The Clinical InSight

June 2018

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Recent FDA Approvals

New Medications

Trade Name Dosage Form Manufacturer Indication(s) Approval Date (generic name) Strength For the treatment of adult patients with moderately to severely active Olumiant Eli Lilly and Tablets, rheumatoid arthritis who have had May 31, 2018 (baricitinib) Company 2 mg an inadequate response to one or more TNF antagonist therapies. To decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non- Fulphila Mylan Injection, myeloid malignancies receiving (pegfilgrastim- Institutional June 4, 2018 6 mg/0.6 mL myelosuppressive anti-cancer drugs jmdb) LLC associated with a clinically significant incidence of febrile neutropenia. Medicines For the treatment of onchocerciasis Moxidectin Development Tablets, due to Onchocerca volvulus in June 13, 2018 (moxidectin) for Global 2 mg patients aged 12 years and older. Health For the treatment of patients 18 Zemdri Achaogen, Injection, years of age or older with June 25, 2018 (plazomicin) Inc. 500 mg/10 mL Complicated Urinary Tract Infections (cUTI) including Pyelonephritis. For the treatment of seizures Greenwich Epidiolex Oral Solution, associated with Lennox-Gastaut Biosciences, June 25, 2018 (cannabidiol) 100 mg/mL syndrome or Dravet syndrome in Inc. patients 2 years of age and older. For use in combination with binimetinib for the treatment of Array Capsules, patients with unresectable or Braftovi BioPharma 50 mg and 75 metastatic melanoma with a BRAF June 27, 2018 (encorafenib) Inc. mg V600E or V600K mutation, as detected by an FDA-approved test.

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Trade Name Dosage Form Manufacturer Indication(s) Approval Date (generic name) Strength For use in combination with encorafenib for the treatment of Array Mektovi Tablets, patients with unresectable or BioPharma June 27, 2018 (binimetinib) 15 mg metastatic melanoma with a BRAF Inc. V600E or V600K mutation, as detected by an FDA-approved test.

New Combinations and Formulations

Trade Name Dosage Form Manufacturer Indication(s) Approval Date (generic name) Strength For the treatment of early Lyme disease (as evidenced LymePak Chartwell by erythema migrans) due to Tablets, (doxycycline Pharmaceuticals, Borrelia burgdorferi in adults June 15, 2018 100 mg hyclate) LLC. and pediatric patients 8 years of age and older weighing 45 kg and above. Sublingual For the treatment of nocturia Nocdurna Ferring Tablets, due to nocturnal polyuria in (desmopressin Pharmaceuticals June 21, 2018 27.7 mcg and adults who awaken at least 2 acetate) Inc. 55.3 mcg times per night to void. To induce controlled cardiac septal infarction to improve Ablysinol Belcher exercise capacity in adults Injection, (dehydrated Pharmaceuticals, with symptomatic hypertrophic June 21, 2018 alcohol) LLC obstructive cardiomyopathy who are not candidates for surgical myectomy.

New Generics

Generic Name Trade Name Dosage Form Manufacturer(s) Approval Date

Clindamycin Phosphate and Onexton Topical Gel Taro Pharmaceuticals Inc. June 5, 2018 Benzoyl Peroxide

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Generic Name Trade Name Dosage Form Manufacturer(s) Approval Date

Buprenorphine Suboxone Dr. Reddy's Laboratories Hydrochloride and Sublingual Sublingual Film SA; Mylan Technologies June 14, 2018 Naloxone Film Inc. Hydrochloride

Pipeline

New Medication Pipeline Mechanism of Anticipated Drug Name Generic Name Route Indication(s) Action Approval Date Jatenzo Testosterone Oral Androgens Hypogonadism 1H 2018 Undecanoate Azedra Ultratrace Injectable Electron transport Neuroendocrine 07/30/2018 Iobenguane I-131 inhibitor tumors Tpoxx Tecovirimat Oral Orthopoxvirus egress Smallpox 08/08/2018 Intravenous inhibitor ALN-TTR02 Patisiran Intravenous Antisense Familial amyloid 08/11/2018 oligonucleotide polyneuropathy Galafold Migalastat Oral Chemical chaperone Fabry disease 08/13/2018

AG-120 Ivosidenib Oral Isocitrate Acute myeloid 08/21/2018 dehydrogenase 1 leukemia (IDH1) inhibitor Stannsoporfin Stannsoporfin Intramuscular Heme oxygenase Hyperbilirubinemia 08/22/2018 inhibitors S-888711 Lusutrombopag Oral Thrombopoietin Thrombocytopenia 08/26/2018 Receptor Agonists SHP643 Lanadelumab Subcutaneous Plasma kallikrein Prophylaxis against 08/26/2018 inhibitor angioedema attacks in hereditary angioedema Eravacycline Eravacycline Oral Fluorocycline Infections 08/28/2018 Intravenous antibiotic Volanesorsen Volanesorsen Subcutaneous Antisense Familial 08/30/2018 apolipoprotein chylomicronemia inhibitor syndrome

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Mechanism of Anticipated Drug Name Generic Name Route Indication(s) Action Approval Date PF-06463922 Lorlatinib Oral Tyrosine kinase Non-small cell lung 08/2018 inhibitor cancer Tafenoquine Tafenoquine Oral Antimalarials Prophylaxis of malaria 08/2018

KW-0761 Mogamulizumab Intravenous Anti-CCR4 antibody Cutaneous T-cell 09/04/2018 lymphoma TEV-48125 Fremanezumab Subcutaneous Calcitonin gene- Migraine; Cluster 09/16/2018 related peptide headache (CGRP) inhibitor Arikayce Liposomal Inhaled Aminoglycoside Nontuberculous 09/28/2018 amikacin antibiotic mycobacteria lung infections Dacomitinib Dacomitinib Oral Tyrosine kinase Non-small cell lung 09/2018 inhibitor cancer BAY 94-9027 Coagulation Intravenous Coagulation factor Hemophilia A 3Q 2018 Factor VIII VIII (recombinant) CAT-8015 Moxetumomab Intravenous Cytotoxic agent Anti- Chronic lymphocytic 3Q 2018 Pasudotox CD22 antibody leukemia Elagolix Elagolix Oral Luteinizing hormone Endometriosis 3Q 2018 releasing hormone (LHRH) antagonist Symtuza Darunavir; Oral Protease inhibitor HIV-1 infection 3Q 2018 Cobicistat; Nucleoside analogue Emtricitabine; reverse transcriptase Tenofovir inhibitor (NRTI) Alafenamide Pharmacokinetic enhancer Baremsis Amisulpride Intravenous Atypical antipsychotic Postoperative nausea 10/05/2018 and vomiting Duvelisib Duvelisib Oral Phosphoinositide 3- Chronic lymphocytic 10/05/2018 kinase (PI3K) leukemia inhibitor Tegsedi Inotersen Subcutaneous Protein synthesis Familial amyloid 10/06/2018 inhibitor polyneuropathy

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Mechanism of Anticipated Drug Name Generic Name Route Indication(s) Action Approval Date DOR/3TC/TDF Doravirine; Oral Nucleoside analogue HIV-1 infection 10/23/2018 Lamivudine; reverse transcriptase Tenofovir inhibitor (NRTI) Non- Disoproxil nucleoside reverse Fumarate transcriptase inhibitor (NNRTI) MK-1439 Doravirine Oral Non-nucleoside HIV infection 10/23/2018 reverse transcriptase inhibitor (NNRTI) REGN2810 Cemiplimab Intravenous Programmed cell Cutaneous squamous 10/28/2018 death 1 (PD-1) cell carcinoma inhibitor LY2951742 Galcanezumab Subcutaneous Calcitonin gene- Migraine; Cluster 10/2018 related peptide headache (CGRP) inhibitor PTK 0796 Omadacycline Oral Aminomethylcycline Acute Bacterial Skin 10/2018 Intravenous antibiotic and Skin Structure Infections; Community-acquired bacterial pneumonia Olinvo Oliceridine Intravenous Opioid agonist Acute pain 11/02/2018

Yutiq Fluocinolone Intravitreal Corticosteroid Non-infectious uveitis 11/05/2018 Acetonide TD-4208 Revefenacin Inhaled Long-acting Chronic obstructive 11/13/2018 muscarinic antagonist pulmonary disease (LAMA) Zemcolo Rifamycin-SV Oral Rifamycin Diarrhea caused by 11/16/2018 antibacterial certain organisms NI-0501 Emapalumab Intravenous Type II interferon Hemophagocytic 11/20/2018 inhibitor lymphohistiocytosis LOXO-101 Larotrectinib Oral Tropomyosin Solid tumors 11/26/2018 receptor kinases Hematological (TRK) inhibitor malignancies Firdapse Amifampridine Oral Potassium Channel Lambert-Eaton 11/28/2018 Phosphate Inhibitor myasthenic syndrome ASP2215 Gilteritinib Oral Receptor tyrosine Acute myeloid 11/29/2018 kinase inhibitor leukemia

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Mechanism of Anticipated Drug Name Generic Name Route Indication(s) Action Approval Date SAGE-547 Brexanolone Intravenous GABA Modulators Postpartum 12/19/2018 depression JZP-110 Solriamfetol Oral CNS stimulant Excessive sleepiness 12/20/2018 in narcolepsy; Excessive daytime sleepiness in obstructive sleep apnea Resolor Prucalopride Oral 5-HT4 serotonin Chronic idiopathic 12/21/2018 receptor agonist constipation Calaspargase Calaspargase Intravenous Antineoplastic Acute lymphocytic 12/22/2018 pegol Pegol enzymes leukemia Xofluza Baloxavir Oral Endonuclease Acute uncomplicated 12/24/2018 marboxil inhibitor influenza PF-04449913 Glasdegib Oral Hedgehog signalling Acute myeloid 12/2018 pathway inhibitor leukemia Talazoparib Talazoparib Oral Poly (ADP-ribose) Breast cancer 12/2018 polymerase (PARP) inhibitor Dextenza Dexamethasone Ophthalmic Corticosteroid Post-operative pain 4Q 2018 Implant VivaGel BV Astodrimer Intravaginal Anti-infective Bacterial vaginosis 4Q 2018 Sodium Seysara Sarecycline Oral Tetracycline antibiotic Acne vulgaris 2H 2018

ALKS 5461 Buprenorphine; Oral Opioid antagonist Major depressive 01/31/2019 Samidorphan Opioid partial agonist disorder Zynquista Sotagliflozin Oral SGLT1 and SGLT2 Diabetes Mellitus 03/22/2019 inhibitor Rekynda Bremelanotide Injectable Peptide melanocortin Female sexual 03/23/2019 receptor agonist dysfunction N8-GP Coagulation Intravenous Coagulation factor Hemophilia A 1Q 2019 Factor VIII VIII (recombinant) (Recombinant) BI 655066 Risankizumab Subcutaneous Interleukin 23 Moderate to severe 2Q 2019 antagonist plaque psoriasis

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Mechanism of Anticipated Drug Name Generic Name Route Indication(s) Action Approval Date Duaklir Aclidinium Inhaled Long-acting beta-2 Chronic obstructive 2Q 2019 Bromide; adrenoreceptor pulmonary disease Formoterol agonist (LABA) Long- acting muscarinic antagonist (LAMA) Elzonris Tagraxofusp Injectable Antineoplastics Blastic plasmacytoid 2Q 2019 dendritic cell neoplasm Iclaprim Iclaprim Intravenous Diaminopyrimidine Acute Bacterial Skin 2Q 2019 antibiotic and Skin Structure Infections IMMU-132 Sacituzumab Intravenous Cytotoxic agent Anti- Breast cancer 2Q 2019 Govitecan Trop2 antibody NKTR-181 TBD Oral Opioid agonist Moderate to severe 2Q 2019 chronic low back pain Scenesse Afamelanotide Implant Alpha-melanocyte Erythropoietic 2Q 2019 stimulating hormone protoporphyria (alpha-MSH) analog

2018 New Generic Pipeline (*loss of 180 day exclusivity)

Anticipated Brand 2017 U.S. Brand Name Generic Name Indication(s) Launch Date Manufacturer(s) Sales 07/2018 ACANYA Benzoyl Peroxide; Dow Pharmaceutical Acne vulgaris $44M Clindamycin Sciences; Valeant Phosphate 07/2018 LETAIRIS Ambrisentan Gilead Pulmonary arterial $215M hypertension 07/2018 RESTASIS Cyclosporine Allergan Dry eye $1,769M

08/12/2018 LOCOID (lotion) Hydrocortisone PreCision Atopic dermatitis $15M Butyrate Dermatology; Valeant 08/19/2018 SOLODYN Minocycline Medicis; Valeant Acne vulgaris $375M (115 mg)* Hydrochloride 08/19/2018 SOLODYN Minocycline Medicis; Valeant Acne vulgaris $375M (65 mg)* Hydrochloride

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Anticipated Brand 2017 U.S. Brand Name Generic Name Indication(s) Launch Date Manufacturer(s) Sales 09/16/2018 NORVIR (tablets)* Ritonavir AbbVie HIV-1 infection $208M

09/19/2018 ALOXI (0.25 mg/5 Palonosetron Helsinn Healthcare; Nausea or vomiting TBD mL injection)* Hydrochloride Eisai 09/20/2018 EPIVIR-HBV Lamivudine GSK; ViiV Chronic hepatitis B $2M (5 mg/ml oral Healthcare solution) 09/24/2018 MOVIPREP Ascorbic Acid; Salix; Valeant Bowel cleansing $38M Polyethylene Glycol 3350; Potassium Chloride; Sodium Ascorbate; Sodium Chloride; Sodium Sulfate 09/27/2018 CIALIS Tadalafil Eli Lilly Benign Prostatic $1,933M Hyperplasia; Erectile Dysfunction 09/30/2018 ZYPREXA Olanzapine Eli Lilly Schizophrenia $10M RELPREVV Pamoate 3Q 2018 ABSTRAL Fentanyl Citrate Sentynl; Orexo Acute breakthrough $7M cancer pain 3Q 2018 ADCIRCA Tadalafil Eli Lilly; United Pulmonary arterial $495M Therapeutics hypertension 3Q 2018 LEVITRA (2.5, 5, Vardenafil Bayer Erectile Dysfunction $127M 10, 20 mg) Hydrochloride 3Q 2018 REMODULIN Treprostinil United Therapeutics Pulmonary arterial TBD hypertension 3Q 2018 SENSIPAR Cinacalcet Amgen Thyroid Cancer $1,722M Hydrochloride 10/21/2018 ONFI (oral Clobazam H. Lundbeck A/S Epilepsy: Lennox- $215M suspension) Gastaut syndrome 10/21/2018 ONFI (tablets) Clobazam H. Lundbeck A/S Epilepsy: Lennox- $538M Gastaut syndrome 10/22/2018 VIVLODEX Meloxicam Iroko; iCeutica Osteoarthritis $24M

10/31/2018 STAXYN Vardenafil Bayer Erectile Dysfunction $8M Hydrochloride

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Anticipated Brand 2017 U.S. Brand Name Generic Name Indication(s) Launch Date Manufacturer(s) Sales 11/18/2018 FINACEA GEL Azelaic Acid Bayer Rosacea $120M

11/26/2018 NEXIUM 24HR Esomeprazole AstraZeneca; Pfizer Gastroesophageal Reflux $81M (tablet) Magnesium Disease 12/15/2018 CANASA Mesalamine Forest; Allergan Ulcerative colitis $244M

12/27/2018 ELIDEL Pimecrolimus Valeant Atopic dermatitis $186M

4Q 2018 PYLERA Bismuth Subcitrate Aptalis; Allergan Eradication of $30M Potassium; Heliobacter pylori Metronidazole; Tetracycline 4Q 2018 RAPAFLO Silodosin Allergan Benign Prostatic $206M Hyperplasia 2H 2018 DELZICOL Mesalamine Allergan Ulcerative colitis $147M

2H 2018 FLECTOR Diclofenac IBSA Institut Acute pain $127M Epolamine Biochemique; Pfizer 2018 ANDROGEL Testosterone AbbVie Hypogonadism TBD (1.62%) (packets) 2018 ANDROGEL Testosterone AbbVie Hypogonadism $952M (1.62%) (pump) 2018 ASTAGRAF XL Tacrolimus Astellas Complications of $12M Transplanted Organs and Tissues 2018 BYETTA Exenatide AstraZeneca Diabetes Mellitus $244M Synthetic 2018 CUPRIMINE Penicillamine Aton; Valeant Cystinuria $120M (250 mg) 2018 KALETRA Lopinavir; Ritonavir AbbVie HIV-1 infection $90M (tablets) 2018 LOTEMAX Loteprednol Bausch + Lomb; Post-operative $114M (gel) Etabonate Valeant inflammation and pain following ocular surgery 2018 LOTEMAX Loteprednol Bausch + Lomb; Ocular Pain $85M (suspension) Etabonate Valeant 2018 NUVARING Ethinyl Estradiol; Organon; Merck & Contraception $822M Etonogestrel Co

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Anticipated Brand 2017 U.S. Brand Name Generic Name Indication(s) Launch Date Manufacturer(s) Sales 2018 PROVENTIL-HFA Albuterol Sulfate 3M; Merck & Co Asthma $207M

2018 TRACLEER (film- Bosentan Actelion; Janssen Pulmonary arterial $83M coated tablet) hypertension 2018 TRISENOX Arsenic Trioxide Cephalon; Teva Leukemia $67M

Medication with Significant Label Changes

Trade Name Summary of Label Changes (generic name) Aciphex, Aciphex 5 Warnings and Precautions Newly created subsection: Sprinkle 5.10 Fundic Gland Polyps (raberprazole PPI use is associated with an increased risk of fundic gland polyps that increases with long-term use, especially sodium) beyond one year. Most PPI users who developed fundic gland polyps were asymptomatic and fundic gland polyps were identified incidentally on endoscopy. Use the shortest duration of PPI therapy appropriate to the condition being treated.

Argatroban in 5 Warnings and Precautions 5.2 Use in Hepatic Impairment Sodium Chloride Additions and/or revisions underlined: (argatroban) When administering argatroban to patients with hepatic impairment, start with a lower dose and carefully titrate until the desired level of anticoagulation is achieved. Achievement of steady-state aPTT levels may take longer and require more argatroban dose adjustments in patients with hepatic impairment compared to patients with normal hepatic function … Avoid the use of high doses of argatroban in patients undergoing PCI who have clinically significant hepatic disease …

Austedo Boxed Warning Additions and/or warnings underlined: (deutetrabenazine) WARNING: DEPRESSION AND SUICIDALITY IN PATIENTS WITH HUNTINGTON’S DISEASE AUSTEDO can increase the risk of depression … 4 Contraindications Additions and/or warnings underlined:  With Huntington’s disease who are suicidal …  Taking tetrabenazine (XENAZINE®) or valbenazine 5 Warnings and Precautions Additions and/or warnings underlined: 5.1 Depression and Suicidality in Patients with Huntington’s Disease Patients with Huntington’s disease are at increased risk for depression, and suicidal ideation or behaviors (suicidality) … 5.2 Clinical Worsening and Adverse Events in Patients with Huntington’s Disease Huntington’s disease is a progressive disorder …

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Trade Name Summary of Label Changes (generic name) 5.3 QTc Prolongation Tetrabenazine, a closely related VMAT2 inhibitor, causes an increase (about 8 msec) in the corrected QT (QTc) interval. A clinically relevant QT prolongation may occur … For patients who are CYP2D6 poor metabolizers or are taking a strong CYP2D6 inhibitor, dose reduction may be necessary. The use of AUSTEDO in combination with other drugs that are known to prolong QTc may result in clinically significant QT prolongations. For patients requiring AUSTEDO doses greater than 24 mg per day who are using AUSTEDO with other drugs known to prolong QTc, assess the QTc interval before and after increasing the dose of AUSTEDO or other medications that are known to prolong QTc. AUSTEDO should also be avoided in patients with congenital long QT syndrome … 5.5 Akathisia, Agitation, and Restlessness AUSTEDO may increase the risk of akathisia, agitation, and restlessness in patients with Huntington’s disease and tardive dyskinesia. In a 12-week, double-blind, placebo-controlled trial in Huntington’s disease patients, akathisia, agitation, or restlessness was reported by 4% of patients treated with AUSTEDO, compared to 2% of patients on placebo; in patients with tardive dyskinesia, 2% of patients treated with AUSTEDO and 1% of patients on placebo experienced these events … 5.6 Parkinsonism in Patients with Huntington’s Disease 5.7 Sedation and Somnolence … In a 12-week, double-blind, placebo-controlled trial examining patients with Huntington’s disease, 11% of AUSTEDO- treated patients …

Benlysta 5 Warnings and Precautions Additions and/or revisions underlined: (belimumab) 5.1 Mortality There were more deaths reported with BENLYSTA than with placebo during the controlled period of the intravenous clinical trials. Out of 2,133 patients … cardiovascular disease, and suicide. In the controlled trial of BENLYSTA administered subcutaneously (N equals 836), a total of 5 deaths occurred during the placebo-controlled, double-blind treatment period (0.7% [2/280] of patients receiving placebo and 0.5% [3/556] of patients receiving BENLYSTA). Infection was the most common cause of death. 5.2 Serious Infections … In the controlled clinical trials of BENLYSTA administered intravenously, the overall incidence … and in 0.1% (1/675) of patients receiving placebo. In the controlled trial of BENLYSTA administered subcutaneously (N equals 836), the overall incidence of infections was 55% in patients treated with BENLYSTA compared with 57% in patients who received placebo (serious infections: 4.1% with BENLYSTA and 5.4% with placebo). The most commonly reported infections with BENLYSTA administered subcutaneously were similar to those reported with BENLYSTA administered intravenously. 5.3 Hypersensitivity Reactions, including Anaphylaxis … In the controlled clinical trials of BENLYSTA administered intravenously, hypersensitivity … BENLYSTA for intravenous use should be administered … and for an appropriate period of time after intravenous administration of BENLYSTA. In the controlled trial of BENLYSTA administered subcutaneously (N equals 836), systemic hypersensitivity reactions were similar to those observed in the intravenous clinical trials. Patients receiving BENLYSTA should be informed of the signs and symptoms … 5.4 Infusion Reactions In the controlled clinical trials of BENLYSTA administered intravenously, adverse events …

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Trade Name Summary of Label Changes (generic name) BENLYSTA for intravenous use should be administered … 5.5 Depression In the controlled clinical trials of BENLYSTA administered intravenously, psychiatric events … in patients receiving BENLYSTA. In the controlled trial of BENLYSTA administered subcutaneously (N equals 836), psychiatric events were reported in 6% of patients treated with BENLYSTA and in 11% of patients who received placebo. Depression- related events were reported in 2.7% of patients receiving BENLYSTA and 3.6% of patients receiving placebo. Serious psychiatric events were reported in 0.2% of patients receiving BENLYSTA and in no patients receiving placebo. There were no serious depression- related events or suicides reported in either group. 5.6 Malignancy In the controlled clinical trials of BENLYSTA administered intravenously, malignancies (including non-melanoma skin cancers) were reported in 0.4% … In the intravenous controlled clinical trials, malignancies, excluding non- melanoma skin cancers, were observed … In the controlled clinical trial of BENLYSTA administered subcutaneously (N equals 836), the data were similar. The mechanism of action …

Bonjesta 5 Warnings and Precautions Addition to following subsection title underlined: (doxylamine 5.1 Somnolence and Severe Drowsiness succinate; Addition of the following subsection pyridoxine 5.3 Interference with Urine Screen for Methadone, Opiates and Phencyclidine Phosphate (PCP) hydrochloride) There have been reports of false positive urine screening tests for methadone, opiates, and PCP with doxylamine succinate/pyridoxine hydrochloride use.

Celebrex 5 Warnings and Precautions 5.1 Cardiovascular Thrombotic Events (celecoxib) (additions underlined) … In the APC (Adenoma Prevention with Celecoxib) trial, there was about a threefold increased risk of the composite endpoint of cardiovascular death, MI, or stroke for the CELEBREX 400 mg twice daily and CELEBREX 200 mg twice daily treatment arms compared to placebo. The increases in both celecoxib dose groups versus placebo-treated patients were mainly due to an increased incidence of myocardial infarction. A randomized controlled trial entitled the Prospective Randomized Evaluation of Celecoxib Integrated Safety vs. Ibuprofen Or Naproxen (PRECISION) was conducted to assess the relative cardiovascular thrombotic risk of a COX-2 inhibitor, celecoxib, compared to the non- selective NSAIDs naproxen and ibuprofen. Celecoxib 100 mg twice daily was non-inferior to naproxen 375 to 500 mg twice daily and ibuprofen 600 to 800 mg three times daily for the composite endpoint of the Antiplatelet Trialists’ Collaboration (APTC), which consists of cardiovascular death (including hemorrhagic death), non-fatal myocardial infarction, and non-fatal stroke.

Chantix 5 Warnings and Precautions 5.5 Cardiovascular Events (verenicline Extensive revisions to this subsection; as below: tartrate) A comprehensive evaluation of cardiovascular (CV) risk with CHANTIX suggests that patients with underlying CV disease may be at increased risk; however, these concerns must be balanced with the health benefits of smoking cessation. CV risk has been assessed for CHANTIX in randomized controlled trials (RCT) and meta- analyses of RCTs. In a smoking cessation trial in patients with stable CV disease, CV events were infrequent overall; however, nonfatal myocardial infarction (MI) and nonfatal stroke occurred more frequently in patients treated with CHANTIX compared to placebo. All-cause and CV mortality was lower in patients treated with

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Trade Name Summary of Label Changes (generic name) CHANTIX. This study was included in a meta-analysis of 15 CHANTIX efficacy trials in various clinical populations that showed an increased hazard ratio for Major Adverse Cardiovascular Events (MACE) of 1.95; however, the finding was not statistically significant (95% CI: 0.79, 4.82). In the large postmarketing neuropsychiatric safety outcome trial, an analysis of adjudicated MACE events was conducted for patients while in the trial and during a 28-week non-treatment extension period. Few MACE events occurred during the trial; therefore, the findings did not contribute substantively to the understanding of CV risk with CHANTIX. Instruct patients to notify their healthcare providers of new or worsening CV symptoms and to seek immediate medical attention if they experience signs and symptoms of MI or stroke.

Darzalex 4 Contraindications Addition of the following: (daratumumab) DARZALEX is contraindicated in patients with a history of severe hypersensitivity (e.g. anaphylactic reactions) to daratumumab or any of the components of the formulation. 5 Warnings and Precautions Additions and/or revisions underlined: 5.1 Infusion Reactions DARZALEX can cause severe and/or serious infusion reactions including anaphylactic reactions. In clinical trials, approximately half of all patients experienced an infusion reaction. Most infusion reactions occurred during the first infusion and were Grade 1-2 … … Permanently discontinue DARZALEX therapy if an anaphylactic reaction or life-threatening (Grade 4) reaction occurs and institute appropriate emergency care. For patients with Grade 1, 2, or 3 reactions …

Desogen Boxed Warning (Additions and/or revisions are underlined) (desogestrel; WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS ethinyl estradiol) 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. 4 Contraindications (Additions and/or revisions are underlined)  Inherited or acquired hypercoagulopathies  Smoke, if over age 35  Receiving Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for ALT elevations. 5 Warnings and Precautions (Extensive changes; please refer to labeling)

Dexilant 5 Warnings and Precautions Newly created subsection: (dexlansoprazole) 5.10 Fundic Gland Polyps PPI use is associated with an increased risk of fundic gland polyps that increases with long-term use, especially beyond one year. Most PPI users who developed fundic gland polyps were asymptomatic and fundic gland polyps were identified incidentally on endoscopy. Use the shortest duration of PPI therapy appropriate to the condition being treated.

Diclegis 5 Warnings and Precautions

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Trade Name Summary of Label Changes (generic name) (doxylamine Newly created subsection: 5.3 Interference with Urine Screen for Methadone, Opiates and Phencyclidine Phosphate (PCP) succinate; There have been reports of false positive urine screening tests for methadone, opiates, and PCP with pyridoxine doxylamine succinate/pyridoxine hydrochloride use. hydrochloride) Eliquis 5 Warnings and Precautions 5.2 Risk of Bleeding (apixaban) (additions underlined) … Reversal of Anticoagulant Effect An agent to reverse the anti-factor Xa activity of rivaroxaban is available. Because of high plasma protein binding, rivaroxaban is not expected to be dialyzable. Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban. Partial reversal of prothrombin time prolongation has been seen after administration of prothrombin complex concentrates (PCCs) in healthy volunteers. The use of other procoagulant reversal agents like activated prothrombin complex concentrate (APCC) or recombinant factor VIIa (rFVIIa) has not been evaluated.

Erbitux Boxed Warning Additions and/or revisions underlined: (cetuximab) WARNING: INFUSION REACTIONS and CARDIOPULMONARY ARREST Infusion Reactions: ERBITUX can cause serious and fatal infusion reactions. Immediately interrupt and permanently discontinue ERBITUX for serious infusion reactions. 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. 5 Warnings and Precautions Additions and/or revisions underlined in the following subsections: 5.1 Infusion Reactions ERBITUX can cause serious and fatal infusion reactions. Infusion reactions of any grade occurred in 8.4% of 1373 patients who received ERBITUX across clinical trials. Severe (Grades 3 and 4) infusion reactions occurred in 2.2% of patients. Signs and symptoms included rapid onset … The risk of anaphylactic reactions may be increased in patients with a history of tick bites, red meat allergy, or in the presence of IgE antibodies directed against galactose-?-1,3-galactose (alpha-gal). … with the first infusion despite premedication with antihistamines. Infusion reactions may occur during or several hours following completion of the infusion. Premedicate with a histamine-1(H1) receptor antagonist as recommended. Monitor patients for at least 1 hour following each ERBITUX infusion, in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis. In patients requiring treatment for infusion reactions, monitor for more than 1 hour to confirm resolution of the reaction. Interrupt the infusion and upon recovery, resume the infusion at a slower rate or permanently discontinue ERBITUX based on severity. 5.2 Cardiopulmonary Arrest ERBITUX can cause cardiopulmonary arrest. Cardiopulmonary arrest or sudden death … BONNER replaces Study 1 EXTREME replaces Study 2 … of 219 patients treated with a cetuximab product in combination with platinum-based therapy and fluorouracil. … or platinum-based therapy with fluorouracil in patients with SCCHN with a history of coronary … 5.3 Pulmonary Toxicity

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Trade Name Summary of Label Changes (generic name) ERBITUX can cause interstitial lung disease … ERBITUX in clinical trials. Monitor patients for signs and symptoms of pulmonary toxicity. Interrupt or permanently discontinue ERBITUX for acute onset … 5.4 Dermatologic Toxicity … Acneiform rash occurred in 82% of the 1373 patients who received ERBITUX across clinical trials. Severe (Grades 3 or 4) acneiform rash occurred in 9.7% of patients. Acneiform rash usually developed within the first two weeks of therapy; the rash lasted more than 28 days after stopping ERBITUX in most patients. … Instruct patients to limit sun exposure during ERBITUX therapy. Withhold, reduce dose or permanently discontinue ERBITUX based on severity of acneiform rash or mucocutaneous disease. 5.5 Risks Associated with Use in Combination with Radiation and Cisplatin … Adverse reactions with fatal outcome were reported in 4% of patients in the ERBITUX combination arm … The addition of ERBITUX to radiation and cisplatin did not improve PFS. ERBITUX is not indicated for the treatment of SCCHN in combination with radiation and cisplatin. 5.6 Hypomagnesemia and Accompanying Electrolyte Abnormalities ERBITUX can cause hypomagnesemia … receiving ERBITUX in Study CA225-025 and two other clinical trials in patients with colorectal cancer (CRC) or head and neck cancer, including Grades 3 and 4 in 6% to 17%. In EXTREME, where a cetuximab product was administered in combination … resulted in an increased incidence of hypomagnesemia of any grade (14%) and of Grade 3 or 4 hypomagnesemia (7%). Hypomagnesemia of any grade occurred in 4% of patients who received cetuximab, carboplatin, and fluorouracil. Hypomagnesemia and accompanying electrolyte abnormalities can occur days to months after initiating ERBITUX. Monitor patients weekly during treatment for hypomagnesemia. 5.7 Increased Tumor Progression, Increased Mortality, or Lack of Benefit in Patients with Ras-Mutant mCRC … hereafter is referred to as “Ras” or when the Ras status is unknown. CRYSTAL replaces Study 4 … resulted in no clinical benefit with treatment related toxicity. Confirm Ras mutation status in tumor specimens prior to initiating ERBITUX.

Esomeprazole 5 Warnings and Precautions Newly created subsection: Strontium 5.12 Fundic Gland Polyps (esomoprazole PPI use is associated with an increased risk of fundic gland polyps that increases with long-term use, strontium) especially beyond one year. Most PPI users who developed fundic gland polyps were asymptomatic and fundic gland polyps were identified incidentally on endoscopy. Use the shortest duration of PPI therapy appropriate to the condition being treated.

Evista 5 Warnings and Precautions 5.4 Premenopausal Use (raloxifene (additions underlined) hydrochloride) There is no indication for premenopausal use of EVISTA. Safety of EVISTA in premenopausal women has not been established and its use is not recommended. Additionally, there is concern regarding inadvertent drug exposure in pregnancy in women of reproductive potential who become pregnant, due to risk of fetal harm.

Gleolan 5 Warnings and Precautions 5.1 Risk of Phototoxic Reaction (Additions and/or revisions are underlined)

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Trade Name Summary of Label Changes (generic name) (aminilevulinic acid Due to the risk of phototoxic reactions, do not administer phototoxic drugs for 24 hours during the perioperative period. Reduce exposure to sunlight or room lights for 48 hours after administration of Gleolan. hydrochloride)

Hycodan Boxed Warning (section updated) (homatropine WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; methylbromide; ACCIDENTAL INGESTION; MEDICATION ERRORS; CYTOCHROME P450 3A4 INTERACTION; hydrocodone CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; INTERACTION WITH bitartrate) ALCOHOL; NEONATAL OPIOID WITHDRAWAL SYNDROME Addiction, Abuse, and Misuse HYCODAN exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Reserve HYCODAN 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 HYCODAN, prescribe HYCODAN 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. Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of HYCODAN. Monitor for respiratory depression, especially during initiation of HYCODAN therapy or when used in patients at higher risk. Accidental Ingestion Accidental ingestion of even one dose of HYCODAN, especially by children, can result in a fatal overdose of hydrocodone. Risk of Medication Errors Ensure accuracy when prescribing, dispensing, and administering HYCODAN. Dosing errors can result in accidental overdose and death. Always use an accurate milliliter measuring device when measuring and administering HYCODAN. Cytochrome P450 3A4 Interaction The concomitant use of HYCODAN with all cytochrome P450 3A4 inhibitors may result in an increase in hydrocodone plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in hydrocodone plasma concentration. Avoid the use of HYCODAN in patients taking a CYP3A4 inhibitor or inducer. 4 Contraindications (additions underlined) HYCODAN is contraindicated for:  All children younger than 6 years of age HYCODAN is also contraindicated in patients with:  Significant respiratory depression  Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment  Known or suspected gastrointestinal obstruction, including paralytic ileus  Hypersensitivity to hydrocodone, homatropine, or any of the inactive ingredients in HYCODAN 5 Warnings and Precautions (PLR conversion: subsections created as below, see label for complete information) 5.1 Addiction, Abuse, and Misuse 5.2 Life-Threatening Respiratory Depression 5.3 Risks with Use in Pediatric Populations

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Trade Name Summary of Label Changes (generic name) 5.4 Risks with Use in Other At-Risk Populations 5.5 Risk of Accidental Overdose and Death due to Medication Errors 5.6 Activities Requiring Mental Alertness: Risks of Driving and Operating Machinery 5.7 Risks from Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers 5.8 Risks from Concomitant Use with Benzodiazepines or other CNS Depressants 5.9 Risks of Use in Patients with Gastrointestinal Conditions 5.10 Risks of Use in Patients with Head Injury, Impaired Consciousness, Increased Intracranial Pressure, or Brain Tumors 5.11 Increased Risk of Seizures in Patients with Seizure Disorders 5.12 Severe Hypotension 5.13 Neonatal Opioid Withdrawal Syndrome 5.14 Adrenal Insufficiency 5.15 Drug/Laboratory Test Interactions

Keytruda 5 Warnings and Precautions 5.7 Other Immune-Mediated Adverse Reactions (pembrolizumab) (Additions and/or revisions are underlined) Immune mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue in patients receiving KEYTRUDA. While immune-mediated adverse reactions usually occur during treatment with PD-1/PD-L1 blocking antibodies, they may occur after discontinuation of treatment.

Kyprolis 5 Warnings and Precautions 5.4 Pulmonary Toxicity (carfilzomib) Approximately replaces less than

Lamictal, 5 Warnings and Precautions 5.2 Hemophagocytic Lymphohistiocytosis Lamictal CD, (new subsection added) Lamictal ODT, Hemophagocytic lymphohistiocytosis (HLH) has occurred in pediatric and adult patients taking LAMICTAL for Lamictal XR various indications. HLH is a life-threatening syndrome of pathologic immune activation characterized by clinical (lamotrigine) signs and symptoms of extreme systemic inflammation. It is associated with high mortality rates if not recognized early and treated. Common findings include fever, hepatosplenomegaly, rash, lymphadenopathy, neurologic symptoms, cytopenias, high serum ferritin, and liver function and coagulation abnormalities. In cases of HLH reported with LAMICTAL, patients have presented with signs of systemic inflammation (fever, rash, hepatosplenomegaly, and organ system dysfunction) and blood dyscrasias. Symptoms have been reported to occur within 8 to 24 days following the initiation of treatment. Patients who develop early manifestations of pathologic immune activation should be evaluated immediately, and a diagnosis of HLH should be considered. LAMICTAL should be discontinued if an alternative etiology for the signs or symptoms cannot be established.

Merrem 5 Warnings and Precautions 5.2 Severe Cutaneous Adverse Reactions (meropenem) Newly added subsection: Severe cutaneous adverse reactions (SCAR) such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), erythema multiforme (EM) and acute generalized exanthematous pustulosis (AGEP) have been reported in patients receiving MERREM

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Trade Name Summary of Label Changes (generic name) IV. If signs and symptoms suggestive of these reactions appear, meropenem should be withdrawn immediately and an alternative treatment should be considered.

Mircera 5 Warnings and Precautions Additions and/or revisions underlined: (methoxy 5.1 Increased Mortality, Myocardial Infarction, Stroke, and Thromboembolism polyethylene Table 3: Randomized Controlled Trials Showing Adverse Cardiovascular Outcomes in Patients With glycol-epoetin CKD beta) 5.2 Randomized, Controlled Trials with Decreased Survival and/or Decreased Locoregional Control Table 4: Randomized, Controlled Trials with Decreased Survival and/or Decreased Locoregional Control some changes to this table; please refer to label for complete information. Newly added subsection: 5.8 Severe Cutaneous Reactions Blistering and skin exfoliation reactions including Erythema multiforme and Stevens-Johnson Syndrome (SJS)/Toxic Epidermal Necrolysis (TEN), have been reported in patients treated with ESAs (including Mircera) in the postmarketing setting. Discontinue Mircera therapy immediately if a severe cutaneous reaction, such as SJS/TEN, is suspected.

Nasonex 5 Warnings and Precautions 5.2 Glaucoma and Cataracts (mometasone Additions and/or revisions underlined: furoate) Glaucoma and cataracts may be reported with systemic and topical (including intranasal, inhaled and intraocular) corticosteroid use. Consider referral to an ophthalmologist in patients who develop ocular symptoms or use NASONEX long term.

Neulasta 5 Warnings and Precautions Additions and/or revisions underlined: (pegfilgrastim) 5.5 Use in Patients with Sickle Cell Disorders Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disorders receiving pegfilgrastim products. Discontinue Neulasta if sickle cell crisis occurs. Newly created subsections: 5.11 Aortitis Aortitis has been reported in patients receiving Neulasta. It may occur as early as the first week after start of therapy. Manifestations may include generalized signs and symptoms such as fever, abdominal pain, malaise, back pain, and increased inflammatory markers (e.g., c-reactive protein and white blood cell count). Consider aortitis in patients who develop these signs and symptoms without known etiology. Discontinue Neulasta if aortitis is suspected. 5.12 Nuclear Imaging Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone imaging results.

Neupogen 5 Warnings and Precautions Additions and/or revisions underlined: (filgrastim) 5.4 Sickle Cell Disorders Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disorders receiving filgrastim products. Discontinue NEUPOGEN if sickle cell crisis occurs.

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Trade Name Summary of Label Changes (generic name) Addition of the following: 5.15 Aortitis Aortitis has been reported in patients receiving NEUPOGEN. It may occur as early as the first week after start of therapy. Manifestations may include generalized signs and symptoms such as fever, abdominal pain, malaise, back pain, and increased inflammatory markers (e.g., c-reactive protein and white blood cell count). Consider aortitis in patients who develop these signs and symptoms without known etiology. Discontinue NEUPOGEN if aortitis is suspected.

Nexium 5 Warnings and Precautions Newly created subsection: (esomeprazole 5.12 Fundic Gland Polyps magnesium) PPI use is associated with an increased risk of fundic gland polyps that increases with long-term use, especially beyond one year. Most PPI users who developed fundic gland polyps were asymptomatic and fundic gland polyps were identified incidentally on endoscopy. Use the shortest duration of PPI therapy appropriate to the condition being treated.

Novolin 70/30 4 Contraindications PLR conversion; as below: (insulin NOVOLIN N is contraindicated: recombinant  During episodes of hypoglycemia human; insulin  In patients who have hypersensitivity reactions to NOVOLIN N or any of its excipients susp isophane 5 Warnings and Precautions PLR Conversion; subsections as below; please refer to label for complete information. recombinant 5.1 Never Share a NOVOLIN N FlexPen or Syringe Between Patients human) 5.2 Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen Novolin N 5.3 Hypoglycemia (insulin susp 5.4 Hypoglycemia Due to Medication Errors 5.5 Hypersensitivity and Allergic Reactions isophane 5.6 Hypokalemia recombinant 5.7 Fluid Retention and Heart Failure with Concomitant Use of PPAR-gamma agonists human) Novolin R (insulin recombinant human) Pepcid 4 Contraindications PLR conversion; revised as below: (famotidine) PEPCID is contraindicated in patients with a history of serious hypersensitivity reactions (e.g., anaphylaxis) to famotidine or other H2 receptor antagonists. 5 Warnings and Precautions PLR conversion; subsections created as below (please see label for complete information): 5.1 Central Nervous System Adverse Reactions 5.2 Concurrent Gastric Malignancy

Phenergan VC Boxed Warning (extensive additions, please refer to label) w/Codeine

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Trade Name Summary of Label Changes (generic name) (codeine 4 Contraindications (additions underlined) phosphate; Promethazine HCl and Codeine Phosphate Oral Solution is contraindicated for: phenylephrine hydrochloride; o All children younger than 12 years of age. promethazine o Postoperative pain management in children younger than 18 years of age following tonsillectomy and/or hydrochloride) adenoidectomy. Phenergan Promethazine HCl and Codeine Phosphate Oral Solution is also contraindicated in patients with: o Significant respiratory depression. w/Codeine o Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment. (codeine o Known or suspected gastrointestinal obstruction, including paralytic ileus. phosphate; o A history of an idiosyncratic reaction to promethazine or to other phenothiazines promethazine o Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within 14 days. o Hypersensitivity to codeine, promethazine, or any of the inactive ingredients in Promethazine HCl and hydrochloride) Codeine Phosphate Oral Solution.Persons known to be hypersensitive to certain other opioids may exhibit cross-reactivity to codeine. 5 Warnings and Precautions (PLR conversion: subsections created as below, see label for complete information) 5.1 Addiction, Abuse, and Misuse 5.2 Life-Threatening Respiratory Depression 5.3 Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children 5.4 Promethazine and Respiratory Depression 5.5 Risks with Use in Pediatric Populations 5.6 Risks with Use in Other At-Risk Populations 5.7 Risk of Accidental Overdose and Death due to Medication Errors 5.8 Activities Requiring Mental Alertness: Risks of Driving and Operating Machinery 5.9 Risks of Interactions with Drugs Affecting Cytochrome P450 Isoenzymes 5.10 Risks from Concomitant Use with Benzodiazepines or other CNS Depressants 5.11 Risks of Use in Patients with Gastrointestinal Conditions 5.12 Risks of Use in Patients with Head Injury, Impaired Consciousness, Increased Intracranial Pressure, or Brain Tumors 5.13 Risk of Neuroleptic Malignant Syndrome 5.14 Risk of Paradoxical Reactions, including Dystonias 5.15 Increased Risk of Seizures in Patients with Seizure Disorders 5.16 Co-administration with Monoamine Oxidase Inhibitors (MAOIs) 5.17 Bone-Marrow Depression 5.18 Severe Hypotension 5.19 Neonatal Opioid Withdrawal Syndrome 5.20 Adrenal Insufficiency 5.21 Drug/Laboratory Test Interactions

Prevacid 5 Warnings and Precautions Newly created subsection: (lansoprazole) 5.9, 5.11, or 5.12 Fundic Gland Polyps Prevpac PPI use is associated with an increased risk of fundic gland polyps that increases with long-term use,

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Trade Name Summary of Label Changes (generic name) (amoxicillin; especially beyond one year. Most PPI users who developed fundic gland polyps were asymptomatic and fundic gland polyps were identified incidentally on endoscopy. Use the shortest duration of PPI therapy appropriate to clarithromycin; the condition being treated. lansoprazole)

Prilosec (omeprazole magnesium) Protonix, Protonix IV (pantoprazole sodium) Prezcobix 4 Contraindications Additions and/or revisions underlined: (cobicistat; PREZCOBIX is contraindicated in patients receiving the following co-administered drugs: darunavir Table 1: Drugs That Are Contraindicated with Prezcobix reformatted to a bulleted line listing; please refer to ethanolate) label for complete information.

Remicade 5 Warnings and Precautions 5.1 Serious Infections (infliximab) Additions and/or revisions underlined: … Opportunistic infections due to bacterial, mycobacterial, invasive fungal, viral, or parasitic organisms including aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, cryptococcosis, histoplasmosis, legionellosis, listeriosis, pneumocystosis, salmonellosis and tuberculosis have been reported with TNF-blockers …

Remodulin 5 Warnings and Precautions Addition of the following two subsections: (treprostinil) 5.4 Risk of Symptomatic Hypotension Treprostinil is a pulmonary and systemic vasodilator. In patients with low systemic arterial pressure, treatment with Remodulin may produce symptomatic hypotension. 5.5 Risk of Bleeding Remodulin inhibits platelet aggregation and increases the risk of bleeding.

Rituxan 5 Warnings and Precautions Additions and/or revisions underlined: (rituximab) 5.1 Infusion Reactions … For RA and PV patients … 5.12 Concomitant Use with Other Biologic Agents and DMARDS other than Methotrexate in RA, GPA, MPA, and PV … has not been studied in GPA or MPA or PV patients exhibiting peripheral …

Stelara 5 Warnings and Precautions Newly created subsection: (ustekinumab) 5.9 Noninfectious Pneumonia

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Trade Name Summary of Label Changes (generic name) Cases of interstitial pneumonia, eosinophilic pneumonia and cryptogenic organizing pneumonia have been reported during post-approval use of STELARA®. Clinical presentations included cough, dyspnea, and interstitial infiltrates following one to three doses. Serious outcomes have included respiratory failure and prolonged hospitalization. Patients improved with discontinuation of therapy and in certain cases administration of corticosteroids. If diagnosis is confirmed, discontinue STELARA® and institute appropriate treatment.

Tussionex Boxed Warning (extensive additions, please refer to label) Pennkinetic 4 Contraindications (chlorpheniramine (additions underlined) polistirex;  All children younger than 6 years of age. hydrocodone TUSSIONEX Pennkinetic is also contraindicated in patients with:  Significant respiratory depression. polistirex)  Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment.  Known or suspected gastrointestinal obstruction, including paralytic ileus. Hypersensitivity to hydrocodone, chlorpheniramine, or any of the inactive ingredients in TUSSIONEX Pennkinetic. 5 Warnings and Precautions (PLR conversion: subsections created as below, see label for complete information) 5.1 Addiction, Abuse, and Misuse 5.2 Life-Threatening Respiratory Depression 5.3 Risks of Use in Pediatric Populations 5.4 Risks of Use in Other At-Risk Populations 5.5 Risk of Accidental Overdose and Death due to Medication Errors 5.6 Activities Requiring Mental Alertness: Risks of Driving and Operating Machinery 5.7 Risks from Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers 5.8 Risks from Concomitant Use with Benzodiazepines or other CNS Depressants 5.9 Risks of Use in Patients with Gastrointestinal Conditions 5.10 Risks of Use in Patients with Head Injury, Impaired Consciousness, Increased Intracranial Pressure, or Brain Tumors 5.11 Increased Risk of Seizures in Patients with Seizure Disorders 5.12 Severe Hypotension 5.13 Neonatal Opioid Withdrawal Syndrome 5.14 Adrenal Insufficiency 5.15 Drug/Laboratory Test Interactions

Venclexta 4 Contraindications Additions and/or revisions underlined: (venetoclax) Concomitant use of VENCLEXTA with strong CYP3A inhibitors at initiation and during ramp- up phase is contraindicated due to the potential for increased risk of tumor lysis syndrome. 5 Warnings and Precautions 5.1 Tumor Lysis Syndrome Additions and/or revisions underlined: Tumor lysis syndrome (TLS), including fatal events and renal failure requiring dialysis, has occurred in patients with previously treated CLL with high tumor burden when treated with VENCLEXTA. With the current (5 week) dose ramp-up, TLS prophylaxis and monitoring, the rate of TLS was 2% in the VENCLEXTA monotherapy studies. The rate of TLS remained consistent with VENCLEXTA in combination with rituximab. With a 2-3-week

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Trade Name Summary of Label Changes (generic name) dose ramp-up and higher starting dose in patients with CLL, the TLS rate was 13% and included deaths and renal failure. 5.2 Neutropenia Additions and/or revisions underlined: Grade 3 or 4 neutropenia developed in 64% (124/194) of patients and Grade 4 neutropenia developed in 31% of patients treated with VENCLEXTA in combination with rituximab (see Table 8). Grade 3 or 4 neutropenia developed in 63% (216/344) of patients and Grade 4 neutropenia developed in 33% of patients treated with VENCLEXTA monotherapy (see Table 10). Febrile neutropenia occurred in 4% of patients treated with VENCLEXTA in combination with rituximab and in 6% of patients treated with VENCLEXTA monotherapy.

Vimovo 5 Warnings and Precautions Newly created subsection: (esomeprazole 5.27 Fundic Gland Polyps magnesium; PPI use is associated with an increased risk of fundic gland polyps that increases with long-term use, naproxen) especially beyond one year. Most PPI users who developed fundic gland polyps were asymptomatic and fundic gland polyps were identified incidentally on endoscopy. Use the shortest duration of PPI therapy appropriate to the condition being treated.

Xarelto 5 Warnings and Precautions 5.2 Risk of Bleeding (rivaroxaban) (additions underlined) … Reversal of Anticoagulant Effect

An agent to reverse the anti-factor Xa activity of rivaroxaban is available. Because of high plasma protein binding, rivaroxaban is not expected to be dialyzable. Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban. Partial reversal of prothrombin time prolongation has been seen after administration of prothrombin complex concentrates (PCCs) in healthy volunteers. The use of other procoagulant reversal agents like activated prothrombin complex concentrate (APCC) or recombinant factor VIIa (rFVIIa) has not been evaluated.

Xgeva 5 Warnings and Precautions Additions and/or revisions underlined: (denosumab) 5.6 Hypercalcemia Following Treatment Discontinuation in Patients with Giant Cell Tumor of Bone and in Patients with Growing Skeletons Clinically significant hypercalcemia requiring hospitalization and complicated by acute renal injury has been reported in Xgeva-treated patients with giant cell tumor of bone and patients with growing skeletons. Hypercalcemia has been reported within the first year after treatment discontinuation. After treatment is discontinued, monitor patients for signs and symptoms of hypercalcemia, assess serum calcium periodically, reevaluate the patient’s calcium and vitamin D supplementation requirements and manage patients as clinically appropriate.

Yosprala 5 Warnings and Precautions Newly created subsection: (aspirin; 5.20 and 5.13 Fundic Gland Polyps omeprazole) PPI use is associated with an increased risk of fundic gland polyps that increases with long-term use, Zegerid

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Trade Name Summary of Label Changes (generic name) (omeprazole; especially beyond one year. Most PPI users who developed fundic gland polyps were asymptomatic and fundic gland polyps were identified incidentally on endoscopy. Use the shortest duration of PPI therapy appropriate to sodium the condition being treated. bicarbonate)

Treatment Guideline Updates

Title Citation/Link

Charles A Sklar, Zoltan Antal, Wassim Chemaitilly, Laurie E Cohen, Cecilia Hypothalamic–Pituitary and Growth Follin, Lillian R Meacham, M Hassan Murad; Hypothalamic–Pituitary and Disorders in Survivors of Childhood Growth Disorders in Survivors of Childhood Cancer: An Endocrine Society Cancer: An Endocrine Society Clinical Clinical Practice Guideline, The Journal of Clinical Endocrinology & Practice Guideline Metabolism, https://doi.org/10.1210/jc.2018-01175 Screening for Osteoporosis to Prevent Fractures. US Preventative Services USPSTF Screening for Osteoporosis Task Force Recommndation Statement. JAMA. 2018; 319 (24):2521-2531. to Prevent Fractures Doi: 10.1001/jama.2018.7498 Update of Recommendations for Use Borisov AS, Bamrah Morris S, Njie GJ, et al. Update of Recommendations for of Once-Weekly Isoniazid-Rifapentine Use of Once-Weekly Isoniazid-Rifapentine Regimen to Treat Latent Regimen to Treat Latent Mycobacterium tuberculosis Infection. MMWR Morb Mortal Wkly Rep Mycobacterium tuberculosis Infection 2018;67:723–726. DOI: http://dx.doi.org/10.15585/mmwr.mm6725a5

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