers. Previously distributed nebulizers were replaced by the new battery pack. By June 2015, all U.S. Tyvaso patients should have transitioned to the new battery pack. The sponsor reports no complaints of thermal events with the new battery pack.

 

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