FDA Actions

The Food and Drug Administration has approved mitomycin pyelocalyceal (Jelmyto) as the first therapy for adults with low-grade upper tract urothelial cancer.

Olivier Le Moal/Getty Images

“This is the first approval specifically for patients with low-grade [upper tract urothelial cancer] and provides an option for some patients who may otherwise require a nephroureterectomy,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence, said in a statement.

“Due to substantial treatment challenges associated with the complex anatomy of the upper urinary tract, many patients need to be treated with radical surgery – usually complete removal of the affected kidney, ureter, and bladder cuff," Dr. Pazdur added. "Jelmyto gives patients, for the first time, an alternative treatment option for low-grade [upper tract urothelial cancer].”

The FDA’s approval of mitomycin is based on results from the phase 3 OLYMPUS trial (NCT02793128). This ongoing, single-arm trial enrolled 71 patients with treatment-naive or recurrent low-grade noninvasive upper tract urothelial cancer with at least one measurable papillary tumor located above the ureteropelvic junction. Patients with larger tumors were allowed to have prior tumor debulking.

The patients received mitomycin weekly for 6 weeks at the recommended dose of 4 mg/mL, instilled via ureteral catheter or nephrostomy tube, with the total instillation volume based on volumetric measurements using pyelography, not exceeding 15 mL (60 mg mitomycin).

Patients who achieved a complete response at 3 months could receive monthly instillations up to a maximum of 11 additional instillations.

At 3 months, 41 patients (58%) achieved a complete response (CR). At 12 months after CR determination, 19 patients were still in CR, and 7 patients had documented recurrences. The median duration of CR was not reached.

The most common adverse events (occurring in at least 20% of patients) were ureteric obstruction, flank pain, urinary tract infection, hematuria, renal dysfunction, fatigue, nausea, abdominal pain, dysuria, and vomiting. Ureteric obstruction occurred in 58% of patients, and 88% of those patients required ureteral stent placement.

In all, 23% of patients discontinued mitomycin due to adverse events, and 34% had dose interruptions due to adverse events.

The approval of mitomycin was granted to UroGen Pharma. The FDA granted the application priority review, fast track designation, and breakthrough therapy designation.

The full prescribing information for mitomycin is available for download from the FDA website.

jensmith@mdedge.com

The Food and Drug Administration has approved mitomycin pyelocalyceal (Jelmyto) as the first therapy for adults with low-grade upper tract urothelial cancer.

Olivier Le Moal/Getty Images

“This is the first approval specifically for patients with low-grade [upper tract urothelial cancer] and provides an option for some patients who may otherwise require a nephroureterectomy,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence, said in a statement.

“Due to substantial treatment challenges associated with the complex anatomy of the upper urinary tract, many patients need to be treated with radical surgery – usually complete removal of the affected kidney, ureter, and bladder cuff," Dr. Pazdur added. "Jelmyto gives patients, for the first time, an alternative treatment option for low-grade [upper tract urothelial cancer].”

The FDA’s approval of mitomycin is based on results from the phase 3 OLYMPUS trial (NCT02793128). This ongoing, single-arm trial enrolled 71 patients with treatment-naive or recurrent low-grade noninvasive upper tract urothelial cancer with at least one measurable papillary tumor located above the ureteropelvic junction. Patients with larger tumors were allowed to have prior tumor debulking.

The patients received mitomycin weekly for 6 weeks at the recommended dose of 4 mg/mL, instilled via ureteral catheter or nephrostomy tube, with the total instillation volume based on volumetric measurements using pyelography, not exceeding 15 mL (60 mg mitomycin).

Patients who achieved a complete response at 3 months could receive monthly instillations up to a maximum of 11 additional instillations.

At 3 months, 41 patients (58%) achieved a complete response (CR). At 12 months after CR determination, 19 patients were still in CR, and 7 patients had documented recurrences. The median duration of CR was not reached.

The most common adverse events (occurring in at least 20% of patients) were ureteric obstruction, flank pain, urinary tract infection, hematuria, renal dysfunction, fatigue, nausea, abdominal pain, dysuria, and vomiting. Ureteric obstruction occurred in 58% of patients, and 88% of those patients required ureteral stent placement.

In all, 23% of patients discontinued mitomycin due to adverse events, and 34% had dose interruptions due to adverse events.

The approval of mitomycin was granted to UroGen Pharma. The FDA granted the application priority review, fast track designation, and breakthrough therapy designation.

The full prescribing information for mitomycin is available for download from the FDA website.

jensmith@mdedge.com

The Food and Drug Administration has approved mitomycin pyelocalyceal (Jelmyto) as the first therapy for adults with low-grade upper tract urothelial cancer.

Olivier Le Moal/Getty Images

“This is the first approval specifically for patients with low-grade [upper tract urothelial cancer] and provides an option for some patients who may otherwise require a nephroureterectomy,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence, said in a statement.

“Due to substantial treatment challenges associated with the complex anatomy of the upper urinary tract, many patients need to be treated with radical surgery – usually complete removal of the affected kidney, ureter, and bladder cuff," Dr. Pazdur added. "Jelmyto gives patients, for the first time, an alternative treatment option for low-grade [upper tract urothelial cancer].”

The FDA’s approval of mitomycin is based on results from the phase 3 OLYMPUS trial (NCT02793128). This ongoing, single-arm trial enrolled 71 patients with treatment-naive or recurrent low-grade noninvasive upper tract urothelial cancer with at least one measurable papillary tumor located above the ureteropelvic junction. Patients with larger tumors were allowed to have prior tumor debulking.

The patients received mitomycin weekly for 6 weeks at the recommended dose of 4 mg/mL, instilled via ureteral catheter or nephrostomy tube, with the total instillation volume based on volumetric measurements using pyelography, not exceeding 15 mL (60 mg mitomycin).

Patients who achieved a complete response at 3 months could receive monthly instillations up to a maximum of 11 additional instillations.

At 3 months, 41 patients (58%) achieved a complete response (CR). At 12 months after CR determination, 19 patients were still in CR, and 7 patients had documented recurrences. The median duration of CR was not reached.

The most common adverse events (occurring in at least 20% of patients) were ureteric obstruction, flank pain, urinary tract infection, hematuria, renal dysfunction, fatigue, nausea, abdominal pain, dysuria, and vomiting. Ureteric obstruction occurred in 58% of patients, and 88% of those patients required ureteral stent placement.

In all, 23% of patients discontinued mitomycin due to adverse events, and 34% had dose interruptions due to adverse events.

The approval of mitomycin was granted to UroGen Pharma. The FDA granted the application priority review, fast track designation, and breakthrough therapy designation.

The full prescribing information for mitomycin is available for download from the FDA website.

jensmith@mdedge.com

The U.S. Food and Drug Administration today approved isatuximab (Sarclisa, Sanofi) in combination with pomalidomide (Revlimid, Celgene) and dexamethasone for the treatment of adult patients with multiple myeloma who have received two or more prior therapies including lenalidomide and a proteasome inhibitor.

Isatuximab is an anti-CD38 monoclonal antibody administered by intravenous infusion that works by helping the immune system attack multiple myeloma cancer cells.

“While there is no cure for multiple myeloma, Sarclisa is now another CD38-directed treatment option added to the list of FDA-approved treatments of patients with multiple myeloma who have progressive disease after previous therapies,” said Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research.

“In the clinical trial, there was a 40% reduction in the risk of disease progression or death with this therapy,” he added.

The new approval is based on results from ICARIA-MM, an open-label, randomized phase 3 clinical trial of isatuximab among 307 patients in this setting.

In the trial, at a median follow-up of 11.6 months, median progression-free survival was 11.5 months in the isatuximab-pomalidomide-dexamethasone group versus 6.5 months in the pomalidomide-dexamethasone group (hazard ratio, 0.60; P = .001), as reported last year. Overall response rates were 60.4% for the triplet-treated group versus 35.3% for the doublet-treated group.

The most common side effects for isatuximab included neutropenia, infusion-related reactions, pneumonia, upper respiratory tract infection, diarrhea, anemia, lymphopenia, and thrombocytopenia.

Deaths because of treatment-related adverse events were reported for one patient (less than 1%) in the isatuximab-pomalidomide-dexamethasone group (sepsis) and two patients (1%) in the pomalidomide-dexamethasone group (pneumonia and urinary tract infection).

The drug can also cause serious side effects, including IV infusion-related reactions. In the case of a grade 3 or higher reaction, the drug should be permanently discontinued and health care professionals should institute appropriate medical management.

The FDA notes there have been higher incidences of second primary malignancies observed in a controlled clinical trial of patients with multiple myeloma receiving the drug.

The FDA also highlighted that laboratory test interference may be caused by isatuximab and that blood banks should be informed that patients are receiving the drug. Isatuximab may interfere with, for example, antibody screening for patients who need a blood transfusion. Isatuximab may also interfere with the assays used to monitor M-protein, which may impact the determination of complete response.

This article originally appeared on Medscape.com.

The U.S. Food and Drug Administration today approved isatuximab (Sarclisa, Sanofi) in combination with pomalidomide (Revlimid, Celgene) and dexamethasone for the treatment of adult patients with multiple myeloma who have received two or more prior therapies including lenalidomide and a proteasome inhibitor.

Isatuximab is an anti-CD38 monoclonal antibody administered by intravenous infusion that works by helping the immune system attack multiple myeloma cancer cells.

“While there is no cure for multiple myeloma, Sarclisa is now another CD38-directed treatment option added to the list of FDA-approved treatments of patients with multiple myeloma who have progressive disease after previous therapies,” said Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research.

“In the clinical trial, there was a 40% reduction in the risk of disease progression or death with this therapy,” he added.

The new approval is based on results from ICARIA-MM, an open-label, randomized phase 3 clinical trial of isatuximab among 307 patients in this setting.

In the trial, at a median follow-up of 11.6 months, median progression-free survival was 11.5 months in the isatuximab-pomalidomide-dexamethasone group versus 6.5 months in the pomalidomide-dexamethasone group (hazard ratio, 0.60; P = .001), as reported last year. Overall response rates were 60.4% for the triplet-treated group versus 35.3% for the doublet-treated group.

The most common side effects for isatuximab included neutropenia, infusion-related reactions, pneumonia, upper respiratory tract infection, diarrhea, anemia, lymphopenia, and thrombocytopenia.

Deaths because of treatment-related adverse events were reported for one patient (less than 1%) in the isatuximab-pomalidomide-dexamethasone group (sepsis) and two patients (1%) in the pomalidomide-dexamethasone group (pneumonia and urinary tract infection).

The drug can also cause serious side effects, including IV infusion-related reactions. In the case of a grade 3 or higher reaction, the drug should be permanently discontinued and health care professionals should institute appropriate medical management.

The FDA notes there have been higher incidences of second primary malignancies observed in a controlled clinical trial of patients with multiple myeloma receiving the drug.

The FDA also highlighted that laboratory test interference may be caused by isatuximab and that blood banks should be informed that patients are receiving the drug. Isatuximab may interfere with, for example, antibody screening for patients who need a blood transfusion. Isatuximab may also interfere with the assays used to monitor M-protein, which may impact the determination of complete response.

This article originally appeared on Medscape.com.

The U.S. Food and Drug Administration today approved isatuximab (Sarclisa, Sanofi) in combination with pomalidomide (Revlimid, Celgene) and dexamethasone for the treatment of adult patients with multiple myeloma who have received two or more prior therapies including lenalidomide and a proteasome inhibitor.

Isatuximab is an anti-CD38 monoclonal antibody administered by intravenous infusion that works by helping the immune system attack multiple myeloma cancer cells.

“While there is no cure for multiple myeloma, Sarclisa is now another CD38-directed treatment option added to the list of FDA-approved treatments of patients with multiple myeloma who have progressive disease after previous therapies,” said Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research.

“In the clinical trial, there was a 40% reduction in the risk of disease progression or death with this therapy,” he added.

The new approval is based on results from ICARIA-MM, an open-label, randomized phase 3 clinical trial of isatuximab among 307 patients in this setting.

In the trial, at a median follow-up of 11.6 months, median progression-free survival was 11.5 months in the isatuximab-pomalidomide-dexamethasone group versus 6.5 months in the pomalidomide-dexamethasone group (hazard ratio, 0.60; P = .001), as reported last year. Overall response rates were 60.4% for the triplet-treated group versus 35.3% for the doublet-treated group.

The most common side effects for isatuximab included neutropenia, infusion-related reactions, pneumonia, upper respiratory tract infection, diarrhea, anemia, lymphopenia, and thrombocytopenia.

Deaths because of treatment-related adverse events were reported for one patient (less than 1%) in the isatuximab-pomalidomide-dexamethasone group (sepsis) and two patients (1%) in the pomalidomide-dexamethasone group (pneumonia and urinary tract infection).

The drug can also cause serious side effects, including IV infusion-related reactions. In the case of a grade 3 or higher reaction, the drug should be permanently discontinued and health care professionals should institute appropriate medical management.

The FDA notes there have been higher incidences of second primary malignancies observed in a controlled clinical trial of patients with multiple myeloma receiving the drug.

The FDA also highlighted that laboratory test interference may be caused by isatuximab and that blood banks should be informed that patients are receiving the drug. Isatuximab may interfere with, for example, antibody screening for patients who need a blood transfusion. Isatuximab may also interfere with the assays used to monitor M-protein, which may impact the determination of complete response.

This article originally appeared on Medscape.com.

The Food and Drug Administration has approved neratinib (NERLYNX) in combination with capecitabine for use in adults with advanced or metastatic HER2-positive breast cancer who have received at least two prior anti-HER2 based regimens in the metastatic setting.

The recommended dose for neratinib in this population is 240 mg once daily with food on days 1-21 of a 21-day cycle. Neratinib should be given with capecitabine at 750 mg/m² twice daily on days 1-14 until progression or unacceptable toxicity.

The full prescribing information for neratinib is available from the FDA website.

The FDA’s new approval of neratinib is based on results from the NALA trial (NCT01808573). The trial enrolled 621 patients with metastatic HER2-positive breast cancer who had received at least two prior anti-HER2 based regimens in the metastatic setting.

The patients were randomized to neratinib plus capecitabine or lapatinib plus capecitabine and received treatment until progression or unacceptable toxicity.

The objective response rate was 32.8% in the neratinib arm and 26.7% in the lapatinib arm. The median duration of response was 8.5 months and 5.6 months, respectively.

The median progression-free survival was 5.6 months in the neratinib arm and 5.5 months in the lapatinib arm (hazard ratio 0.76; P = .0059). The median overall survival was 21 months and 18.7 months, respectively (HR 0.88; P = .2086).

The most common grade 3/4 adverse events in the neratinib arm were diarrhea, nausea, vomiting, fatigue, and decreased appetite.

jensmith@mdedge.com

The Food and Drug Administration has approved neratinib (NERLYNX) in combination with capecitabine for use in adults with advanced or metastatic HER2-positive breast cancer who have received at least two prior anti-HER2 based regimens in the metastatic setting.

The recommended dose for neratinib in this population is 240 mg once daily with food on days 1-21 of a 21-day cycle. Neratinib should be given with capecitabine at 750 mg/m² twice daily on days 1-14 until progression or unacceptable toxicity.

The full prescribing information for neratinib is available from the FDA website.

The FDA’s new approval of neratinib is based on results from the NALA trial (NCT01808573). The trial enrolled 621 patients with metastatic HER2-positive breast cancer who had received at least two prior anti-HER2 based regimens in the metastatic setting.

The patients were randomized to neratinib plus capecitabine or lapatinib plus capecitabine and received treatment until progression or unacceptable toxicity.

The objective response rate was 32.8% in the neratinib arm and 26.7% in the lapatinib arm. The median duration of response was 8.5 months and 5.6 months, respectively.

The median progression-free survival was 5.6 months in the neratinib arm and 5.5 months in the lapatinib arm (hazard ratio 0.76; P = .0059). The median overall survival was 21 months and 18.7 months, respectively (HR 0.88; P = .2086).

The most common grade 3/4 adverse events in the neratinib arm were diarrhea, nausea, vomiting, fatigue, and decreased appetite.

jensmith@mdedge.com

The Food and Drug Administration has approved neratinib (NERLYNX) in combination with capecitabine for use in adults with advanced or metastatic HER2-positive breast cancer who have received at least two prior anti-HER2 based regimens in the metastatic setting.

The recommended dose for neratinib in this population is 240 mg once daily with food on days 1-21 of a 21-day cycle. Neratinib should be given with capecitabine at 750 mg/m² twice daily on days 1-14 until progression or unacceptable toxicity.

The full prescribing information for neratinib is available from the FDA website.

The FDA’s new approval of neratinib is based on results from the NALA trial (NCT01808573). The trial enrolled 621 patients with metastatic HER2-positive breast cancer who had received at least two prior anti-HER2 based regimens in the metastatic setting.

The patients were randomized to neratinib plus capecitabine or lapatinib plus capecitabine and received treatment until progression or unacceptable toxicity.

The objective response rate was 32.8% in the neratinib arm and 26.7% in the lapatinib arm. The median duration of response was 8.5 months and 5.6 months, respectively.

The median progression-free survival was 5.6 months in the neratinib arm and 5.5 months in the lapatinib arm (hazard ratio 0.76; P = .0059). The median overall survival was 21 months and 18.7 months, respectively (HR 0.88; P = .2086).

The most common grade 3/4 adverse events in the neratinib arm were diarrhea, nausea, vomiting, fatigue, and decreased appetite.

jensmith@mdedge.com

Mr. R, age 30, is referred to you by his primary care physician, who diagnosed him with depression approximately 2 years ago. When he was first diagnosed, Mr. R was prescribed sertraline, 100 mg/d, which was effective. He maintained this response for approximately 1 year, but then the sertraline stopped working. During the last year, Mr. R received citalopram, 20 mg/d, and paroxetine, 20 mg/d. Neither medication was effective for his recurrent depressive symptoms and resulted in significant adverse effects.

Mr. R says that based on his primary care physician’s recommendation, he had undergone pharmacogenomics testing to help guide therapy. He presents the results to you, and you notice that he has the cytochrome P450 (CYP) 2C19 *2/*3 genotype and a CYP2D6*4/*5 genotype. Both are associated with a poor metabolism phenotype. Should you use these findings to determine which medication Mr. R should be treated with next?

While the field of pharmacogenomics is not new, within the last few years this science has begun to transition into clinical practice. A recent meta-analysis found support for using pharmacogenomics testing results in clinical practice.¹ This study included more than 1,700 patients who took part in 5 controlled trials that randomized participants to either pharmacogenetics-guided or unguided (ie, standard) treatment. Each participant was assessed using the Hamilton Depression Rating Scale-17 (HDRS-17) a minimum of 3 times over a minimum of 8 weeks.¹ While the exact inclusion and exclusion criteria for each trial differed, they all defined remission of depression as achieving an HDRS-17 score ≤7. Overall, the authors concluded that based on the random-effects pooled risk ratio, there was a significant association between pharmacogenetics-guided prescribing and remission (relative risk = 1.71, 95% confidence interval [CI], 1.17 to 2.48; P = .005). The results of this meta-analysis are controversial, however, because all 5 studies were industry-funded, and interpretation of the testing results was based on proprietary algorithms.

Experts in the field and professional societies, such as the International Society of Psychiatric Genetics (ISPG), have issued policy statements on genetic testing within psychiatry.^2,3 While the ISPG did not necessarily endorse use of pharmacogenomics in practice, they recommended that clinicians follow good medical practice and stay current on changes to drug labeling and adverse event reports.³ The ISPG also noted that useful but not exhaustive lists of pharmacogenetic tests are maintained by the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the US FDA.³

Laboratory developed vs direct-to-consumer tests

In a previous Savvy Psychopharmacology article,⁴ we had discussed the role of CPIC, but not the role of the FDA. This issue is key because there is a lack of clarity regarding pharmacogenomics tests and whether they are considered Class II devices by the FDA, which would require their review and approval. Until recently, the FDA was fairly quiet regarding pharmacogenomics tests because most of these tests were considered laboratory developed tests, which were regulated under the Clinic Laboratory Improvements Amendments program. The critical distinction of a laboratory developed test is that it is developed and performed in a single laboratory and is offered to patients only when prescribed by a clinician. Due to this distinction, laboratory developed pharmacogenomics tests did not need FDA 510(k) clearance, which is a premarket submission common for medical devices.

Direct-to-consumer pharmacogenomics tests are different in that the FDA has classified these platforms as medical devices; however, they are reviewed by the FDA only if they are being used for moderate- to high-risk medical purposes, or if the results of the testing may have a higher impact on medical care. As part of its review, the FDA examines test accuracy and reliably measures to determine if the measurement is predictive of a certain state of health and supported by what the company claims about the test and how well it works. Additionally, the FDA examines the company-provided descriptive information to ensure that consumers can easily understand it without the help of a clinician.⁵

Conflicting FDA statements

Recently the FDA issued 2 statements—one a policy statement and the other a safety communication—about laboratory developed tests and direct-to-consumer tests. The statements appear to contradict themselves, despite focusing on using pharmacogenomics testing in practice.

Continue to: The FDA's first statement

The FDA’s first statement. On October 31, 2018, the FDA released a policy statement that they had “permitted marketing, with special controls,” of the Personal Genome Service Pharmacogenetic Reports test through 23andMe (a direct-to-consumer genetic testing company) for 33 different variants within specific pharmacogenomic genes (CYP2C19, CYP2C9, CYP3A5, UGT1A1, DPYD, TPMT, SLC01B1, and CYP2D6) that may impact drug metabolism or response.⁶ As part of its review of this Personal Genome Service Pharmacogenetic Reports test, the FDA found that the company-provided data showed that the test is accurate and can correctly identify the 33 specific genetic variants. The FDA review also showed that the testing results were reproducible, and the test instructions and reports could be understood by consumers.

While the specific reports related to this testing are not yet available within 23andMe, this approval allows for greater oversight by the FDA with regard to the pharmacogenomics information provided through this company’s Personal Genome Service Pharmacogenetic Reports test. The FDA noted that this approval was only for adults age >18⁵ and that consumers “should not use the test results to stop or change any medication.”⁶ Further, the FDA stated that the results of the direct-to-consumer test should be confirmed with independent pharmacogenomics testing before making any medical decision. Unfortunately, the FDA did not offer guidance on what would be an appropriate independent pharmacogenomics test, but it did provide a link to a list of FDA-approved nucleic acid–based tests, on which 23andMe’s Personal Genome Service Pharmacogenetic Reports test is included.⁷

The FDA’s second statement. On November 1, 2018, the FDA issued a separate safety communication that cautioned clinicians and patients that most of the current commercially available testing platforms for pharmacogenomics have not been FDA-reviewed, meaning that they may lack clinical evidence supporting their use.⁸ Further, the FDA safety communication stated, “Changing drug treatment based on the results from such a genetic test could lead to inappropriate treatment decisions and potentially serious health consequences for the patient.”⁸

Taken together, these FDA statements appear to support pharmacogenomics testing with approval of the 23andMe’s Personal Genome Service Pharmacogenetic Reports test but warn that the testing results should not be used to make treatment decisions, and that they should be verified. However, the FDA does not offer any guidance on what an appropriate testing platform would be to confirm the results.

What the FDA advises

The FDA has provided some guidance to clinicians and patients regarding next steps for patients who are interested in having pharmacogenomics testing or who have already undergone testing. The FDA’s first point is that both clinicians and patients need to be aware that pharmacogenomics testing is not FDA-reviewed, that patients should discuss the results of their testing with their clinicians, and that they should not stop their medication based on the results of the testing. Additionally, the FDA recommends that clinicians and patients should be aware that any claims made by the testing companies regarding the specific effect of a medication may not be supported by evidence. Furthermore, the FDA strongly recommends that clinicians consult the FDA-approved drug label, or the label of the FDA-cleared or FDA-approved genetic test, for information regarding how genetic information should be used in making treatment decisions. The FDA recommends reviewing the Warning section, as well as the Indications and Usage, Dosage and Administration, or Use in Specific Populations sections of the FDA-approved drug labeling.

Continue to: Unfortunately, this information...

Unfortunately, this information might be difficult to locate due to the lack of consistency regarding where it is placed in the FDA-approved drug labeling. The Pharmacogenomics Knowledgebase (https://www.pharmgkb.org/) can help clinicians quickly identify information regarding medications, their metabolic pathways, CPIC dosing guidelines, and the FDA-approved drug labeling information.⁹ By searching for specific medications within the Pharmacogenomic Knowledge Base, information regarding the FDA-approved drug labeling can be easily found, which is important because currently >120 medications contain pharmacogenomics information in their FDA-approved drug labeling.¹⁰

CASE CONTINUED

Overall Mr. R’s pharmacogenomics testing results indicate that he has 2 genotypes that are associated with poor metabolism phenotypes and could result in reduced metabolism of medications that are metabolized by these CYP enzymes, leading to higher blood levels and an increased risk of adverse effects. The Table¹¹ lists pharmacogenomics information from the FDA-approved drug labeling and from the Pharmacogenomics Knowledgebase for both the medications Mr. R has previously been prescribed and for several potential medications to consider.

It would be prudent to first discuss with Mr. R the FDA’s recent policy statement and safety communication. While you could recommend that he pursue additional pharmacogenomics testing, it is unclear which specific laboratory is available to conduct this confirmatory analysis.

Because Mr. R has had unsuccessful trials of several medications that primarily fall in the selective serotonin reuptake inhibitors class, it might be time to consider a medication from a different class. A quick review of the FDA-approved drug labeling for bupropion indicates that its metabolism is not dependent on CYP2D6 or CYP2C19, which might make this drug a good choice. Furthermore, the metabolism of venlafaxine does not appear to be influenced by CYP2D6 poor metabolism, which might also make it a good choice for Mr. R.

Related Resources

• Gammal RS, Gardner KN, Burghardt KJ. Where to find guidance on using pharmacogenomics in psychiatric practice. Current Psychiatry. 2016;15(9):93-94.
• Clinical Pharmacogenomics Implementation Consortium. What is CPIC? https://www.pharmgkb.org/page/cpic.

Drug Brand Names

Bupropion • Wellbutrin, Zyban
Citalopram • Celexa
Paroxetine • Paxil
Sertraline • Zoloft
Venlafaxine • Effexor

Mr. R, age 30, is referred to you by his primary care physician, who diagnosed him with depression approximately 2 years ago. When he was first diagnosed, Mr. R was prescribed sertraline, 100 mg/d, which was effective. He maintained this response for approximately 1 year, but then the sertraline stopped working. During the last year, Mr. R received citalopram, 20 mg/d, and paroxetine, 20 mg/d. Neither medication was effective for his recurrent depressive symptoms and resulted in significant adverse effects.

Mr. R says that based on his primary care physician’s recommendation, he had undergone pharmacogenomics testing to help guide therapy. He presents the results to you, and you notice that he has the cytochrome P450 (CYP) 2C19 *2/*3 genotype and a CYP2D6*4/*5 genotype. Both are associated with a poor metabolism phenotype. Should you use these findings to determine which medication Mr. R should be treated with next?

While the field of pharmacogenomics is not new, within the last few years this science has begun to transition into clinical practice. A recent meta-analysis found support for using pharmacogenomics testing results in clinical practice.¹ This study included more than 1,700 patients who took part in 5 controlled trials that randomized participants to either pharmacogenetics-guided or unguided (ie, standard) treatment. Each participant was assessed using the Hamilton Depression Rating Scale-17 (HDRS-17) a minimum of 3 times over a minimum of 8 weeks.¹ While the exact inclusion and exclusion criteria for each trial differed, they all defined remission of depression as achieving an HDRS-17 score ≤7. Overall, the authors concluded that based on the random-effects pooled risk ratio, there was a significant association between pharmacogenetics-guided prescribing and remission (relative risk = 1.71, 95% confidence interval [CI], 1.17 to 2.48; P = .005). The results of this meta-analysis are controversial, however, because all 5 studies were industry-funded, and interpretation of the testing results was based on proprietary algorithms.

Experts in the field and professional societies, such as the International Society of Psychiatric Genetics (ISPG), have issued policy statements on genetic testing within psychiatry.^2,3 While the ISPG did not necessarily endorse use of pharmacogenomics in practice, they recommended that clinicians follow good medical practice and stay current on changes to drug labeling and adverse event reports.³ The ISPG also noted that useful but not exhaustive lists of pharmacogenetic tests are maintained by the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the US FDA.³

Laboratory developed vs direct-to-consumer tests

In a previous Savvy Psychopharmacology article,⁴ we had discussed the role of CPIC, but not the role of the FDA. This issue is key because there is a lack of clarity regarding pharmacogenomics tests and whether they are considered Class II devices by the FDA, which would require their review and approval. Until recently, the FDA was fairly quiet regarding pharmacogenomics tests because most of these tests were considered laboratory developed tests, which were regulated under the Clinic Laboratory Improvements Amendments program. The critical distinction of a laboratory developed test is that it is developed and performed in a single laboratory and is offered to patients only when prescribed by a clinician. Due to this distinction, laboratory developed pharmacogenomics tests did not need FDA 510(k) clearance, which is a premarket submission common for medical devices.

Direct-to-consumer pharmacogenomics tests are different in that the FDA has classified these platforms as medical devices; however, they are reviewed by the FDA only if they are being used for moderate- to high-risk medical purposes, or if the results of the testing may have a higher impact on medical care. As part of its review, the FDA examines test accuracy and reliably measures to determine if the measurement is predictive of a certain state of health and supported by what the company claims about the test and how well it works. Additionally, the FDA examines the company-provided descriptive information to ensure that consumers can easily understand it without the help of a clinician.⁵

Conflicting FDA statements

Recently the FDA issued 2 statements—one a policy statement and the other a safety communication—about laboratory developed tests and direct-to-consumer tests. The statements appear to contradict themselves, despite focusing on using pharmacogenomics testing in practice.

Continue to: The FDA's first statement

The FDA’s first statement. On October 31, 2018, the FDA released a policy statement that they had “permitted marketing, with special controls,” of the Personal Genome Service Pharmacogenetic Reports test through 23andMe (a direct-to-consumer genetic testing company) for 33 different variants within specific pharmacogenomic genes (CYP2C19, CYP2C9, CYP3A5, UGT1A1, DPYD, TPMT, SLC01B1, and CYP2D6) that may impact drug metabolism or response.⁶ As part of its review of this Personal Genome Service Pharmacogenetic Reports test, the FDA found that the company-provided data showed that the test is accurate and can correctly identify the 33 specific genetic variants. The FDA review also showed that the testing results were reproducible, and the test instructions and reports could be understood by consumers.

While the specific reports related to this testing are not yet available within 23andMe, this approval allows for greater oversight by the FDA with regard to the pharmacogenomics information provided through this company’s Personal Genome Service Pharmacogenetic Reports test. The FDA noted that this approval was only for adults age >18⁵ and that consumers “should not use the test results to stop or change any medication.”⁶ Further, the FDA stated that the results of the direct-to-consumer test should be confirmed with independent pharmacogenomics testing before making any medical decision. Unfortunately, the FDA did not offer guidance on what would be an appropriate independent pharmacogenomics test, but it did provide a link to a list of FDA-approved nucleic acid–based tests, on which 23andMe’s Personal Genome Service Pharmacogenetic Reports test is included.⁷

The FDA’s second statement. On November 1, 2018, the FDA issued a separate safety communication that cautioned clinicians and patients that most of the current commercially available testing platforms for pharmacogenomics have not been FDA-reviewed, meaning that they may lack clinical evidence supporting their use.⁸ Further, the FDA safety communication stated, “Changing drug treatment based on the results from such a genetic test could lead to inappropriate treatment decisions and potentially serious health consequences for the patient.”⁸

Taken together, these FDA statements appear to support pharmacogenomics testing with approval of the 23andMe’s Personal Genome Service Pharmacogenetic Reports test but warn that the testing results should not be used to make treatment decisions, and that they should be verified. However, the FDA does not offer any guidance on what an appropriate testing platform would be to confirm the results.

What the FDA advises

The FDA has provided some guidance to clinicians and patients regarding next steps for patients who are interested in having pharmacogenomics testing or who have already undergone testing. The FDA’s first point is that both clinicians and patients need to be aware that pharmacogenomics testing is not FDA-reviewed, that patients should discuss the results of their testing with their clinicians, and that they should not stop their medication based on the results of the testing. Additionally, the FDA recommends that clinicians and patients should be aware that any claims made by the testing companies regarding the specific effect of a medication may not be supported by evidence. Furthermore, the FDA strongly recommends that clinicians consult the FDA-approved drug label, or the label of the FDA-cleared or FDA-approved genetic test, for information regarding how genetic information should be used in making treatment decisions. The FDA recommends reviewing the Warning section, as well as the Indications and Usage, Dosage and Administration, or Use in Specific Populations sections of the FDA-approved drug labeling.

Continue to: Unfortunately, this information...

Unfortunately, this information might be difficult to locate due to the lack of consistency regarding where it is placed in the FDA-approved drug labeling. The Pharmacogenomics Knowledgebase (https://www.pharmgkb.org/) can help clinicians quickly identify information regarding medications, their metabolic pathways, CPIC dosing guidelines, and the FDA-approved drug labeling information.⁹ By searching for specific medications within the Pharmacogenomic Knowledge Base, information regarding the FDA-approved drug labeling can be easily found, which is important because currently >120 medications contain pharmacogenomics information in their FDA-approved drug labeling.¹⁰

CASE CONTINUED

Overall Mr. R’s pharmacogenomics testing results indicate that he has 2 genotypes that are associated with poor metabolism phenotypes and could result in reduced metabolism of medications that are metabolized by these CYP enzymes, leading to higher blood levels and an increased risk of adverse effects. The Table¹¹ lists pharmacogenomics information from the FDA-approved drug labeling and from the Pharmacogenomics Knowledgebase for both the medications Mr. R has previously been prescribed and for several potential medications to consider.

It would be prudent to first discuss with Mr. R the FDA’s recent policy statement and safety communication. While you could recommend that he pursue additional pharmacogenomics testing, it is unclear which specific laboratory is available to conduct this confirmatory analysis.

Because Mr. R has had unsuccessful trials of several medications that primarily fall in the selective serotonin reuptake inhibitors class, it might be time to consider a medication from a different class. A quick review of the FDA-approved drug labeling for bupropion indicates that its metabolism is not dependent on CYP2D6 or CYP2C19, which might make this drug a good choice. Furthermore, the metabolism of venlafaxine does not appear to be influenced by CYP2D6 poor metabolism, which might also make it a good choice for Mr. R.

Related Resources

• Gammal RS, Gardner KN, Burghardt KJ. Where to find guidance on using pharmacogenomics in psychiatric practice. Current Psychiatry. 2016;15(9):93-94.
• Clinical Pharmacogenomics Implementation Consortium. What is CPIC? https://www.pharmgkb.org/page/cpic.

Drug Brand Names

Bupropion • Wellbutrin, Zyban
Citalopram • Celexa
Paroxetine • Paxil
Sertraline • Zoloft
Venlafaxine • Effexor

Mr. R, age 30, is referred to you by his primary care physician, who diagnosed him with depression approximately 2 years ago. When he was first diagnosed, Mr. R was prescribed sertraline, 100 mg/d, which was effective. He maintained this response for approximately 1 year, but then the sertraline stopped working. During the last year, Mr. R received citalopram, 20 mg/d, and paroxetine, 20 mg/d. Neither medication was effective for his recurrent depressive symptoms and resulted in significant adverse effects.

Mr. R says that based on his primary care physician’s recommendation, he had undergone pharmacogenomics testing to help guide therapy. He presents the results to you, and you notice that he has the cytochrome P450 (CYP) 2C19 *2/*3 genotype and a CYP2D6*4/*5 genotype. Both are associated with a poor metabolism phenotype. Should you use these findings to determine which medication Mr. R should be treated with next?

While the field of pharmacogenomics is not new, within the last few years this science has begun to transition into clinical practice. A recent meta-analysis found support for using pharmacogenomics testing results in clinical practice.¹ This study included more than 1,700 patients who took part in 5 controlled trials that randomized participants to either pharmacogenetics-guided or unguided (ie, standard) treatment. Each participant was assessed using the Hamilton Depression Rating Scale-17 (HDRS-17) a minimum of 3 times over a minimum of 8 weeks.¹ While the exact inclusion and exclusion criteria for each trial differed, they all defined remission of depression as achieving an HDRS-17 score ≤7. Overall, the authors concluded that based on the random-effects pooled risk ratio, there was a significant association between pharmacogenetics-guided prescribing and remission (relative risk = 1.71, 95% confidence interval [CI], 1.17 to 2.48; P = .005). The results of this meta-analysis are controversial, however, because all 5 studies were industry-funded, and interpretation of the testing results was based on proprietary algorithms.

Experts in the field and professional societies, such as the International Society of Psychiatric Genetics (ISPG), have issued policy statements on genetic testing within psychiatry.^2,3 While the ISPG did not necessarily endorse use of pharmacogenomics in practice, they recommended that clinicians follow good medical practice and stay current on changes to drug labeling and adverse event reports.³ The ISPG also noted that useful but not exhaustive lists of pharmacogenetic tests are maintained by the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the US FDA.³

Laboratory developed vs direct-to-consumer tests

In a previous Savvy Psychopharmacology article,⁴ we had discussed the role of CPIC, but not the role of the FDA. This issue is key because there is a lack of clarity regarding pharmacogenomics tests and whether they are considered Class II devices by the FDA, which would require their review and approval. Until recently, the FDA was fairly quiet regarding pharmacogenomics tests because most of these tests were considered laboratory developed tests, which were regulated under the Clinic Laboratory Improvements Amendments program. The critical distinction of a laboratory developed test is that it is developed and performed in a single laboratory and is offered to patients only when prescribed by a clinician. Due to this distinction, laboratory developed pharmacogenomics tests did not need FDA 510(k) clearance, which is a premarket submission common for medical devices.

Direct-to-consumer pharmacogenomics tests are different in that the FDA has classified these platforms as medical devices; however, they are reviewed by the FDA only if they are being used for moderate- to high-risk medical purposes, or if the results of the testing may have a higher impact on medical care. As part of its review, the FDA examines test accuracy and reliably measures to determine if the measurement is predictive of a certain state of health and supported by what the company claims about the test and how well it works. Additionally, the FDA examines the company-provided descriptive information to ensure that consumers can easily understand it without the help of a clinician.⁵

Conflicting FDA statements

Recently the FDA issued 2 statements—one a policy statement and the other a safety communication—about laboratory developed tests and direct-to-consumer tests. The statements appear to contradict themselves, despite focusing on using pharmacogenomics testing in practice.

Continue to: The FDA's first statement

The FDA’s first statement. On October 31, 2018, the FDA released a policy statement that they had “permitted marketing, with special controls,” of the Personal Genome Service Pharmacogenetic Reports test through 23andMe (a direct-to-consumer genetic testing company) for 33 different variants within specific pharmacogenomic genes (CYP2C19, CYP2C9, CYP3A5, UGT1A1, DPYD, TPMT, SLC01B1, and CYP2D6) that may impact drug metabolism or response.⁶ As part of its review of this Personal Genome Service Pharmacogenetic Reports test, the FDA found that the company-provided data showed that the test is accurate and can correctly identify the 33 specific genetic variants. The FDA review also showed that the testing results were reproducible, and the test instructions and reports could be understood by consumers.

While the specific reports related to this testing are not yet available within 23andMe, this approval allows for greater oversight by the FDA with regard to the pharmacogenomics information provided through this company’s Personal Genome Service Pharmacogenetic Reports test. The FDA noted that this approval was only for adults age >18⁵ and that consumers “should not use the test results to stop or change any medication.”⁶ Further, the FDA stated that the results of the direct-to-consumer test should be confirmed with independent pharmacogenomics testing before making any medical decision. Unfortunately, the FDA did not offer guidance on what would be an appropriate independent pharmacogenomics test, but it did provide a link to a list of FDA-approved nucleic acid–based tests, on which 23andMe’s Personal Genome Service Pharmacogenetic Reports test is included.⁷

The FDA’s second statement. On November 1, 2018, the FDA issued a separate safety communication that cautioned clinicians and patients that most of the current commercially available testing platforms for pharmacogenomics have not been FDA-reviewed, meaning that they may lack clinical evidence supporting their use.⁸ Further, the FDA safety communication stated, “Changing drug treatment based on the results from such a genetic test could lead to inappropriate treatment decisions and potentially serious health consequences for the patient.”⁸

Taken together, these FDA statements appear to support pharmacogenomics testing with approval of the 23andMe’s Personal Genome Service Pharmacogenetic Reports test but warn that the testing results should not be used to make treatment decisions, and that they should be verified. However, the FDA does not offer any guidance on what an appropriate testing platform would be to confirm the results.

What the FDA advises

The FDA has provided some guidance to clinicians and patients regarding next steps for patients who are interested in having pharmacogenomics testing or who have already undergone testing. The FDA’s first point is that both clinicians and patients need to be aware that pharmacogenomics testing is not FDA-reviewed, that patients should discuss the results of their testing with their clinicians, and that they should not stop their medication based on the results of the testing. Additionally, the FDA recommends that clinicians and patients should be aware that any claims made by the testing companies regarding the specific effect of a medication may not be supported by evidence. Furthermore, the FDA strongly recommends that clinicians consult the FDA-approved drug label, or the label of the FDA-cleared or FDA-approved genetic test, for information regarding how genetic information should be used in making treatment decisions. The FDA recommends reviewing the Warning section, as well as the Indications and Usage, Dosage and Administration, or Use in Specific Populations sections of the FDA-approved drug labeling.

Continue to: Unfortunately, this information...

Unfortunately, this information might be difficult to locate due to the lack of consistency regarding where it is placed in the FDA-approved drug labeling. The Pharmacogenomics Knowledgebase (https://www.pharmgkb.org/) can help clinicians quickly identify information regarding medications, their metabolic pathways, CPIC dosing guidelines, and the FDA-approved drug labeling information.⁹ By searching for specific medications within the Pharmacogenomic Knowledge Base, information regarding the FDA-approved drug labeling can be easily found, which is important because currently >120 medications contain pharmacogenomics information in their FDA-approved drug labeling.¹⁰

CASE CONTINUED

Overall Mr. R’s pharmacogenomics testing results indicate that he has 2 genotypes that are associated with poor metabolism phenotypes and could result in reduced metabolism of medications that are metabolized by these CYP enzymes, leading to higher blood levels and an increased risk of adverse effects. The Table¹¹ lists pharmacogenomics information from the FDA-approved drug labeling and from the Pharmacogenomics Knowledgebase for both the medications Mr. R has previously been prescribed and for several potential medications to consider.

It would be prudent to first discuss with Mr. R the FDA’s recent policy statement and safety communication. While you could recommend that he pursue additional pharmacogenomics testing, it is unclear which specific laboratory is available to conduct this confirmatory analysis.

Because Mr. R has had unsuccessful trials of several medications that primarily fall in the selective serotonin reuptake inhibitors class, it might be time to consider a medication from a different class. A quick review of the FDA-approved drug labeling for bupropion indicates that its metabolism is not dependent on CYP2D6 or CYP2C19, which might make this drug a good choice. Furthermore, the metabolism of venlafaxine does not appear to be influenced by CYP2D6 poor metabolism, which might also make it a good choice for Mr. R.

Related Resources

• Gammal RS, Gardner KN, Burghardt KJ. Where to find guidance on using pharmacogenomics in psychiatric practice. Current Psychiatry. 2016;15(9):93-94.
• Clinical Pharmacogenomics Implementation Consortium. What is CPIC? https://www.pharmgkb.org/page/cpic.

Drug Brand Names

Bupropion • Wellbutrin, Zyban
Citalopram • Celexa
Paroxetine • Paxil
Sertraline • Zoloft
Venlafaxine • Effexor

The FDA’s MedWatch program safety labeling changes for boxed warnings are compiled quarterly for drugs and therapeutic biologics where important changes have been made to the safety information. These and other label changes are searchable in the Drug Safety Labeling Changes (SLC) database, where data are available to the public in downloadable and searchable formats. Boxed warnings are ordinarily used to highlight either adverse reactions so serious in proportion to the potential benefi t from the drug that it is essential that it be considered in assessing the risks and benefi ts of using the drug; or serious adverse reactions that can be prevented/reduced in frequency or severity by appropriate use of the drug; or FDA approved the drug with restrictions to ensure safe use because FDA concluded that the drug can be safely used only if distribution or use is restricted. For complete FDA Drug Safety Labeling changes, please visit http://www.accessdata.fda.gov/scripts/cder/safetylabelingchanges.

DESOGEN (DESOGESTREL AND ETHINYL ESTRADIOL TABLETS

• Edited boxed warning, June 2018

WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS

Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive (COC) use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, COCs are contraindicated in women who are over 35 years of age, and smoke.

TRIZIVIR (ABACAVIR, LAMIVUDINE, AND ZIDOVUDINE TABLETS)

• Edited boxed warning, April 2018

Lactic Acidosis and Severe Hepatomegaly with Steatosis: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues, including abacavir, lamivudine, and zidovudine (components of TRIZIVIR). Discontinue TRIZIVIR if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur [see Warnings and Precautions (5.4)].

ERBITUX (CETUXIMAB)

• Edited boxed warning, June 2018

WARNING: INFUSION REACTIONS and CARDIOPULMONARY ARREST

Infusion Reactions: ERBITUX can cause serious and fatal infusion reactions [see Warnings and Precautions (5.1), Adverse Reactions (6)]. Immediately interrupt and permanently discontinue ERBITUX for serious infusion reactions [see Dosage and Administration (2.4)].

Cardiopulmonary Arrest: Cardiopulmonary arrest or sudden death occurred in patients with squamous cell carcinoma of the head and neck receiving ERBITUX with radiation therapy or a cetuximab product with platinum-based therapy and fluorouracil. Monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after ERBITUX administration [see Warnings and Precautions (5.2, 5.6)].

AUSTEDO (DEUTETRABENAZINE)

• Edited boxed warning, June 2018

WARNING: DEPRESSION AND SUICIDALITY IN PATIENTS WITH HUNTINGTON’S DISEASE

AUSTEDO can increase the risk of depression …

EXJADE (DEFERASIROX)

• Edited boxed warning, May 2018

Renal Failure: EXJADE can cause acute renal failure and death, particularly in patients with comorbidities and those who are in the advanced stages of their hematologic disorders. Evaluate baseline renal function prior to starting or increasing Exjade dosing in all patients. Exjade is contraindicated in adult and pediatric patients with eGFR less than 40 mL/min/1.73 m2. Measure serum creatinine in duplicate prior to initiation of therapy. Monitor renal function at least monthly. For patients with baseline renal impairment or increased risk of acute renal failure, monitor renal function weekly for the first month, then at least monthly. Reduce the starting dose in patients with pre-existing renal disease. During therapy, increase the frequency of monitoring and modify the dose for patients with an increased risk of renal impairment, including use of concomitant nephrotoxic drugs, and pediatric patients with volume depletion or overchelation.

TUXARIN ER (CODEINE PHOSPHATE AND CHLORPHENIRAMINE MALEATE)

• Edited boxed warning, June 2018

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; ULTRA-RAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN; MEDICATION ERRORS; INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES; CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; NEONATAL OPIOID WITHDRAWAL SYNDROME.

Addiction, Abuse, and Misuse: TUXARIN ER exposes patients and other users to the risks of opioid addiction, abuse, and misuse,
which can lead to overdose and death. Reserve TUXARIN ER for use in adult patients for whom the benefits of cough suppression
are expected to outweigh the risks, and in whom an adequate assessment of the etiology of the cough has been made. Assess each
patient’s risk prior to prescribing TUXARIN ER, prescribe TUXARIN ER for the shortest duration that is consistent with individual patient
treatment goals, monitor all patients regularly for the development of addition or abuse, and refill only after reevaluation of the need for continued treatment. [see Warnings and Precautions (5.1)]

Life-Threatening Respiratory Depression: Serious, life-threatening, or fatal respiratory depression may occur with use of TUXARIN ER.
Monitor for respiratory depression, especially during initiation of TUXARIN ER therapy or when used in patients at higher risk [see Warnings and Precautions (5.2)].

Accidental Ingestion: Accidental ingestion of even one dose of TUXARIN ER, especially by children, can result in a fatal overdose of codeine [see Warnings and Precautions (5.2)].

Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children: Life threatening
respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a
CYP2D6 polymorphism. [see Warnings and Precautions (5.3)]. TUXARIN ER is contraindicated in children younger than 12 years of age and
in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Contraindications (4)]. Avoid the use of TUXARIN ER in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine. [see Warnings and Precautions (5.1)].

Interactions with Drugs Affecting Cytochrome P450 Isoenzymes: The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with codeine are complex, requiring careful consideration of the effects on the parent drug, codeine, and the active metabolite, morphine. Avoid the use of TUXARIN ER in patients who are taking a CYP3A4 inhibitor, CYP3A4 inducer, or 2D6 inhibitor [see Warnings and Precautions (5.8), Drug Interactions (7.1,7.2, 7.4)]

Risks from Concomitant Use with Benzodiazepines, CNS Depressants: Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Avoid use of TUXARIN ER in patients taking benzodiazepines, other CNS depressants, or alcohol. [see Warning and Precautions (5.9) Drug Interactions (7.5)].

Neonatal Opioid Withdrawal Syndrome: TUXARIN ER is not recommended for use in pregnant women [see Use in Specific Populations
(8.1)]. Prolonged use of TUXARIN ER during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If TUXARIN ER is used for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Warnings and Precautions (5.15)].

PROGRAF (TACROLIMUS)

• Edited boxed warning, May 2018

Increased risk for developing serious infections and malignancies with PROGRAF or other immunosuppressants that may lead to hospitalization or death [(see Warnings and Precautions 5.1,5.2)].

SAMSCA (TOLVAPTAN)

• Edited boxed warning, April 2018

Addition of the following:

WARNING: NOT FOR USE FOR AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE (ADPKD)

Because of the risk of hepatoxicity, tolvaptan should not be used for ADPKD outside of the FDA-approved REMS

GLUCOPHAGE/GLUCOPHAGE XR (METFORMIN HYDROCHLORIDE)

• Edited boxed warning, May 2018

PLR conversion; Lactic Acidosis warning is highlighted as boxed warning.

The FDA’s MedWatch program safety labeling changes for boxed warnings are compiled quarterly for drugs and therapeutic biologics where important changes have been made to the safety information. These and other label changes are searchable in the Drug Safety Labeling Changes (SLC) database, where data are available to the public in downloadable and searchable formats. Boxed warnings are ordinarily used to highlight either adverse reactions so serious in proportion to the potential benefi t from the drug that it is essential that it be considered in assessing the risks and benefi ts of using the drug; or serious adverse reactions that can be prevented/reduced in frequency or severity by appropriate use of the drug; or FDA approved the drug with restrictions to ensure safe use because FDA concluded that the drug can be safely used only if distribution or use is restricted. For complete FDA Drug Safety Labeling changes, please visit http://www.accessdata.fda.gov/scripts/cder/safetylabelingchanges.

DESOGEN (DESOGESTREL AND ETHINYL ESTRADIOL TABLETS

• Edited boxed warning, June 2018

WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS

Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive (COC) use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, COCs are contraindicated in women who are over 35 years of age, and smoke.

TRIZIVIR (ABACAVIR, LAMIVUDINE, AND ZIDOVUDINE TABLETS)

• Edited boxed warning, April 2018

Lactic Acidosis and Severe Hepatomegaly with Steatosis: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues, including abacavir, lamivudine, and zidovudine (components of TRIZIVIR). Discontinue TRIZIVIR if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur [see Warnings and Precautions (5.4)].

ERBITUX (CETUXIMAB)

• Edited boxed warning, June 2018

WARNING: INFUSION REACTIONS and CARDIOPULMONARY ARREST

Infusion Reactions: ERBITUX can cause serious and fatal infusion reactions [see Warnings and Precautions (5.1), Adverse Reactions (6)]. Immediately interrupt and permanently discontinue ERBITUX for serious infusion reactions [see Dosage and Administration (2.4)].

Cardiopulmonary Arrest: Cardiopulmonary arrest or sudden death occurred in patients with squamous cell carcinoma of the head and neck receiving ERBITUX with radiation therapy or a cetuximab product with platinum-based therapy and fluorouracil. Monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after ERBITUX administration [see Warnings and Precautions (5.2, 5.6)].

AUSTEDO (DEUTETRABENAZINE)

• Edited boxed warning, June 2018

WARNING: DEPRESSION AND SUICIDALITY IN PATIENTS WITH HUNTINGTON’S DISEASE

AUSTEDO can increase the risk of depression …

EXJADE (DEFERASIROX)

• Edited boxed warning, May 2018

Renal Failure: EXJADE can cause acute renal failure and death, particularly in patients with comorbidities and those who are in the advanced stages of their hematologic disorders. Evaluate baseline renal function prior to starting or increasing Exjade dosing in all patients. Exjade is contraindicated in adult and pediatric patients with eGFR less than 40 mL/min/1.73 m2. Measure serum creatinine in duplicate prior to initiation of therapy. Monitor renal function at least monthly. For patients with baseline renal impairment or increased risk of acute renal failure, monitor renal function weekly for the first month, then at least monthly. Reduce the starting dose in patients with pre-existing renal disease. During therapy, increase the frequency of monitoring and modify the dose for patients with an increased risk of renal impairment, including use of concomitant nephrotoxic drugs, and pediatric patients with volume depletion or overchelation.

TUXARIN ER (CODEINE PHOSPHATE AND CHLORPHENIRAMINE MALEATE)

• Edited boxed warning, June 2018

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; ULTRA-RAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN; MEDICATION ERRORS; INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES; CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; NEONATAL OPIOID WITHDRAWAL SYNDROME.

Addiction, Abuse, and Misuse: TUXARIN ER exposes patients and other users to the risks of opioid addiction, abuse, and misuse,
which can lead to overdose and death. Reserve TUXARIN ER for use in adult patients for whom the benefits of cough suppression
are expected to outweigh the risks, and in whom an adequate assessment of the etiology of the cough has been made. Assess each
patient’s risk prior to prescribing TUXARIN ER, prescribe TUXARIN ER for the shortest duration that is consistent with individual patient
treatment goals, monitor all patients regularly for the development of addition or abuse, and refill only after reevaluation of the need for continued treatment. [see Warnings and Precautions (5.1)]

Life-Threatening Respiratory Depression: Serious, life-threatening, or fatal respiratory depression may occur with use of TUXARIN ER.
Monitor for respiratory depression, especially during initiation of TUXARIN ER therapy or when used in patients at higher risk [see Warnings and Precautions (5.2)].

Accidental Ingestion: Accidental ingestion of even one dose of TUXARIN ER, especially by children, can result in a fatal overdose of codeine [see Warnings and Precautions (5.2)].

Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children: Life threatening
respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a
CYP2D6 polymorphism. [see Warnings and Precautions (5.3)]. TUXARIN ER is contraindicated in children younger than 12 years of age and
in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Contraindications (4)]. Avoid the use of TUXARIN ER in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine. [see Warnings and Precautions (5.1)].

Interactions with Drugs Affecting Cytochrome P450 Isoenzymes: The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with codeine are complex, requiring careful consideration of the effects on the parent drug, codeine, and the active metabolite, morphine. Avoid the use of TUXARIN ER in patients who are taking a CYP3A4 inhibitor, CYP3A4 inducer, or 2D6 inhibitor [see Warnings and Precautions (5.8), Drug Interactions (7.1,7.2, 7.4)]

Risks from Concomitant Use with Benzodiazepines, CNS Depressants: Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Avoid use of TUXARIN ER in patients taking benzodiazepines, other CNS depressants, or alcohol. [see Warning and Precautions (5.9) Drug Interactions (7.5)].

Neonatal Opioid Withdrawal Syndrome: TUXARIN ER is not recommended for use in pregnant women [see Use in Specific Populations
(8.1)]. Prolonged use of TUXARIN ER during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If TUXARIN ER is used for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Warnings and Precautions (5.15)].

PROGRAF (TACROLIMUS)

• Edited boxed warning, May 2018

Increased risk for developing serious infections and malignancies with PROGRAF or other immunosuppressants that may lead to hospitalization or death [(see Warnings and Precautions 5.1,5.2)].

SAMSCA (TOLVAPTAN)

• Edited boxed warning, April 2018

Addition of the following:

WARNING: NOT FOR USE FOR AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE (ADPKD)

Because of the risk of hepatoxicity, tolvaptan should not be used for ADPKD outside of the FDA-approved REMS

GLUCOPHAGE/GLUCOPHAGE XR (METFORMIN HYDROCHLORIDE)

• Edited boxed warning, May 2018

PLR conversion; Lactic Acidosis warning is highlighted as boxed warning.

The FDA’s MedWatch program safety labeling changes for boxed warnings are compiled quarterly for drugs and therapeutic biologics where important changes have been made to the safety information. These and other label changes are searchable in the Drug Safety Labeling Changes (SLC) database, where data are available to the public in downloadable and searchable formats. Boxed warnings are ordinarily used to highlight either adverse reactions so serious in proportion to the potential benefi t from the drug that it is essential that it be considered in assessing the risks and benefi ts of using the drug; or serious adverse reactions that can be prevented/reduced in frequency or severity by appropriate use of the drug; or FDA approved the drug with restrictions to ensure safe use because FDA concluded that the drug can be safely used only if distribution or use is restricted. For complete FDA Drug Safety Labeling changes, please visit http://www.accessdata.fda.gov/scripts/cder/safetylabelingchanges.

DESOGEN (DESOGESTREL AND ETHINYL ESTRADIOL TABLETS

• Edited boxed warning, June 2018

WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS

Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive (COC) use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, COCs are contraindicated in women who are over 35 years of age, and smoke.

TRIZIVIR (ABACAVIR, LAMIVUDINE, AND ZIDOVUDINE TABLETS)

• Edited boxed warning, April 2018

Lactic Acidosis and Severe Hepatomegaly with Steatosis: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues, including abacavir, lamivudine, and zidovudine (components of TRIZIVIR). Discontinue TRIZIVIR if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur [see Warnings and Precautions (5.4)].

ERBITUX (CETUXIMAB)

• Edited boxed warning, June 2018

WARNING: INFUSION REACTIONS and CARDIOPULMONARY ARREST

Infusion Reactions: ERBITUX can cause serious and fatal infusion reactions [see Warnings and Precautions (5.1), Adverse Reactions (6)]. Immediately interrupt and permanently discontinue ERBITUX for serious infusion reactions [see Dosage and Administration (2.4)].

Cardiopulmonary Arrest: Cardiopulmonary arrest or sudden death occurred in patients with squamous cell carcinoma of the head and neck receiving ERBITUX with radiation therapy or a cetuximab product with platinum-based therapy and fluorouracil. Monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after ERBITUX administration [see Warnings and Precautions (5.2, 5.6)].

AUSTEDO (DEUTETRABENAZINE)

• Edited boxed warning, June 2018

WARNING: DEPRESSION AND SUICIDALITY IN PATIENTS WITH HUNTINGTON’S DISEASE

AUSTEDO can increase the risk of depression …

EXJADE (DEFERASIROX)

• Edited boxed warning, May 2018

Renal Failure: EXJADE can cause acute renal failure and death, particularly in patients with comorbidities and those who are in the advanced stages of their hematologic disorders. Evaluate baseline renal function prior to starting or increasing Exjade dosing in all patients. Exjade is contraindicated in adult and pediatric patients with eGFR less than 40 mL/min/1.73 m2. Measure serum creatinine in duplicate prior to initiation of therapy. Monitor renal function at least monthly. For patients with baseline renal impairment or increased risk of acute renal failure, monitor renal function weekly for the first month, then at least monthly. Reduce the starting dose in patients with pre-existing renal disease. During therapy, increase the frequency of monitoring and modify the dose for patients with an increased risk of renal impairment, including use of concomitant nephrotoxic drugs, and pediatric patients with volume depletion or overchelation.

TUXARIN ER (CODEINE PHOSPHATE AND CHLORPHENIRAMINE MALEATE)

• Edited boxed warning, June 2018

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; ULTRA-RAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN; MEDICATION ERRORS; INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES; CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; NEONATAL OPIOID WITHDRAWAL SYNDROME.

Addiction, Abuse, and Misuse: TUXARIN ER exposes patients and other users to the risks of opioid addiction, abuse, and misuse,
which can lead to overdose and death. Reserve TUXARIN ER for use in adult patients for whom the benefits of cough suppression
are expected to outweigh the risks, and in whom an adequate assessment of the etiology of the cough has been made. Assess each
patient’s risk prior to prescribing TUXARIN ER, prescribe TUXARIN ER for the shortest duration that is consistent with individual patient
treatment goals, monitor all patients regularly for the development of addition or abuse, and refill only after reevaluation of the need for continued treatment. [see Warnings and Precautions (5.1)]

Life-Threatening Respiratory Depression: Serious, life-threatening, or fatal respiratory depression may occur with use of TUXARIN ER.
Monitor for respiratory depression, especially during initiation of TUXARIN ER therapy or when used in patients at higher risk [see Warnings and Precautions (5.2)].

Accidental Ingestion: Accidental ingestion of even one dose of TUXARIN ER, especially by children, can result in a fatal overdose of codeine [see Warnings and Precautions (5.2)].

Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children: Life threatening
respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a
CYP2D6 polymorphism. [see Warnings and Precautions (5.3)]. TUXARIN ER is contraindicated in children younger than 12 years of age and
in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Contraindications (4)]. Avoid the use of TUXARIN ER in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine. [see Warnings and Precautions (5.1)].

Interactions with Drugs Affecting Cytochrome P450 Isoenzymes: The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with codeine are complex, requiring careful consideration of the effects on the parent drug, codeine, and the active metabolite, morphine. Avoid the use of TUXARIN ER in patients who are taking a CYP3A4 inhibitor, CYP3A4 inducer, or 2D6 inhibitor [see Warnings and Precautions (5.8), Drug Interactions (7.1,7.2, 7.4)]

Risks from Concomitant Use with Benzodiazepines, CNS Depressants: Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Avoid use of TUXARIN ER in patients taking benzodiazepines, other CNS depressants, or alcohol. [see Warning and Precautions (5.9) Drug Interactions (7.5)].

Neonatal Opioid Withdrawal Syndrome: TUXARIN ER is not recommended for use in pregnant women [see Use in Specific Populations
(8.1)]. Prolonged use of TUXARIN ER during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If TUXARIN ER is used for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Warnings and Precautions (5.15)].

PROGRAF (TACROLIMUS)

• Edited boxed warning, May 2018

Increased risk for developing serious infections and malignancies with PROGRAF or other immunosuppressants that may lead to hospitalization or death [(see Warnings and Precautions 5.1,5.2)].

SAMSCA (TOLVAPTAN)

• Edited boxed warning, April 2018

Addition of the following:

WARNING: NOT FOR USE FOR AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE (ADPKD)

Because of the risk of hepatoxicity, tolvaptan should not be used for ADPKD outside of the FDA-approved REMS

GLUCOPHAGE/GLUCOPHAGE XR (METFORMIN HYDROCHLORIDE)

• Edited boxed warning, May 2018

PLR conversion; Lactic Acidosis warning is highlighted as boxed warning.

The FDA’s MedWatch program safety labeling changes for boxed warnings are compiled quarterly for drugs and therapeutic biologics where important changes have been made to the safety information. These and other label changes are searchable in the Drug Safety Labeling Changes (SLC) database, where data are available to the public in downloadable and searchable formats. Boxed warnings are ordinarily used to highlight either adverse reactions so serious in proportion to the potential benefi t from the drug that it is essential that it be considered in assessing the risks and benefi ts of using the drug; or serious adverse reactions that can be prevented/reduced in frequency or severity by appropriate use of the drug; or FDA approved the drug with restrictions to ensure safe use because FDA concluded that the drug can be safely used only if distribution or use is restricted. For complete FDA Drug Safety Labeling changes, please visit http://www.accessdata.fda.gov/scripts/cder/safetylabelingchanges.

VIDEX AND VIDEX EC (DIDANOSINE):

• Edited boxed warning, January 2018

WARNING: PANCREATITIS, LACTIC ACIDOSIS and HEPATOMEGALY with STEATOSIS

Coadministration of VIDEX or VIDEX EC and stavudine is contraindicated because of increased risk of serious and/or life-threatening events. Suspend treatment if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occurs.

ZYDELIG (IDELALISIB):

• Edited boxed warning, January 2018

WARNING: FATAL AND SERIOUS TOXICITIES: HEPATIC, SEVERE DIARRHEA, COLITIS, PNEUMONITIS, INFECTIONS, and INTESTINAL PERFORATION

Fatal and/or serious hepatotoxicity occurred in 16% to 18% of Zydelig-treated patients…

Fatal and/or serious and severe diarrhea or colitis occurred in 14% to 20% of Zydelig-treated patients…

Fatal and/or serious infections occurred in 21% to 48% of Zydelig-treated patients…

AQUAMEPHYTON (PHYTONADIONE):

• Edited boxed warning, March 2018

WARNING: HYPERSENSITIVITY REACTIONS WITH INTRAVENOUS AND INTRAMUSCULAR USE

Fatal hypersensitivity reactions, including anaphylaxis, have occurred during and immediately after INTRAVENOUS and INTRAMUSCULAR injection of Aqua-MEPHYTON. Reactions have occurred despite dilution to avoid rapid infusion and upon first dose. Avoid the intravenous and intramuscular routes of administration unless the subcutaneous route is not feasible and the serious risk is justified.

FERAHEME (FERUMOXYTOL):

• Edited boxed warning, February 2018

WARNING: RISK FOR SERIOUS HYPERSENSITIVITY/ANAPHYLAXIS REACTIONS

Fatal and serious hypersensitivity reactions including anaphylaxis have occurred in patients receiving feraheme. Initial symptoms may
include hypotension, syncope, unresponsiveness, cardiac/cardiorespiratory arrest.

Only administer feraheme as an intravenous infusion over at least 15 minutes and only when personnel and therapies are immediately available for the treatment of anaphylaxis and other hypersensitivity reactions.

METHADONE HYDROCHLORIDE, METHADOSE (METHADONE HYDROCHLORIDE):

• Edited boxed warning, February 2018

RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS

Concomitant use with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, is a risk factor for respiratory depression and death.

Reserve concomitant prescribing of benzodiazepines or other CNS depressants for use in patients for whom alternatives to benzodiazepines or other CNS depressants are inadequate.

Follow patients for signs and symptoms of respiratory depression and sedation. If the patient is visibly sedated, evaluate the cause of sedation, and consider delaying or omitting daily methadone dosing.

DOLOPHINE HYDROCHLORIDE (METHADONE HYDROCHLORIDE):

• Edited boxed warning, February 2018

RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS

Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death.

Reserve concomitant prescribing of DOLOPHINE Tablets and benzodiazepines or other CNS depressants for use in patients for whom alternatives to benzodiazepines or other CNS depressants are inadequate.

Limit dosages and durations to the minimum required for patients being treated for pain.

Follow patients for signs and symptoms of respiratory depression and sedation. If the patient is visibly sedated, evaluate the cause of sedation, and consider delaying or omitting the daily methadone dose.

PARNATE (TRANYLCYPROMINE SULFATE):

• Edited boxed warning, January 2018

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS AND HYPERTENSIVE CRISIS WITH SIGNIFICANT TYRAMINE USE

SUICIDAL THOUGHTS AND BEHAVIORS
Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors. PARNATE is not approved for use in pediatric patients.

HYPERTENSIVE CRISIS WITH SIGNIFICANT TYRAMINE USE
Excessive consumption of foods or beverages with significant tyramine content or the use of certain drugs with PARNATE or after PARNATE discontinuation can precipitate hypertensive crisis. Monitor blood pressure and allow for medication-free intervals between administration of PARNATE and interacting drugs. Instruct patients to avoid ingestion of foods and beverages with high tyramine content.

OCALIVA (OBETICHOLIC ACID):

• New boxed warning/Newly added section, February 2018

WARNING: HEPATIC DECOMPENSATION AND FAILURE IN INCORRECTLY DOSED PBC PATIENTS WITH CHILD-PUGH CLASS B OR C OR DECOMPENSATED CIRRHOSIS

In postmarketing reports, hepatic decompensation and failure, in some cases fatal, have been reported in patients with primary biliary cholangitis (PBC) with decompensated cirrhosis or Child-Pugh Class B or C hepatic impairment when OCALIVA was dosed more frequently than recommended.

The recommended starting dosage of OCALIVA is 5 mg once weekly for patients with Child-Pugh Class B or C hepatic impairment or a prior decompensation event.

The FDA’s MedWatch program safety labeling changes for boxed warnings are compiled quarterly for drugs and therapeutic biologics where important changes have been made to the safety information. These and other label changes are searchable in the Drug Safety Labeling Changes (SLC) database, where data are available to the public in downloadable and searchable formats. Boxed warnings are ordinarily used to highlight either adverse reactions so serious in proportion to the potential benefi t from the drug that it is essential that it be considered in assessing the risks and benefi ts of using the drug; or serious adverse reactions that can be prevented/reduced in frequency or severity by appropriate use of the drug; or FDA approved the drug with restrictions to ensure safe use because FDA concluded that the drug can be safely used only if distribution or use is restricted. For complete FDA Drug Safety Labeling changes, please visit http://www.accessdata.fda.gov/scripts/cder/safetylabelingchanges.

VIDEX AND VIDEX EC (DIDANOSINE):

• Edited boxed warning, January 2018

WARNING: PANCREATITIS, LACTIC ACIDOSIS and HEPATOMEGALY with STEATOSIS

Coadministration of VIDEX or VIDEX EC and stavudine is contraindicated because of increased risk of serious and/or life-threatening events. Suspend treatment if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occurs.

ZYDELIG (IDELALISIB):

• Edited boxed warning, January 2018

WARNING: FATAL AND SERIOUS TOXICITIES: HEPATIC, SEVERE DIARRHEA, COLITIS, PNEUMONITIS, INFECTIONS, and INTESTINAL PERFORATION

Fatal and/or serious hepatotoxicity occurred in 16% to 18% of Zydelig-treated patients…

Fatal and/or serious and severe diarrhea or colitis occurred in 14% to 20% of Zydelig-treated patients…

Fatal and/or serious infections occurred in 21% to 48% of Zydelig-treated patients…

AQUAMEPHYTON (PHYTONADIONE):

• Edited boxed warning, March 2018

WARNING: HYPERSENSITIVITY REACTIONS WITH INTRAVENOUS AND INTRAMUSCULAR USE

Fatal hypersensitivity reactions, including anaphylaxis, have occurred during and immediately after INTRAVENOUS and INTRAMUSCULAR injection of Aqua-MEPHYTON. Reactions have occurred despite dilution to avoid rapid infusion and upon first dose. Avoid the intravenous and intramuscular routes of administration unless the subcutaneous route is not feasible and the serious risk is justified.

FERAHEME (FERUMOXYTOL):

• Edited boxed warning, February 2018

WARNING: RISK FOR SERIOUS HYPERSENSITIVITY/ANAPHYLAXIS REACTIONS

Fatal and serious hypersensitivity reactions including anaphylaxis have occurred in patients receiving feraheme. Initial symptoms may
include hypotension, syncope, unresponsiveness, cardiac/cardiorespiratory arrest.

Only administer feraheme as an intravenous infusion over at least 15 minutes and only when personnel and therapies are immediately available for the treatment of anaphylaxis and other hypersensitivity reactions.

METHADONE HYDROCHLORIDE, METHADOSE (METHADONE HYDROCHLORIDE):

• Edited boxed warning, February 2018

RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS

Concomitant use with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, is a risk factor for respiratory depression and death.

Reserve concomitant prescribing of benzodiazepines or other CNS depressants for use in patients for whom alternatives to benzodiazepines or other CNS depressants are inadequate.

Follow patients for signs and symptoms of respiratory depression and sedation. If the patient is visibly sedated, evaluate the cause of sedation, and consider delaying or omitting daily methadone dosing.

DOLOPHINE HYDROCHLORIDE (METHADONE HYDROCHLORIDE):

• Edited boxed warning, February 2018

RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS

Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death.

Reserve concomitant prescribing of DOLOPHINE Tablets and benzodiazepines or other CNS depressants for use in patients for whom alternatives to benzodiazepines or other CNS depressants are inadequate.

Limit dosages and durations to the minimum required for patients being treated for pain.

Follow patients for signs and symptoms of respiratory depression and sedation. If the patient is visibly sedated, evaluate the cause of sedation, and consider delaying or omitting the daily methadone dose.

PARNATE (TRANYLCYPROMINE SULFATE):

• Edited boxed warning, January 2018

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS AND HYPERTENSIVE CRISIS WITH SIGNIFICANT TYRAMINE USE

SUICIDAL THOUGHTS AND BEHAVIORS
Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors. PARNATE is not approved for use in pediatric patients.

HYPERTENSIVE CRISIS WITH SIGNIFICANT TYRAMINE USE
Excessive consumption of foods or beverages with significant tyramine content or the use of certain drugs with PARNATE or after PARNATE discontinuation can precipitate hypertensive crisis. Monitor blood pressure and allow for medication-free intervals between administration of PARNATE and interacting drugs. Instruct patients to avoid ingestion of foods and beverages with high tyramine content.

OCALIVA (OBETICHOLIC ACID):

• New boxed warning/Newly added section, February 2018

WARNING: HEPATIC DECOMPENSATION AND FAILURE IN INCORRECTLY DOSED PBC PATIENTS WITH CHILD-PUGH CLASS B OR C OR DECOMPENSATED CIRRHOSIS

In postmarketing reports, hepatic decompensation and failure, in some cases fatal, have been reported in patients with primary biliary cholangitis (PBC) with decompensated cirrhosis or Child-Pugh Class B or C hepatic impairment when OCALIVA was dosed more frequently than recommended.

The recommended starting dosage of OCALIVA is 5 mg once weekly for patients with Child-Pugh Class B or C hepatic impairment or a prior decompensation event.

The FDA’s MedWatch program safety labeling changes for boxed warnings are compiled quarterly for drugs and therapeutic biologics where important changes have been made to the safety information. These and other label changes are searchable in the Drug Safety Labeling Changes (SLC) database, where data are available to the public in downloadable and searchable formats. Boxed warnings are ordinarily used to highlight either adverse reactions so serious in proportion to the potential benefi t from the drug that it is essential that it be considered in assessing the risks and benefi ts of using the drug; or serious adverse reactions that can be prevented/reduced in frequency or severity by appropriate use of the drug; or FDA approved the drug with restrictions to ensure safe use because FDA concluded that the drug can be safely used only if distribution or use is restricted. For complete FDA Drug Safety Labeling changes, please visit http://www.accessdata.fda.gov/scripts/cder/safetylabelingchanges.

VIDEX AND VIDEX EC (DIDANOSINE):

• Edited boxed warning, January 2018

WARNING: PANCREATITIS, LACTIC ACIDOSIS and HEPATOMEGALY with STEATOSIS

Coadministration of VIDEX or VIDEX EC and stavudine is contraindicated because of increased risk of serious and/or life-threatening events. Suspend treatment if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occurs.

ZYDELIG (IDELALISIB):

• Edited boxed warning, January 2018

WARNING: FATAL AND SERIOUS TOXICITIES: HEPATIC, SEVERE DIARRHEA, COLITIS, PNEUMONITIS, INFECTIONS, and INTESTINAL PERFORATION

Fatal and/or serious hepatotoxicity occurred in 16% to 18% of Zydelig-treated patients…

Fatal and/or serious and severe diarrhea or colitis occurred in 14% to 20% of Zydelig-treated patients…

Fatal and/or serious infections occurred in 21% to 48% of Zydelig-treated patients…

AQUAMEPHYTON (PHYTONADIONE):

• Edited boxed warning, March 2018

WARNING: HYPERSENSITIVITY REACTIONS WITH INTRAVENOUS AND INTRAMUSCULAR USE

Fatal hypersensitivity reactions, including anaphylaxis, have occurred during and immediately after INTRAVENOUS and INTRAMUSCULAR injection of Aqua-MEPHYTON. Reactions have occurred despite dilution to avoid rapid infusion and upon first dose. Avoid the intravenous and intramuscular routes of administration unless the subcutaneous route is not feasible and the serious risk is justified.

FERAHEME (FERUMOXYTOL):

• Edited boxed warning, February 2018

WARNING: RISK FOR SERIOUS HYPERSENSITIVITY/ANAPHYLAXIS REACTIONS

Fatal and serious hypersensitivity reactions including anaphylaxis have occurred in patients receiving feraheme. Initial symptoms may
include hypotension, syncope, unresponsiveness, cardiac/cardiorespiratory arrest.

Only administer feraheme as an intravenous infusion over at least 15 minutes and only when personnel and therapies are immediately available for the treatment of anaphylaxis and other hypersensitivity reactions.

METHADONE HYDROCHLORIDE, METHADOSE (METHADONE HYDROCHLORIDE):

• Edited boxed warning, February 2018

RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS

Concomitant use with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, is a risk factor for respiratory depression and death.

Reserve concomitant prescribing of benzodiazepines or other CNS depressants for use in patients for whom alternatives to benzodiazepines or other CNS depressants are inadequate.

Follow patients for signs and symptoms of respiratory depression and sedation. If the patient is visibly sedated, evaluate the cause of sedation, and consider delaying or omitting daily methadone dosing.

DOLOPHINE HYDROCHLORIDE (METHADONE HYDROCHLORIDE):

• Edited boxed warning, February 2018

RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS

Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death.

Reserve concomitant prescribing of DOLOPHINE Tablets and benzodiazepines or other CNS depressants for use in patients for whom alternatives to benzodiazepines or other CNS depressants are inadequate.

Limit dosages and durations to the minimum required for patients being treated for pain.

Follow patients for signs and symptoms of respiratory depression and sedation. If the patient is visibly sedated, evaluate the cause of sedation, and consider delaying or omitting the daily methadone dose.

PARNATE (TRANYLCYPROMINE SULFATE):

• Edited boxed warning, January 2018

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS AND HYPERTENSIVE CRISIS WITH SIGNIFICANT TYRAMINE USE

SUICIDAL THOUGHTS AND BEHAVIORS
Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors. PARNATE is not approved for use in pediatric patients.

HYPERTENSIVE CRISIS WITH SIGNIFICANT TYRAMINE USE
Excessive consumption of foods or beverages with significant tyramine content or the use of certain drugs with PARNATE or after PARNATE discontinuation can precipitate hypertensive crisis. Monitor blood pressure and allow for medication-free intervals between administration of PARNATE and interacting drugs. Instruct patients to avoid ingestion of foods and beverages with high tyramine content.

OCALIVA (OBETICHOLIC ACID):

• New boxed warning/Newly added section, February 2018

WARNING: HEPATIC DECOMPENSATION AND FAILURE IN INCORRECTLY DOSED PBC PATIENTS WITH CHILD-PUGH CLASS B OR C OR DECOMPENSATED CIRRHOSIS

In postmarketing reports, hepatic decompensation and failure, in some cases fatal, have been reported in patients with primary biliary cholangitis (PBC) with decompensated cirrhosis or Child-Pugh Class B or C hepatic impairment when OCALIVA was dosed more frequently than recommended.

The recommended starting dosage of OCALIVA is 5 mg once weekly for patients with Child-Pugh Class B or C hepatic impairment or a prior decompensation event.

The FDA’s MedWatch program safety labeling changes for boxed warnings are compiled quarterly for drugs and therapeutic biologics where important changes have been made to the safety information. These and other label changes are searchable in the Drug Safety Labeling Changes (SLC) database, where data are available to the public in downloadable and searchable formats. Boxed warnings are ordinarily used to highlight either adverse reactions so serious in proportion to the potential benefit from the drug that it is essential that it be considered in assessing the risks and benefits of using the drug; or serious adverse reactions that can be prevented/reduced in frequency or severity by appropriate use of the drug; or FDA approved the drug with restrictions to ensure safe use because FDA concluded that the drug can be safely used only if distribution or use is restricted. For complete FDA Drug Safety Labeling changes, please visit http://www.accessdata.fda.gov/scripts/cder/safetylabelingchanges.

CODEINE SULFATE: EPIVIR-HBV (LAMIVUDINE)

• Added to warning September 2017

WARNING: LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, EXACERBATIONS OF HEPATITIS B, and RISK OF HIV-1 RESISTANCE IF EPIVIR-HBV IS USED IN PATIENTS WITH UNRECOGNIZED OR UNTREATED HIV-1 INFECTION

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues and other antiretrovirals. Discontinue EPIVIR-HBV if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur.

Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti-hepatitis B therapy (including EPIVIR-HBV). Hepatic function should be monitored closely with both clinical and laboratory followup for at least several months in patients who discontinue anti-hepatitis B therapy. If appropriate, initiation of anti-hepatitis B therapy may be warranted.

EPIVIR-HBV is not approved for the treatment of HIV-1 infection because the lamivudine dosage in EPIVIR-HBV is subtherapeutic and monotherapy is inappropriate for the treatment of HIV-1 infection. HIV-1 resistance may emerge in chronic hepatitis B-infected patients with unrecognized or untreated HIV-1 infection. HIV counseling and testing should be offered to all patients before beginning treatment with EPIVIR-HBV and periodically during treatment.

INVOKANA (CANAGLIFLOZIN)

• Added section to warning July 2017

WARNING: LOWER LIMB AMPUTATION

• An approximately 2-fold increased risk of lower limb amputations associated with INVOKANA use was observed in CANVAS and CANVAS-R, two large, randomized, placebo-controlled trials in patients with type 2 diabetes who had established cardiovascular disease (CVD) or were at risk for CVD.
• Amputations of the toe and midfoot were most frequent; however, amputations involving the leg were also observed. Some patients had multiple amputations, some involving both limbs.
• Before initiating, consider factors that may increase the risk of amputation, such as a history of prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers.

Monitor patients receiving INVOKANA for infection, new pain or tenderness, sores or ulcers involving the lower limbs, and discontinue if these complications occur.

INVOKAMET (CANAGLIFLOZIN; METFORMIN HYDROCHLORIDE)

• Edited warning August 2017

WARNING: LACTIC ACIDOSIS and LOWER LIMB AMPUTATION

Lactic Acidosis

• Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment.

Risk of Lower Limb Amputation

• In patients with type 2 diabetes who have established cardiovascular disease (CVD) or at risk for CVD, canagliflozin, a component of INVOKAMET, has been associated with lower limb amputations, most frequently of the toe and midfoot; some also involved the leg.

INVOKAMET XR (CANAGLIFLOZIN; METFORMIN HYDROCHLORIDE)

• Edited warning August 2017

WARNING: LACTIC ACIDOSIS and LOWER LIMB AMPUTATION

Lactic Acidosis

• Post-marketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as
  malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (> 5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/ pyruvate ratio; and metformin plasma levels generally >5 mcg/mL.
• Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (eg, cationic drugs such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (eg, acute congestive heart failure), excessive alcohol intake, and hepatic impairment.
• Steps to reduce the risk of and manage metforminassociated lactic acidosis in these high risk groups are provided in the full prescribing information.
• If metformin-associated lactic acidosis is suspected, immediately discontinue INVOKAMET and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.

Risk of Lower Limb Amputation

• An approximately 2-fold increased risk of lower limb amputations associated with canagliflozin, a component of INVOKAMET, was observed in CANVAS and CANVAS-R, two large, randomized, placebo-controlled trials in patients with type 2 diabetes who had established cardiovascular disease (CVD) or were at risk for CVD.
• Amputations of the toe and midfoot were most frequent; however, amputations involving the leg were also observed. Some patients had multiple amputations, some involving both limbs.
• Before initiating, consider factors that may increase the risk of amputation, such as a history of prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers.
• Monitor patients receiving INVOKAMET for infection, new pain or tenderness, sores or ulcers involving the lower limbs, and discontinue if these complications occur.

JEVTANA KIT (CABAZITAXEL)

• Edited warning September 2017

WARNING: NEUTROPENIA AND HYPERSENSITIVITY

Neutropenia: Neutropenic deaths have been reported. Monitor for neutropenia with frequent blood cell counts. JEVTANA is contraindicated in patients with neutrophil counts of less than or equal to 1,500 cells/mm3. Primary prophylaxis with G-CSF is recommended in patients with high-risk clinical features.

THYRO-TABS (LEVOTHYROXINE SODIUM)

• Added section to warning August 2017

WARNING: NOT FOR TREATMENT OF OBESITY OR FOR WEIGHT LOSS

Thyroid hormones, including THYRO-TABS, either alone or with other therapeutic agents, should not be used for the treatment of obesity or for weight loss.

In euthyroid patients, doses within the range of daily hormonal requirements are ineffective for weight reduction.

Larger doses may produce serious or even life threatening manifestations of toxicity, particularly when given in association with sympathomimetic amines such as those used for their anorectic effects.

REGLAN (METOCLOPRAMIDE HYDROCHLORIDE)

• Edited warning August 2017

WARNING: TARDIVE DYSKINESIA

• Reglan can cause tardive dyskinesia (TD), a serious movement disorder that is often irreversible. There is no known treatment for TD. The risk of developing TD increases with duration of treatment and total cumulative dosage.
• Discontinue Reglan in patients who develop signs or symptoms of TD. In some patients, symptoms may lessen or resolve after Reglan is stopped.
• Avoid treatment with Reglan for longer than 12 weeks because of the increased risk of developing TD with longer-term use.

The FDA’s MedWatch program safety labeling changes for boxed warnings are compiled quarterly for drugs and therapeutic biologics where important changes have been made to the safety information. These and other label changes are searchable in the Drug Safety Labeling Changes (SLC) database, where data are available to the public in downloadable and searchable formats. Boxed warnings are ordinarily used to highlight either adverse reactions so serious in proportion to the potential benefit from the drug that it is essential that it be considered in assessing the risks and benefits of using the drug; or serious adverse reactions that can be prevented/reduced in frequency or severity by appropriate use of the drug; or FDA approved the drug with restrictions to ensure safe use because FDA concluded that the drug can be safely used only if distribution or use is restricted. For complete FDA Drug Safety Labeling changes, please visit http://www.accessdata.fda.gov/scripts/cder/safetylabelingchanges.

CODEINE SULFATE: EPIVIR-HBV (LAMIVUDINE)

• Added to warning September 2017

WARNING: LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, EXACERBATIONS OF HEPATITIS B, and RISK OF HIV-1 RESISTANCE IF EPIVIR-HBV IS USED IN PATIENTS WITH UNRECOGNIZED OR UNTREATED HIV-1 INFECTION

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues and other antiretrovirals. Discontinue EPIVIR-HBV if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur.

Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti-hepatitis B therapy (including EPIVIR-HBV). Hepatic function should be monitored closely with both clinical and laboratory followup for at least several months in patients who discontinue anti-hepatitis B therapy. If appropriate, initiation of anti-hepatitis B therapy may be warranted.

EPIVIR-HBV is not approved for the treatment of HIV-1 infection because the lamivudine dosage in EPIVIR-HBV is subtherapeutic and monotherapy is inappropriate for the treatment of HIV-1 infection. HIV-1 resistance may emerge in chronic hepatitis B-infected patients with unrecognized or untreated HIV-1 infection. HIV counseling and testing should be offered to all patients before beginning treatment with EPIVIR-HBV and periodically during treatment.

INVOKANA (CANAGLIFLOZIN)

• Added section to warning July 2017

WARNING: LOWER LIMB AMPUTATION

• An approximately 2-fold increased risk of lower limb amputations associated with INVOKANA use was observed in CANVAS and CANVAS-R, two large, randomized, placebo-controlled trials in patients with type 2 diabetes who had established cardiovascular disease (CVD) or were at risk for CVD.
• Amputations of the toe and midfoot were most frequent; however, amputations involving the leg were also observed. Some patients had multiple amputations, some involving both limbs.
• Before initiating, consider factors that may increase the risk of amputation, such as a history of prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers.

Monitor patients receiving INVOKANA for infection, new pain or tenderness, sores or ulcers involving the lower limbs, and discontinue if these complications occur.

INVOKAMET (CANAGLIFLOZIN; METFORMIN HYDROCHLORIDE)

• Edited warning August 2017

WARNING: LACTIC ACIDOSIS and LOWER LIMB AMPUTATION

Lactic Acidosis

• Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment.

Risk of Lower Limb Amputation

• In patients with type 2 diabetes who have established cardiovascular disease (CVD) or at risk for CVD, canagliflozin, a component of INVOKAMET, has been associated with lower limb amputations, most frequently of the toe and midfoot; some also involved the leg.

INVOKAMET XR (CANAGLIFLOZIN; METFORMIN HYDROCHLORIDE)

• Edited warning August 2017

WARNING: LACTIC ACIDOSIS and LOWER LIMB AMPUTATION

Lactic Acidosis

• Post-marketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as
  malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (> 5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/ pyruvate ratio; and metformin plasma levels generally >5 mcg/mL.
• Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (eg, cationic drugs such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (eg, acute congestive heart failure), excessive alcohol intake, and hepatic impairment.
• Steps to reduce the risk of and manage metforminassociated lactic acidosis in these high risk groups are provided in the full prescribing information.
• If metformin-associated lactic acidosis is suspected, immediately discontinue INVOKAMET and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.

Risk of Lower Limb Amputation

• An approximately 2-fold increased risk of lower limb amputations associated with canagliflozin, a component of INVOKAMET, was observed in CANVAS and CANVAS-R, two large, randomized, placebo-controlled trials in patients with type 2 diabetes who had established cardiovascular disease (CVD) or were at risk for CVD.
• Amputations of the toe and midfoot were most frequent; however, amputations involving the leg were also observed. Some patients had multiple amputations, some involving both limbs.
• Before initiating, consider factors that may increase the risk of amputation, such as a history of prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers.
• Monitor patients receiving INVOKAMET for infection, new pain or tenderness, sores or ulcers involving the lower limbs, and discontinue if these complications occur.

JEVTANA KIT (CABAZITAXEL)

• Edited warning September 2017

WARNING: NEUTROPENIA AND HYPERSENSITIVITY

Neutropenia: Neutropenic deaths have been reported. Monitor for neutropenia with frequent blood cell counts. JEVTANA is contraindicated in patients with neutrophil counts of less than or equal to 1,500 cells/mm3. Primary prophylaxis with G-CSF is recommended in patients with high-risk clinical features.

THYRO-TABS (LEVOTHYROXINE SODIUM)

• Added section to warning August 2017

WARNING: NOT FOR TREATMENT OF OBESITY OR FOR WEIGHT LOSS

Thyroid hormones, including THYRO-TABS, either alone or with other therapeutic agents, should not be used for the treatment of obesity or for weight loss.

In euthyroid patients, doses within the range of daily hormonal requirements are ineffective for weight reduction.

Larger doses may produce serious or even life threatening manifestations of toxicity, particularly when given in association with sympathomimetic amines such as those used for their anorectic effects.

REGLAN (METOCLOPRAMIDE HYDROCHLORIDE)

• Edited warning August 2017

WARNING: TARDIVE DYSKINESIA

• Reglan can cause tardive dyskinesia (TD), a serious movement disorder that is often irreversible. There is no known treatment for TD. The risk of developing TD increases with duration of treatment and total cumulative dosage.
• Discontinue Reglan in patients who develop signs or symptoms of TD. In some patients, symptoms may lessen or resolve after Reglan is stopped.
• Avoid treatment with Reglan for longer than 12 weeks because of the increased risk of developing TD with longer-term use.

The FDA’s MedWatch program safety labeling changes for boxed warnings are compiled quarterly for drugs and therapeutic biologics where important changes have been made to the safety information. These and other label changes are searchable in the Drug Safety Labeling Changes (SLC) database, where data are available to the public in downloadable and searchable formats. Boxed warnings are ordinarily used to highlight either adverse reactions so serious in proportion to the potential benefit from the drug that it is essential that it be considered in assessing the risks and benefits of using the drug; or serious adverse reactions that can be prevented/reduced in frequency or severity by appropriate use of the drug; or FDA approved the drug with restrictions to ensure safe use because FDA concluded that the drug can be safely used only if distribution or use is restricted. For complete FDA Drug Safety Labeling changes, please visit http://www.accessdata.fda.gov/scripts/cder/safetylabelingchanges.

CODEINE SULFATE: EPIVIR-HBV (LAMIVUDINE)

• Added to warning September 2017

WARNING: LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, EXACERBATIONS OF HEPATITIS B, and RISK OF HIV-1 RESISTANCE IF EPIVIR-HBV IS USED IN PATIENTS WITH UNRECOGNIZED OR UNTREATED HIV-1 INFECTION

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues and other antiretrovirals. Discontinue EPIVIR-HBV if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur.

Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti-hepatitis B therapy (including EPIVIR-HBV). Hepatic function should be monitored closely with both clinical and laboratory followup for at least several months in patients who discontinue anti-hepatitis B therapy. If appropriate, initiation of anti-hepatitis B therapy may be warranted.

EPIVIR-HBV is not approved for the treatment of HIV-1 infection because the lamivudine dosage in EPIVIR-HBV is subtherapeutic and monotherapy is inappropriate for the treatment of HIV-1 infection. HIV-1 resistance may emerge in chronic hepatitis B-infected patients with unrecognized or untreated HIV-1 infection. HIV counseling and testing should be offered to all patients before beginning treatment with EPIVIR-HBV and periodically during treatment.

INVOKANA (CANAGLIFLOZIN)

• Added section to warning July 2017

WARNING: LOWER LIMB AMPUTATION

• An approximately 2-fold increased risk of lower limb amputations associated with INVOKANA use was observed in CANVAS and CANVAS-R, two large, randomized, placebo-controlled trials in patients with type 2 diabetes who had established cardiovascular disease (CVD) or were at risk for CVD.
• Amputations of the toe and midfoot were most frequent; however, amputations involving the leg were also observed. Some patients had multiple amputations, some involving both limbs.
• Before initiating, consider factors that may increase the risk of amputation, such as a history of prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers.

Monitor patients receiving INVOKANA for infection, new pain or tenderness, sores or ulcers involving the lower limbs, and discontinue if these complications occur.

INVOKAMET (CANAGLIFLOZIN; METFORMIN HYDROCHLORIDE)

• Edited warning August 2017

WARNING: LACTIC ACIDOSIS and LOWER LIMB AMPUTATION

Lactic Acidosis

• Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment.

Risk of Lower Limb Amputation

• In patients with type 2 diabetes who have established cardiovascular disease (CVD) or at risk for CVD, canagliflozin, a component of INVOKAMET, has been associated with lower limb amputations, most frequently of the toe and midfoot; some also involved the leg.

INVOKAMET XR (CANAGLIFLOZIN; METFORMIN HYDROCHLORIDE)

• Edited warning August 2017

WARNING: LACTIC ACIDOSIS and LOWER LIMB AMPUTATION

Lactic Acidosis

• Post-marketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as
  malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (> 5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/ pyruvate ratio; and metformin plasma levels generally >5 mcg/mL.
• Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (eg, cationic drugs such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (eg, acute congestive heart failure), excessive alcohol intake, and hepatic impairment.
• Steps to reduce the risk of and manage metforminassociated lactic acidosis in these high risk groups are provided in the full prescribing information.
• If metformin-associated lactic acidosis is suspected, immediately discontinue INVOKAMET and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.

Risk of Lower Limb Amputation

• An approximately 2-fold increased risk of lower limb amputations associated with canagliflozin, a component of INVOKAMET, was observed in CANVAS and CANVAS-R, two large, randomized, placebo-controlled trials in patients with type 2 diabetes who had established cardiovascular disease (CVD) or were at risk for CVD.
• Amputations of the toe and midfoot were most frequent; however, amputations involving the leg were also observed. Some patients had multiple amputations, some involving both limbs.
• Before initiating, consider factors that may increase the risk of amputation, such as a history of prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers.
• Monitor patients receiving INVOKAMET for infection, new pain or tenderness, sores or ulcers involving the lower limbs, and discontinue if these complications occur.

JEVTANA KIT (CABAZITAXEL)

• Edited warning September 2017

WARNING: NEUTROPENIA AND HYPERSENSITIVITY

Neutropenia: Neutropenic deaths have been reported. Monitor for neutropenia with frequent blood cell counts. JEVTANA is contraindicated in patients with neutrophil counts of less than or equal to 1,500 cells/mm3. Primary prophylaxis with G-CSF is recommended in patients with high-risk clinical features.

THYRO-TABS (LEVOTHYROXINE SODIUM)

• Added section to warning August 2017

WARNING: NOT FOR TREATMENT OF OBESITY OR FOR WEIGHT LOSS

Thyroid hormones, including THYRO-TABS, either alone or with other therapeutic agents, should not be used for the treatment of obesity or for weight loss.

In euthyroid patients, doses within the range of daily hormonal requirements are ineffective for weight reduction.

Larger doses may produce serious or even life threatening manifestations of toxicity, particularly when given in association with sympathomimetic amines such as those used for their anorectic effects.

REGLAN (METOCLOPRAMIDE HYDROCHLORIDE)

• Edited warning August 2017

WARNING: TARDIVE DYSKINESIA

• Reglan can cause tardive dyskinesia (TD), a serious movement disorder that is often irreversible. There is no known treatment for TD. The risk of developing TD increases with duration of treatment and total cumulative dosage.
• Discontinue Reglan in patients who develop signs or symptoms of TD. In some patients, symptoms may lessen or resolve after Reglan is stopped.
• Avoid treatment with Reglan for longer than 12 weeks because of the increased risk of developing TD with longer-term use.

The FDA’s MedWatch program safety labeling changes for boxed warnings are compiled quarterly for drugs and therapeutic biologics where important changes have been made to the safety information. These and other label changes are searchable in the Drug Safety Labeling Changes (SLC) database, where data are available to the public in downloadable and searchable formats. Boxed warnings are ordinarily used to highlight either adverse reactions so serious in proportion to the potential bene t from the drug that it is essential that it be considered in assessing the risks and bene ts of using the drug; or serious adverse reactions that can be prevented/reduced in frequency or severity by appropriate use of the drug; or FDA approved the drug with restrictions to ensure safe use because FDA concluded that the drug can be safely used only if distribution or use is restricted. For complete FDA Drug Safety Labeling changes, please visit http://www.accessdata.fda.gov/scripts/cder/safetylabelingchanges.

CODEINE SULFATE

• Edited and updated warning August 2017

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; ULTRARAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN; NEONATAL OPIOID WITHDRAWAL SYNDROME; INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES; AND RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS

Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children

Life-threatening respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a CYP2D6 polymorphism. Codeine sulfate tablets are contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of codeine sulfate tablets in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine.

TUXARIN ER (CODEINE PHOSPHATE AND CHLORPHENIRAMINE MALEATE):

• Edited warning August 2017

ULTRA-RAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN AND RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS

Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children

Life-threatening respiratory depression and death have occurred in children who received codeine; most cases followed tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultrarapid metabolizer of codeine due to a CYP2D6 polymorphism. Tuxarin ER is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of Tuxarin ER in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine.

Concomitant Use with Benzodiazepines, CNS Depressants

Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound
sedation, respiratory depression, coma, and death. Avoid use of opioid cough medications in patients taking benzodiazepines, other CNS depressants, or alcohol.

TUZISTRA XR (CHLORPHENIRAMINE POLISTIREX; CODEINE POLISTIREX):

• Edited warning August 2017

ULTRA-RAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN

Life-threatening respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultrarapid metabolizer of codeine due to a
CYP2D6 polymorphism. Tuzistra XR is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of Tuzistra XR in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine.

FIORICET W/CODEINE (ACETAMINOPHEN; BUTALBITAL; CAFFEINE; CODEINE PHOSPHATE):

• Edited warning August 2017

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; ULTRA-RAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN; NEONATAL OPIOID WITHDRAWAL SYNDROME; INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES; and HEPATOTOXICITY

Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children

Life-threatening respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a CYP2D6 polymorphism. Butalbital, acetaminophen, caffeine, and codeine phosphate capsules are contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of butalbital, acetaminophen, caffeine, and codeine phosphate capsules in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine.

FIORINAL W/CODEINE (ASPIRIN; BUTALBITAL; CAFFEINE; CODEINE PHOSPHATE):

• Edited warning August 2017

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; ULTRA-RAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN; NEONATAL OPIOID WITHDRAWAL SYNDROME; and INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES.

Risks From Concomitant Use With Benzodiazepines or Other CNS Depressants

Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death.

• Reserve concomitant prescribing of Fiorinal with codeine and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate.
• Limit dosages and durations to the minimum required.
• Follow patients for signs and symptoms of respiratory depression and sedation.

Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children

Life-threatening respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a
CYP2D6 polymorphism. Fiorinal with codeine is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of Fiorinal with codeine in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine.

PHENERGAN VC W/CODEINE (CODEINE PHOSPHATE; PHENYLEPHRINE HYDROCHLORIDE; PROMETHAZINE HYDROCHLORIDE): PHENERGAN W/CODEINE (CODEINE PHOSPHATE; PROMETHAZINE HYDROCHLORIDE):

• Edited warning August 2017

WARNING: ULTRA-RAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS

Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children

Life-threatening respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a CYP2D6 polymorphism. Promethazine HCl and codeine phosphate oral solution is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of promethazine HCl and codeine phosphate oral solution in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine.

Promethazine and Respiratory Depression in Children

Postmarketing cases of respiratory depression, including fatalities have been reported with use of promethazine in pediatric patients. Children may be particularly sensitive to the additive respiratory depressant effects when promethazine is combined with other respiratory depressants, including codeine.

SYNALGOS-DC (ASPIRIN; CAFFEINE; DIHYDROCODEINE BITARTRATE):

• Edited warning August 2017

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; ULTRA-RAPID METABOLISM OF DIHYDROCODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN; NEONATAL OPIOID WITHDRAWAL SYNDROME; INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS

Life-threatening respiratory depression and death have occurred in children who received codeine; most cases followed tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a CYP2D6 polymorphism. Synalgos-DC is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of Synalgos-DC in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of dihydrocodeine.

CONZIP (TRAMADOL HYDROCHLORIDE): ULTRAM (TRAMADOL HYDROCHLORIDE): ULTRACET (ACETAMINOPHEN; TRAMADOL HYDROCHLORIDE):

• Edited warning August 2017

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFETHREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; ULTRA-RAPID METABOLISM OF TRAMADOL AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN; NEONATAL OPIOID WITHDRAWAL SYNDROME; INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS

Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children

Life-threatening respiratory depression and death have occurred in children who received tramadol. Some of the reported cases followed tonsillectomy and/or adenoidectomy; and at least one case, the child had evidence of being an ultra-rapid metabolizer of tramadol due to a CYP2D6 polymorphism. Ultram is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of Ultram in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of tramadol.

The FDA’s MedWatch program safety labeling changes for boxed warnings are compiled quarterly for drugs and therapeutic biologics where important changes have been made to the safety information. These and other label changes are searchable in the Drug Safety Labeling Changes (SLC) database, where data are available to the public in downloadable and searchable formats. Boxed warnings are ordinarily used to highlight either adverse reactions so serious in proportion to the potential bene t from the drug that it is essential that it be considered in assessing the risks and bene ts of using the drug; or serious adverse reactions that can be prevented/reduced in frequency or severity by appropriate use of the drug; or FDA approved the drug with restrictions to ensure safe use because FDA concluded that the drug can be safely used only if distribution or use is restricted. For complete FDA Drug Safety Labeling changes, please visit http://www.accessdata.fda.gov/scripts/cder/safetylabelingchanges.

CODEINE SULFATE

• Edited and updated warning August 2017

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; ULTRARAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN; NEONATAL OPIOID WITHDRAWAL SYNDROME; INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES; AND RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS

Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children

Life-threatening respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a CYP2D6 polymorphism. Codeine sulfate tablets are contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of codeine sulfate tablets in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine.

TUXARIN ER (CODEINE PHOSPHATE AND CHLORPHENIRAMINE MALEATE):

• Edited warning August 2017

ULTRA-RAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN AND RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS

Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children

Life-threatening respiratory depression and death have occurred in children who received codeine; most cases followed tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultrarapid metabolizer of codeine due to a CYP2D6 polymorphism. Tuxarin ER is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of Tuxarin ER in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine.

Concomitant Use with Benzodiazepines, CNS Depressants

Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound
sedation, respiratory depression, coma, and death. Avoid use of opioid cough medications in patients taking benzodiazepines, other CNS depressants, or alcohol.

TUZISTRA XR (CHLORPHENIRAMINE POLISTIREX; CODEINE POLISTIREX):

• Edited warning August 2017

ULTRA-RAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN

Life-threatening respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultrarapid metabolizer of codeine due to a
CYP2D6 polymorphism. Tuzistra XR is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of Tuzistra XR in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine.

FIORICET W/CODEINE (ACETAMINOPHEN; BUTALBITAL; CAFFEINE; CODEINE PHOSPHATE):

• Edited warning August 2017

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; ULTRA-RAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN; NEONATAL OPIOID WITHDRAWAL SYNDROME; INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES; and HEPATOTOXICITY

Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children

Life-threatening respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a CYP2D6 polymorphism. Butalbital, acetaminophen, caffeine, and codeine phosphate capsules are contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of butalbital, acetaminophen, caffeine, and codeine phosphate capsules in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine.

FIORINAL W/CODEINE (ASPIRIN; BUTALBITAL; CAFFEINE; CODEINE PHOSPHATE):

• Edited warning August 2017

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; ULTRA-RAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN; NEONATAL OPIOID WITHDRAWAL SYNDROME; and INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES.

Risks From Concomitant Use With Benzodiazepines or Other CNS Depressants

Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death.

• Reserve concomitant prescribing of Fiorinal with codeine and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate.
• Limit dosages and durations to the minimum required.
• Follow patients for signs and symptoms of respiratory depression and sedation.

Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children

Life-threatening respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a
CYP2D6 polymorphism. Fiorinal with codeine is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of Fiorinal with codeine in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine.

PHENERGAN VC W/CODEINE (CODEINE PHOSPHATE; PHENYLEPHRINE HYDROCHLORIDE; PROMETHAZINE HYDROCHLORIDE): PHENERGAN W/CODEINE (CODEINE PHOSPHATE; PROMETHAZINE HYDROCHLORIDE):

• Edited warning August 2017

WARNING: ULTRA-RAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS

Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children

Life-threatening respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a CYP2D6 polymorphism. Promethazine HCl and codeine phosphate oral solution is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of promethazine HCl and codeine phosphate oral solution in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine.

Promethazine and Respiratory Depression in Children

Postmarketing cases of respiratory depression, including fatalities have been reported with use of promethazine in pediatric patients. Children may be particularly sensitive to the additive respiratory depressant effects when promethazine is combined with other respiratory depressants, including codeine.

SYNALGOS-DC (ASPIRIN; CAFFEINE; DIHYDROCODEINE BITARTRATE):

• Edited warning August 2017

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; ULTRA-RAPID METABOLISM OF DIHYDROCODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN; NEONATAL OPIOID WITHDRAWAL SYNDROME; INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS

Life-threatening respiratory depression and death have occurred in children who received codeine; most cases followed tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a CYP2D6 polymorphism. Synalgos-DC is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of Synalgos-DC in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of dihydrocodeine.

CONZIP (TRAMADOL HYDROCHLORIDE): ULTRAM (TRAMADOL HYDROCHLORIDE): ULTRACET (ACETAMINOPHEN; TRAMADOL HYDROCHLORIDE):

• Edited warning August 2017

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFETHREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; ULTRA-RAPID METABOLISM OF TRAMADOL AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN; NEONATAL OPIOID WITHDRAWAL SYNDROME; INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS

Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children

Life-threatening respiratory depression and death have occurred in children who received tramadol. Some of the reported cases followed tonsillectomy and/or adenoidectomy; and at least one case, the child had evidence of being an ultra-rapid metabolizer of tramadol due to a CYP2D6 polymorphism. Ultram is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of Ultram in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of tramadol.

The FDA’s MedWatch program safety labeling changes for boxed warnings are compiled quarterly for drugs and therapeutic biologics where important changes have been made to the safety information. These and other label changes are searchable in the Drug Safety Labeling Changes (SLC) database, where data are available to the public in downloadable and searchable formats. Boxed warnings are ordinarily used to highlight either adverse reactions so serious in proportion to the potential bene t from the drug that it is essential that it be considered in assessing the risks and bene ts of using the drug; or serious adverse reactions that can be prevented/reduced in frequency or severity by appropriate use of the drug; or FDA approved the drug with restrictions to ensure safe use because FDA concluded that the drug can be safely used only if distribution or use is restricted. For complete FDA Drug Safety Labeling changes, please visit http://www.accessdata.fda.gov/scripts/cder/safetylabelingchanges.

CODEINE SULFATE

• Edited and updated warning August 2017

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; ULTRARAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN; NEONATAL OPIOID WITHDRAWAL SYNDROME; INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES; AND RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS

Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children

Life-threatening respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a CYP2D6 polymorphism. Codeine sulfate tablets are contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of codeine sulfate tablets in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine.

TUXARIN ER (CODEINE PHOSPHATE AND CHLORPHENIRAMINE MALEATE):

• Edited warning August 2017

ULTRA-RAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN AND RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS

Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children

Life-threatening respiratory depression and death have occurred in children who received codeine; most cases followed tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultrarapid metabolizer of codeine due to a CYP2D6 polymorphism. Tuxarin ER is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of Tuxarin ER in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine.

Concomitant Use with Benzodiazepines, CNS Depressants

Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound
sedation, respiratory depression, coma, and death. Avoid use of opioid cough medications in patients taking benzodiazepines, other CNS depressants, or alcohol.

TUZISTRA XR (CHLORPHENIRAMINE POLISTIREX; CODEINE POLISTIREX):

• Edited warning August 2017

ULTRA-RAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN

Life-threatening respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultrarapid metabolizer of codeine due to a
CYP2D6 polymorphism. Tuzistra XR is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of Tuzistra XR in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine.

FIORICET W/CODEINE (ACETAMINOPHEN; BUTALBITAL; CAFFEINE; CODEINE PHOSPHATE):

• Edited warning August 2017

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; ULTRA-RAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN; NEONATAL OPIOID WITHDRAWAL SYNDROME; INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES; and HEPATOTOXICITY

Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children

Life-threatening respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a CYP2D6 polymorphism. Butalbital, acetaminophen, caffeine, and codeine phosphate capsules are contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of butalbital, acetaminophen, caffeine, and codeine phosphate capsules in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine.

FIORINAL W/CODEINE (ASPIRIN; BUTALBITAL; CAFFEINE; CODEINE PHOSPHATE):

• Edited warning August 2017

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; ULTRA-RAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN; NEONATAL OPIOID WITHDRAWAL SYNDROME; and INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES.

Risks From Concomitant Use With Benzodiazepines or Other CNS Depressants

Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death.

• Reserve concomitant prescribing of Fiorinal with codeine and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate.
• Limit dosages and durations to the minimum required.
• Follow patients for signs and symptoms of respiratory depression and sedation.

Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children

Life-threatening respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a
CYP2D6 polymorphism. Fiorinal with codeine is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of Fiorinal with codeine in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine.

PHENERGAN VC W/CODEINE (CODEINE PHOSPHATE; PHENYLEPHRINE HYDROCHLORIDE; PROMETHAZINE HYDROCHLORIDE): PHENERGAN W/CODEINE (CODEINE PHOSPHATE; PROMETHAZINE HYDROCHLORIDE):

• Edited warning August 2017

WARNING: ULTRA-RAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS

Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children

Life-threatening respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a CYP2D6 polymorphism. Promethazine HCl and codeine phosphate oral solution is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of promethazine HCl and codeine phosphate oral solution in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine.

Promethazine and Respiratory Depression in Children

Postmarketing cases of respiratory depression, including fatalities have been reported with use of promethazine in pediatric patients. Children may be particularly sensitive to the additive respiratory depressant effects when promethazine is combined with other respiratory depressants, including codeine.

SYNALGOS-DC (ASPIRIN; CAFFEINE; DIHYDROCODEINE BITARTRATE):

• Edited warning August 2017

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; ULTRA-RAPID METABOLISM OF DIHYDROCODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN; NEONATAL OPIOID WITHDRAWAL SYNDROME; INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS

Life-threatening respiratory depression and death have occurred in children who received codeine; most cases followed tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a CYP2D6 polymorphism. Synalgos-DC is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of Synalgos-DC in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of dihydrocodeine.

CONZIP (TRAMADOL HYDROCHLORIDE): ULTRAM (TRAMADOL HYDROCHLORIDE): ULTRACET (ACETAMINOPHEN; TRAMADOL HYDROCHLORIDE):

• Edited warning August 2017

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFETHREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; ULTRA-RAPID METABOLISM OF TRAMADOL AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN; NEONATAL OPIOID WITHDRAWAL SYNDROME; INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS

Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children

Life-threatening respiratory depression and death have occurred in children who received tramadol. Some of the reported cases followed tonsillectomy and/or adenoidectomy; and at least one case, the child had evidence of being an ultra-rapid metabolizer of tramadol due to a CYP2D6 polymorphism. Ultram is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of Ultram in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of tramadol.

The Food and Drug Administration has announced a new policy that addresses the rapid growth and development of regenerative medicine products, which include novel cellular therapies, with the aim of ensuring their safety and effectiveness.

“The framework – outlined in a suite of four guidance documents – builds upon the FDA’s existing risk-based regulatory approach to more clearly describe what products are regulated as drugs, devices, and/or biological products,” the FDA announced in a statement released on Nov. 16.

ilacy@frontlinemedcom.com

The Food and Drug Administration has announced a new policy that addresses the rapid growth and development of regenerative medicine products, which include novel cellular therapies, with the aim of ensuring their safety and effectiveness.

“The framework – outlined in a suite of four guidance documents – builds upon the FDA’s existing risk-based regulatory approach to more clearly describe what products are regulated as drugs, devices, and/or biological products,” the FDA announced in a statement released on Nov. 16.

ilacy@frontlinemedcom.com

The Food and Drug Administration has announced a new policy that addresses the rapid growth and development of regenerative medicine products, which include novel cellular therapies, with the aim of ensuring their safety and effectiveness.

“The framework – outlined in a suite of four guidance documents – builds upon the FDA’s existing risk-based regulatory approach to more clearly describe what products are regulated as drugs, devices, and/or biological products,” the FDA announced in a statement released on Nov. 16.

ilacy@frontlinemedcom.com