eChapter 2016 (Part 2): The Goodman & Gilman Year in Review: New and Noteworthy FDA Approvals

In 2016 the U.S. Food and Drug Administration (FDA) approved 22 new small-molecule drugs and granted 32 noteworthy biologic licenses. Among the 22 small molecules are:

• Six pharmacological "firsts" (see Part 1);

• Three diagnostic imaging agents for use with PET imaging (see Part 1);

• Three previously unapproved marketed drugs (ephedrine [Akovaz] injection,¹ tetracaine ophthalmic solution,² and methylene blue (Provayblue) injection (an orphan drug);³

• Two entities previously regulated only as dietary supplements (prasterone [dehydroepiandrosterone [DHEA]⁴ and vitamin B₂ [riboflavin]⁵; see Table 6); and

• Eight new molecular entities that are pharmacologically similar to previously approved drugs (see Table 5):

  1. Brivaracetam (Briviact):⁶ the second synaptic vesicle protein (SV2A) ligand to be marketed in the United States, it is an analogue of levetiracetam;

  2. Crisaborole (Eucrisa):⁷ the third FDA-approved phosphodiesterase 4 (PDE-4) inhibitor;

  3. Elbasvir and grazoprevir (Zepatier):⁸ was granted breakthrough therapy status for the treatment of chronic HCV genotype 1 infection in patients with end-stage renal disease on hemodialysis and for the treatment of chronic HCV genotype 4 infection⁹

     • Elbasvir is the third HCV NS5A protein inhibitor to win FDA approval (it is only marketed in a fixed-dose combination with grazoprevir under the brand name, Zepatier);⁸

     • Grazoprevir is the fifth HCV NS3/4A protease inhibitor to win FDA approval (it too is only marketed in a fixed-dose combination with elbasvir under the brand name, Zepatier);⁸

  4. Lixisenatide (Adlyxin);¹⁰ lixisenatide and insulin glargine (Soliqua 100/33):¹¹ lixisenatide is the fifth glucagon-like peptide-1 (GLP-1) receptor agonist to be marketed in the United States and the second GLP-1 receptor agonist to be marketed in a fixed-dose combination with a long-acting insulin (each 3-mL prefilled pen device contains 100 units/mL of insulin glargine and 33 mcg/mL of lixisenatide);¹¹

  5. Obeticholic acid (Ocaliva):¹² The fourth bile acid agent to marketed in the United States;

  6. Rucaparib (Rubraca):¹³ the second poly (ADP-ribose) polymerase (PARP) inhibitor to reach the U.S. market, it was designated by FDA as a breakthrough drug and approved in conjunction with the FoundationFocus CDxBRCA assay¹⁴ to detect the gene alterations in BRCA1 and BRCA2 necessary for patients to qualify to receive this new treatment¹⁵ (see Part 1); and

  7. Velpatasvir and sofosbuvir (Epclusa):¹⁶ Velpatasvir is the third HCV NS5A protein inhibitor to win FDA approval, it is marketed only in a fixed-dose combination with sofosbuvir, making it the second NS5A protein inhibitor/sofosbuvir combination to enter the U.S. market, but also the first for the treatment of all six genotypes of HCV.¹⁷

Part 1 looked back at first-in-class drug approvals; other breakthrough therapies and orphan indications; important new diagnostic tests; and novel medical devices. The noteworthy biologics approved in 2016 are described in Part 3. Throughout the series, orphan, breakthrough, and cancer therapy designations are notated by the symbols †, $, and #, respectively, and biologics are notated by the symbol ¶. "Me-too" drug approvals are listed in Tables 5 and 6 (below), followed by a compilation of other 2016 noteworthy FDA regulatory activities.

Other 2016 Noteworthy FDA Regulatory Activities

Index to Other 2016 Noteworthy FDA Regulatory Activities

(Note: Index entries are hyperlinked via bookmarks to monographs below.)

Brand Name Change for Vortioxetine

Cybersecurity for Medical Devices

Dietary Supplement Actions

• Switch to Prescription Status

  • - DHEA (prasterone)

  • - Riboflavin

• Folic Acid Fortification

• Premarket Safety Notifications

Market Withdrawals

• Niacin/Statin Combined Formulations

• 19 OTC Antimicrobial Soap Ingredients

• Lutropin Alfa

Nutrition-Related Actions

• Improved Nutrition Facts Labeling

• Sodium Reduction Guidelines

Other Drug Efficacy and Safety Updates

• Dipeptidyl Peptidase-4 Inhibitors

• Direct-Acting Antivirals

• Fatty Acid Amide Hydrolase Inhibitors

• Fluconazole Use in Pregnancy

• Fluoroquinolone Antibiotics, Disabling Side Effects

• Lotronex REMS Program Requirements Softened

• Metformin Use Expanded to Patients with Mild to Moderate Renal Impairment

• Olanzapine DRESS Warning

• Opioids

  • - Harm from Concomitant Use with Benzodiazepines

  • - Loperamide Toxicity Trending Up

  • - REMS Program Updates for Extended-Release and Long-Acting Analgesics

  • - Serotonin Syndrome, Adrenal Insufficiency, and Androgen Deficiency

• Parathyroid hormone^¶ REMS Program

• Pioglitazone Bladder Cancer Signal Update

• Posaconazole Dosing Errors

• Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors

  • - Acute Kidney Injuries

  • - Conflicting Signals for Amputation Risks Identified for Canagliflozin

  • - Expanded Indication for Empagliflozin Combined with Metformin

• Stop-Smoking Medicines—Mental Health Side Effects Update

• Statins, Indication for Combined Therapy with Niacin/Fenofibrate Withdrawn

• Sumatriptan Iontophoretic Transdermal Patch Suspension

Pediatric Safety and Efficacy Labeling

Prescription to Over-the-Counter Switches

• - Adapalene topical gel for acne

• - Fluticasone furoate nasal spray for allergy symptoms

Tobacco

Details of Other 2016 Noteworthy FDA Regulatory Activities

(Note: Index entries above are hyperlinked via bookmarks to monographs below.)

• - Brand Name Change: FDA approved changing the brand name for the antidepressant drug vortioxetine from Brintellix to Trintellix.⁵⁶ The action is aimed at eliminating medication substitution errors involving the similar name, Brilinta, which belongs to the platelet aggregation inhibitor ticagrelor.

• - Cybersecurity for Medical Devices: FDA issued final guidance on December 27, 2016, informing manufacturers of recommendations for postmarket cybersecurity for medical devices.^57,58

• - Dietary Supplements

  • Switch to Prescription Status: FDA approved new drug applications for two dietary supplements in 2016:

    • - Prasterone (Intrarosa;⁵⁹ DHEA) is a synthetic steroid that is chemically identical to the endogenous prohormone 5-dehydroepiandrosterone (5-DHEA), which is normally secreted by the adrenal cortex, gonads, and brain tissue. DHEA has historically been marketed in the united states as a nutritional supplement. Prasterone is marketed as a prescription-only intravaginal insert indicated for the treatment of moderate to severe postmenopausal dyspareunia; and

    • - Riboflavin 5'-phosphate (Photrexa; Photrexa Viscous)⁵ is a B vitamin FDA-approved as a 0.146% ophthalmic solution for keratoconus^† and for the treatment of corneal ectasia following refractive surgery^†, both orphan indications. Ophthalmic riboflavin is used in conjunction with UVA light generated by a proprietary (KXL) system to slightly change the properties of the cornea and manipulate its shape. Using this system, riboflavin 5'-phosphate drops followed by UV light illumination generates singlet oxygen (¹O₂), which in turn induces the formation of corneal cross-links. Cross-linking makes the cornea slightly more rigid and thereby changes (reduces) its curvature (also see table 6).

  • Folic Acid Fortification: In 2016 FDA authorized the voluntary fortification of corn masa flour allowed to reduce the risk of neural tube defects in babies born to women who may have a dietary deficiency.^60,61

  • Premarket Dietary Supplement Safety Notifications: The 2011 draft guidance aimed at improving dietary supplement companies' new dietary ingredient (NDI) premarket safety notifications to the agency was revised in 2016. These notifications are intended to help the FDA identify safety concerns before products reach consumers. FDA extended the public comment period on the revisions into December of last year, and no timeline for issuing the final rule has been announced.⁶²

• - Market Withdrawals

  • Extended-Release Niacin Tablets Presented in Combination with Statins: Citing reasons of safety and lack of effectiveness, FDA withdrew approval for two extended-release niacin products marked in combination with an HMG-CoA reductase inhibitor (statin).⁶³ Drawing on evidence from two large cardiovascular outcome trials demonstrating that the addition of niacin increased side-effects without contributing a discernable benefit over statin therapy alone, FDA withdrew approval for the combined use of niacin in combination with a statin and also withdrew marketing approval for Advicor (extended-release niacin and lovastatin) and Simcor (extended-release niacin and simvastatin) tablets.^64-65

  • 19 Ingredients Contained in OTC Antimicrobial Soaps: As part of the ongoing Over-the-Counter (OTC) Drug Review, FDA issued a final rule categorizing 19 ingredients contained in antimicrobial soaps as not generally regarded as safe and effective (not GRASE).⁶⁶ After September 6, 2017, an approved new drug application (NDA) will be necessary to market OTC soaps to consumers containing any of these antimicrobials. The rule does not include OTC waterless antiseptic rubs, first-aid antiseptics, or soaps marketed for use in health care or food service settings.^67,68

• Cloflucarban

• Fluorosalan

• Hexachlorophene

• Hexylresorcinol

• Iodophors (iodine-containing ingredients)

• Iodine complex (ammonium ether sulfate and polyoxyethylene sorbitan monolaurate)

• Iodine complex (phosphate ester of alkylaryloxy polyethylene glycol)

• Methylbenzethonium chloride

• Nonylphenoxypoly (ethyleneoxy) ethanol iodine

• Phenol (>1.5%)

• Phenol (<1.5%)

• Poloxamer–iodine complex

• Povidone-iodine 5–10%

• Secondary amyltricresols

• Sodium oxychlorosene

• Tribromsalan

• Triclocarban

• Triclosan

• Triple dye

• Undecoylium chloride iodine complex

• Lutropin Alfa (Luveris): FDA-accelerated approval for lutropin alfa for injection was withdrawn following the assertion by the drug's sponsor that a required postmarketing clinical trial is not feasible.⁶⁹ Lutropin alfa was FDA approved in 2004 for concomitant administration with follitropin alfa for stimulation of follicular development in infertile hypogonadotropic hypogonadal women with profound luteinizing hormone deficiency. Lutropin alfa has not been marketed in the United States since 2012. Lutropin alfa remains licensed and available in the European Union. Because FDA could not establish the clinical benefit of lutropin alfa without further study, it has not been established to be safe and effective and would require approval of a new drug application to be returned to the U.S. market.

- Noteworthy Nutrition-Related Actions

• Improved Nutrition Facts Labeling: In 2016 FDA finalized improvements to the nutrition labeling required on packaged foods.⁷⁰ These changes are set to be phased in starting in 2018 but will not apply to certain meat and poultry products, which are regulated by the U.S. Department of Agriculture's Food Safety and Inspection Service.

• Voluntary Sodium Reduction Guidelines for the Food industry: FDA solicited public comment on guidance drafted to promote public health improvements by setting voluntary long- and short-term goals for sodium reduction in foods. The public comment period ended in October 2016 and no timeline for issuing the final rule has been announced.^71,72

- Other Drug Efficacy and Safety Updates

• Dipeptidyl Peptidase-4 (DPP-4) Inhibitors: Slightly Increased Risk of Hospitalization for Heart Failure with Alogliptin and Saxagliptin: Based on the results of the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR)⁷³ and the Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care in Patients with Type 2 Diabetes Mellitus and Acute Coronary Syndrome (EXAMINE)⁷⁴ trials, FDA added new warnings regarding the risk of hospitalization for heart failure to the labeling for these two dipeptidyl peptidase-4 (DPP-4) inhibitors, alogliptin and saxagliptin.⁷⁵

• Direct-Acting Antivirals: A black box warning regarding reactivation of hepatitis B infection was added to the labeling of direct acting antivirals used for hepatitis C infections.⁷⁶ The new labeling requirement followed the identification of 2 deaths and a liver transplant among 24 cases of hepatitis B reactivation in co-infected patients during the 31-month period ending in July 2016. Prescribers are advised to take into account the possibility of hepatitis B reactivation and test for co-infection prior to initiating antiviral therapy for hepatitis C.

• Fatty Acid Amide Hydrolase (FAAH) Inhibitors: After review, FDA concluded that the neurotoxicity of BIA 10-2474 does not appear to extend to the other drugs in the class that are currently under investigation in the United States.⁷⁷ FDA's investigation followed the abrupt termination of a phase 1 clinical trial in which administration of BIA 10-2474 was associated with serious neurological illnesses, including one death. FAAAH inhibitors are being investigated for various neurological indications, including the treatment of pain. The failed trial of BIA 10-2474 sent shockwaves through the research community and initially dampened the enthusiasm for this pathway as a target for drug development.⁷⁸

• Fluconazole Use in Pregnancy: The results of a new study⁷⁹ appear to confirm current Centers for Disease Control and Prevention guidelines recommending that only topical antifungals be used to treat vulvovaginal yeast infections during pregnancy.⁸⁰ The new study demonstrated a statistically significant increased risk of spontaneous abortion among women prescribed as little as one or two 150-mg tablets of oral fluconazole during pregnancy. Since the finding is counter to the current U.S. oral fluconazole product labeling, it is likely that FDA will incorporate this new information in a future update.⁸¹

• Fluoroquinolone Antibiotic Disabling Side Effects: A black box warning has been added to the labeling of fluoroquinolone antibiotics advising that they be reserved for use in patients who have no other treatment options for acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, and uncomplicated urinary tract infections.^82,83 The reason for the advisory is because a preponderance of the evidence suggests that the risk of (sometimes permanent) toxicity to tendons, muscles, joints, nerves, and the CNS generally outweighs the benefits to patients with these three specific infection types.

• Alosetron (Lotronex) REMS Program Requirements Softened: Alosetron is a selective serotonin 5-HT₃ antagonist that is approved with restrictions for the treatment of women with diarrhea-predominant irritable bowel syndrome. FDA has eliminated the following restrictions because they are no longer thought to be necessary to ensure the safe use of the drug: (1) prescribers no longer have to enroll in the alosetron Risk Evaluation and Mitigation Strategy (REMS) program; (2) prescribers no longer have to affix stickers to written prescriptions for alosetron; 3) pharmacies may now dispense sticker-less prescriptions for alosetron and also may accept electronic prescriptions for the medication; and 4) patients no longer have to complete and sign an acknowledgement of risks.⁸⁴

• Metformin Approved Uses Expanded to Patients with Mild to Moderate Renal Impairment: FDA has concluded that a preponderance of the evidence demonstrates that metformin can safely be used in patients with mild to moderate renal function and recommends using glomerular filtration rate estimating equation (eGFR) as a gauge of its suitability among patients with diabetes and renal impairment.^85,86

• Olanzapine DRESS Warning Added to Labeling: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a potentially fatal drug reaction with a mortality rate of up to 10%.⁸⁷ DRESS is listed as an adverse effect in the product labeling of approximately 60 drug products marketed in the United States.⁸⁸ DRESS is thought to be caused by a combination of deranged metabolism resulting in toxic metabolites that trigger an immune response. Reactivation of viral infections (e.g., herpes or Epstein-Barr) may contribute to amplification of the immune reaction.⁸⁷ A total of 23 cases of DRESS have been associated with the worldwide use of olanzapine since 1966.⁸⁹

• Opioids:

  • - Concomitant use With Benzodiazepines: A black box warning encouraging prescribers to limit prescribing opioids together with benzodiazepines and other CNS depressants has been added to the labeling of opioid analgesics, prescription opioid cough medicines, and benzodiazepines. The labeling change is based on the detection of increasing trends of harms associated with concomitant use of opioids and benzodiazepines.⁹⁰

  • - Loperamide Toxicity Cases Trending Up: Loperamide is a peripherally acting μ-opioid receptor agonist available by prescription and over the counter for the management of diarrhea. FDA has detected a noticeable uptick in the intentional overuse and misuse of loperamide dating back about 10 years.⁹¹ As a substrate for CYP3A4, CYP2C8, CYP2B6, CYP2D6, and P-gp transport, systemic exposures to loperamide can be influenced by the co-administration with many other drugs. Excessive systemic exposures are associated with serious cardiac toxicities including QT interval prolongation, Torsades de Pointes, other ventricular arrhythmias, syncope, and cardiac arrest. The maximum recommended dose of prescription loperamide is 16 mg daily, and OTC use is limited to 8 mg daily. Healthcare practitioners and patients should be aware of life-threatening toxicities associated with high-level exposures to loperamide.

  • - REMS Program Updates for Extended-Release and Long-Acting Analgesics^92,93

  • - Update on Serotonin Syndrome, Adrenal Insufficiency, and Androgen Deficiency: The class labeling for opioid analgesics was revised to incorporate new information on serotonin syndrome (particularly for fentanyl, oxycodone, and methadone), adrenal insufficiency (particularly fentanyl, oxycodone, and buprenorphine), and androgen deficiency (unclear association).⁹⁴

• Parathyroid Hormone^¶ REMS Program: The REMS program for parathyroid hormone (Natpara)⁹⁵ was expanded with the addition of a required online prescriber certification process.

• Pioglitazone Bladder Cancer Signal Update: Pioglitazone (Actos)⁹⁶ is a thiazolidinedione indicated for the management of diabetes. In 2010, FDA picked up an early signal that it might be linked to the development of bladder cancer.⁹⁷ An update undertaken in 2016 did not alleviate the concern because study results are conflicting. While the signal isn't strong enough to withdraw approval for the drug, the product label has been revised to recommend avoiding prescribing pioglitazone to patients with active bladder cancer and advising caution when ordering it for patients with a prior history of bladder cancer.

• Posaconazole Dosing Errors: Posaconazole is marketed as an oral suspension and also as delayed-release capsules. The bioavailability of the delayed-release tablets is higher than the oral suspension, so the two formulations cannot be directly substituted for one another. Thus, the dose and frequency of administration for posaconazole depend on the formulation and the indication for use. To avoid under- or overdosing errors, prescribers should specify the dosage form, strength, and frequency on all prescriptions for posaconazole.⁹⁸

• Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors

  • - Acute Kidney Injuries: A review of FDA's Adverse Drug Event Reporting Database identified 101 reports of acute kidney injury associated with canagliflozin and dapagliflozin in the 31-month period ending in October 2015.⁹⁹ As a result, the existing warning for the 3 marketed agents in this class (canagliflozin, dapagliflozin, and empagliflozin) was strengthened.

  • - Conflicting Signals for Amputation Risks Identified for Canagliflozin: FDA is investigating conflicting signals related to amputations detected in two clinical studies of canagliflozin.¹⁰⁰ The Canagliflozin Cardiovascular Assessment Study (CANVAS) appears to have picked up a signal for an increase in canagliflozin-associated foot and leg amputations while the similar CANVAS-R trial has not.¹⁰⁰ All patients with diabetes should be monitored for signs and symptoms of disease-related complications, including poorly healing wounds that may require surgical intervention. Prescribers of SGLT2 inhibitors should be familiar with the current product labeling and remain alert for updates.

  • - Expanded Indication for Empagliflozin and Empagliflozin Combined with Metformin: The label for empagliflozin (Jardiance)¹⁰¹ and empagliflozin combined with metformin (Synjardy)¹⁰² were expanded to include reducing the risk of cardiovascular death in adults with type 2 diabetes mellitus and cardiovascular disease.^102,103

• Stop-Smoking Medicines—Update on Mental Health Side Effects: An early signal indicating that the serious and unwanted mental health side effects of varenicline (Chantix)¹⁰⁴ and bupropion (Zyban)¹⁰⁵ may outweigh the benefit of quitting smoking has been debunked by the results of a 24-week, double-blind, active- and placebo-controlled, multicenter, parallel group trial proving the opposite.¹⁰⁶ As a consequence, FDA has removed the black box warning from the varenicline labeling and removed the associated warning from the bupropion black box. A Medication Guide for stop-smoking medications is still required with every prescription, but other REMS requirements have been softened. In conclusion, when used as directed, patients with and without preexisting psychiatric disorders don't appear to be at additional mental health risks from these medications.¹⁰⁶ The agents are demonstrated to be significantly more effective than placebo, and the long-term health benefits for patients that successfully quit smoking are undeniable.¹⁰⁶

• Statin Combination Therapy with Niacin/Fenofibrate Withdrawn: FDA has determined that the benefits of niacin extended-release tablets and fenofibric acid delayed-release capsules for coadministration with statins no longer outweigh the risks.⁶³ All approvals for this indication have been withdrawn, and the labels of all single-entity statin products have been revised. In addition, all fixed-dose combination presentations have been withdrawn from the U.S. market (see Market Withdrawals, above).⁶³ Drawing on evidence from three large cardiovascular outcomes trials published in the New England Journal of Medicine (ACCORD,¹⁰⁷ AIM-HIGH,⁶⁴ and HPS2-THRIVE⁶⁵), FDA has concluded that "the totality of the scientific evidence no longer supports the conclusion that a drug-induced reduction in triglyceride levels and/or increase in HDL-cholesterol levels in statin-treated patients results in a reduction in the risk of cardiovascular events".⁶³

• Sumatriptan Iontophoretic Transdermal Patch Adverse Application Site Reactions: Sales, marketing, and distribution of the sumatriptan iontophoretic transdermal system (Zecuity)¹⁰⁸ have been temporarily suspended on account of burns and scaring associated with using the system.¹⁰⁹ The Zecuity¹⁰⁸ system is indicated for short-term application for acute migraine attacks and is designed to deliver sumatriptan by way of a single-use, battery-powered patch wrapped around the upper arm or thigh. Healthcare professionals should offer alternatives, and patients should be advised to stop using Zecuity¹⁰⁸ transdermal patches.^109,110

  • - Pediatric Safety and Efficacy Labeling Progress: The FDA Safety and Innovation Act of 2012 again had a significant impact.^111,112 As of November 30, official pediatric labeling had been approved for 46 new and existing drugs and biologics in 2016, raising the total count of pediatric labeling actions well above 500.¹¹³ While not officially listed in FDA's pediatric labeling database, seven additional 2016 actions also seem to qualify:

• Insulin degludec (Tresiba)¹¹⁴: Approval was expanded to include patients as young as 1 year of age.

• C1 esterase inhibitor (Berinert)¹¹⁵: The adolescent-to-adult age range for the treatment of acute attacks of hereditary angioedema was eliminated.

• Influenza vaccine (Flucelvax Quadrivalent)¹¹⁶: The age range for use was extended to include persons as young as 4 years of age.¹¹⁵

• Haemophilus b conjugate vaccine (Hiberix)¹¹⁷: The lower age limit for administration was lowered from 15 months to 6 weeks.¹¹⁵

• Antihemophilic factor (recombinant), Fc fusion protein (Eloctate)¹¹⁸: Approval was expanded to include children.¹¹⁵

• Ivacaftor + lumacaftor (Orkambi)^119,120: The age limit for use in pediatric patients with cystic fibrosis (an orphan indication) was lowered from 12 years to 6 years. (See Table 3 in Part 1.)

• Anesthetic warnings: FDA added warnings to the labels of general anesthetic and sedative drugs regarding adverse affects on brain development following prolonged or repeat exposures in children younger than 3 years and pregnant women in their third trimester.¹²¹ Prescribers are advised that the new potential harms to children should be carefully weighed against the risks of withholding medical procedures requiring anesthesia and/or sedation.¹²²

  • - Prescription to Over-the-Counter Switches: FDA authorized the Rx-to-OTC switch of two drug products in 2016:

• Adapalene 1% topical gel (Differin),¹²³ the first topical retinoid approved for the self-treatment of acne

• Fluticasone furoate (Flonase Sensimist Allergy Relief)¹²⁴ nasal spray joins fluticasone propionate (Flonase Allergy Relief), which swung to OTC status in 2014.¹²⁴

  • - Tobacco Regulation Authority Enhanced: As part of the implementation of the Family Smoking Prevention and Tobacco Control Act of 2009, in 2016 FDA's authority to regulate tobacco was extend to all products, including e-cigarettes, cigars, hookah tobacco, and pipe tobacco.¹²⁵ Effective as of May 5, 2016, the sale of these tobacco products to minors nationwide is prohibited.