Cutaneous Adverse Events in Newly Approved FDA Non-cancer Drugs: A Systematic Review.

One hundred and eighty non-oncologic medications received US Food and Drug Administration approval between 2013 and 2018. Twenty-one of these medications were associated with cutaneous adverse events from mild rashes to severe reactions including Stevens–Johnson syndrome. Clinicians should consider these newly approved medications when managing cutaneous pathologies.

Table 2 reviews monoclonal antibody medications approved between 2013 and 2018 with reported adverse cutaneous events in greater than 5% of patients. Table 3 reviews small-molecule medications approved between 2013 and 2018 that reported adverse cutaneous events in greater than 5% of patients. Table 2 Monoclonal antibody drugs approved by the US Food and Drug Administration between 2013 and 2018 known to cause adverse cutaneous events in more than 5% of patients Drug name Brand name Indication Mechanism Year approved % of patients who developed a rash with this drug during a pivotal clinical trial % of patients who developed a rash while taking a placebo Rash description (clinical trial) Rash description (supplemental case report) Daclizumab a Zinbryta Multiple sclerosis (kidney transplant rejection prevention) Binds to CD25, a high-affinity IL-2 receptor subunit on T cells 2016 (1997) 7 3 Erythematous, exfoliative, macular, maculopapular, papular, pruritic, and vesicular Urticarial, papulovesicular, acne Dupilumab Dupixent Eczema Antagonizes IL-4 and IL-13 receptors 2017 Head and neck erythema, dermatitis, granulomatosis Ibalizumab-uiyk Trogarzo HIV Prevents viral fusion 2018 5 Erythematous, generalized, macular, maculopapular, papular Siltuximab Sylvant Multicentric Castleman disease Binds to IL-6 2014 28 12 Generalized, maculopapular, popular, and pruritic Rash HIV human immunodeficiency virus, IL interleukin a Indicates that the drug has been either previously approved (either in the USA or abroad), or approved abroad for an alternative indication. Parentheses indicate the associated indications and dates for this alternative approval Table 3 Small-molecule drugs approved by the US Food and Drug Administration between 2013 and 2018 known to cause adverse cutaneous events in more than 5% of patients Drug name Brand name Indication Mechanism Year approved % patients who developed a rash during a pivotal clinical trial % patients who developed a rash on placebo during a pivotal clinical trial Rash description (clinical trial) Rash description (supplemental case report) Benznidazole a Benznidazole Chagas disease Unknown 2017 (1970s) 16 0 Rash Rash, skin eruptions, hypersensitivity dermatitis, drug eruption, AGEP, DRESS syndrome, SJS/TEN, classic generalized morbilliform eruption, skin peeling Cannabidiol Epidiolex Epilepsy Unknown 2018 13 3 Rash Diffuse, erythematous, pustular rash of the bilateral arms, axillae, buttocks, and groin Dasabuvir Viekira Pak HCV Inhibits NS5B palm polymerase, preventing viral replication 2014 16 9 Pruritus, erythema, eczema, maculo-papular, macular, dermatitis, papular, skin exfoliation, pruritic, erythematous, generalized, dermatitis allergic, dermatitis contact, exfoliative, dermatitis, photosensitivity reaction, psoriasis, skin reaction, ulcer, urticaria Generalized maculopapular rash Dimethyl fumarate a Tecfidera Multiple sclerosis (psoriasis) Activates the nuclear erythroid 2-related factor 2 transcriptional pathway 2013 (2017) 8 3 Rash EN, rash, and pruritus in children Edaravone a Radicava ALS (ischemic stroke) Free radical scavenger 2017 (2009) 8 5 Dermatitis, eczema Fish oil triglycerides Omegaven Parenteral nutrition-associated cholestasis Source of calories and essential fatty acids 2018 8 Rash Fostamatinib Tavalisse ITP Inhibits spleen tyrosine kinase (SYK) 2018 9 2 Erythematous and macular Isavuconazonium sulfate Cresemba Invasive mucormycosis Prevents ergosterol synthesis by inhibition of lanosterol 14-alpha-demethylase 2015 8.6 13.9 (voriconazole, not placebo) Pruritus Lumacaftor 200 mg a /Ivacaftor 125 mg Orkambi Cystic fibrosis Lumacaftor: increases the amount of CFTR at the cell surface Ivacaftor: enhances the CFTR protein's function 2015 (2012) 7 2 Rash Rash Moxidectin Moxidectin Onchocerciasis due to Onchocerca volvulus Binds to GluCl channels, GABA receptors, and/or ABC transporters 2018 37 21 (ivermectin, not placebo) Papular, urticaria Pruritus and rash Obeticholic acid Ocaliva Chronic liver disease Agonist for FXR; a regulator of bile acid, inflammatory, fibrotic, and metabolic pathways 2016 10 8 Urticaria, macular, papular, maculo-papular, heat rash, cholinergic urticaria Ombitasvir Viekira Pak HCV Inhibits HCV non-structural protein 5A 2014 16 9 Pruritus, erythema, eczema, maculo-papular, macular, dermatitis, papular, skin exfoliation, pruritic, erythematous, generalized, dermatitis allergic, dermatitis contact, exfoliative, dermatitis, photosensitivity reaction, psoriasis, skin reaction, ulcer, urticaria Generalized maculopapular rash Paritaprevir Viekira Pak HCV Inhibits HCV NS3/4A serine protease, thereby preventing viral replication 2014 16 9 Pruritus, erythema, eczema, maculo-papular, macular, dermatitis, papular, skin exfoliation, pruritic, erythematous, generalized, dermatitis allergic, dermatitis contact, exfoliative, dermatitis, photosensitivity reaction, psoriasis, skin reaction, ulcer, urticaria Generalized maculopapular rash Pirfenidone a Esbriet Idiopathic pulmonary fibrosis Inhibits TGF-beta production and response, thereby reducing collagen production 2014 (2011) 30 10 Rash Erythematous rash with edema, photosensitivity reaction (acute dermatitis with focal presence of necrotic keratinocytes) Selexipag Uptravi Pulmonary arterial hypertension Oral prostacyclin receptor agonist 2015 11 8 Rash Simeprevir Olysio HCV Prevents viral maturation through inhibition of the NS3/4A protease 2013 12 Photosensitivity Eczematous, maculopapular, and lichenoid (14.3%) Sofosbuvir Sovaldi HCV Inhibits NS5B, thereby inhibiting HCV RNA synthesis 2013 8 Pruritus SJS AGEP acute generalized exanthematous pustulosis, ALS amyotrophic lateral sclerosis, CFTR cystic fibrosis transmembrane conductance regulator, DRESS Drug Rash with Eosinophilia and Systemic Symptoms syndrome, EN erythema nodosum, FXR farnesoid X receptor, HCV hepatitis C virus, ITP immune thrombocytopenic purpura, SJS/TEN Stevens–Johnson syndrome/toxic epidermal necrolysis, TGF transforming growth factor a Drug has been either previously approved (either in the USA or abroad), or approved abroad for an alternative indication. Parentheses indicate the associated indications and dates for this alternative approval Monoclonal antibody drugs approved by the US Food and Drug Administration between 2013 and 2018 known to cause adverse cutaneous events in more than 5% of patients HIV human immunodeficiency virus, IL interleukin a Indicates that the drug has been either previously approved (either in the USA or abroad), or approved abroad for an alternative indication. Parentheses indicate the associated indications and dates for this alternative approval Small-molecule drugs approved by the US Food and Drug Administration between 2013 and 2018 known to cause adverse cutaneous events in more than 5% of patients AGEP acute generalized exanthematous pustulosis, ALS amyotrophic lateral sclerosis, CFTR cystic fibrosis transmembrane conductance regulator, DRESS Drug Rash with Eosinophilia and Systemic Symptoms syndrome, EN erythema nodosum, FXR farnesoid X receptor, HCV hepatitis C virus, ITP immune thrombocytopenic purpura, SJS/TEN Stevens–Johnson syndrome/toxic epidermal necrolysis, TGF transforming growth factor a Drug has been either previously approved (either in the USA or abroad), or approved abroad for an alternative indication. Parentheses indicate the associated indications and dates for this alternative approval Daclizumab was previously approved in 1997 under the brand name Zenapax to prevent organ rejection in de novo allogenic renal transplant recipients [ 4 ]. This form of daclizumab was associated with the development of acne seen in 8.9% of patients taking daclizumab vs 7.2% of patients using placebo [ 4 ]. However, this form of daclizumab was ultimately discontinued in 2009 because of diminishing market demand rather than safety concerns [ 5 ]. In 2016, daclizumab was approved for the treatment of multiple sclerosis. However, daclizumab was voluntarily removed from the market owing to reports of encephalitis associated with its use [ 6 ]. Daclizumab binds to CD25, a high-affinity interleukin (IL)-2 receptor subunit on T cells, to prevent IL-2-mediated T-cell activation in patients with multiple sclerosis [ 7 ]. Rashes were seen in 7% of patients taking daclizumab during clinical trials vs 3% of patients taking placebo. Details of the clinical trial indicate that the observed rash was described as an erythematous rash, exfoliative rash, macular rash, maculopapular rash, papular rash, pruritic rash, rash, and vesicular rash [ 8 ]. Additional details are limited; however, a supplementary case series also demonstrated an urticarial papulovesicular rash occurring roughly 3 months after discontinuation of daclizumab [ 9 ]. While this drug is immunosuppressive, it is possible that a wide variety of morbilliform hypersensitivity reactions may be seen due to an additional loss or delayed loss of immune tolerance from an off-target decrease in T-regulatory cells also displaying the CD25 antigen [ 7 ]. Dupilumab, approved in 2017, is a medication used to treat eczema. It inhibits IL-4 and IL-13 signaling by specifically binding to the IL-4Rα subunit shared by the IL-4 and IL-13 receptor complexes. While the clinical trials did not reveal any novel cutaneous adverse events apart from injection-site reactions, which were seen in 10% of patients taking dupilumab compared with 6% of patients taking placebo [ 10 ], a recent case series describes a paradoxical head and neck erythema in seven patients after taking dupilumab for 10–39 weeks [ 11 ]. Both clinical and histopathological findings suggested that these were drug-induced skin reactions. A multi-institution retrospective medical record review revealed that dupilumab-induced facial redness was seen in approximately 10% of patients treated with dupilumab in daily practice [ 12 ]. A French national retrospective study found that approximately 4% of patients taking dupilumab developed head and neck dermatitis [ 13 ]. A recent case report has suggested that this dupilumab-induced facial redness is attributable to hypersensitivity to Malassezia species and advocates for the use of oral itraconazole in the management of this symptom [ 14 ]. Yet another case report describes systemic sarcoid-like granulomatosis occurring 4 months after initiation of dupilumab therapy [ 15 ]. Ibalizumab-uiyk was approved in 2018 for the treatment of human immunodeficiency virus. It is a fusion inhibitor, blocking the human immunodeficiency virus-1 virus from infecting CD4+ T cells by binding to domain 2 of CD4. This interferes with post-attachment steps required for the entry of human immunodeficiency virus-1 particles into host cells, thus preventing the viral transmission that occurs via cell–cell fusion. Rashes were seen in 5% of patients taking ibalizumab-uiyk during clinical trials and were described as a rash, erythematous rash, generalized rash, macular rash, maculopapular rash, and papular rash [ 16 ]. Supplemental case reports have not been published to further describe the skin adverse events. Approved in 2014, siltuximab is a medication used to treat multicentric Castleman disease. It binds to IL-6, thereby preventing its association with both soluble and membrane-bound IL-6 receptors. Rashes were seen in 28% of patients taking siltuximab during clinical trials vs 12% of patients taking placebo. Details of the clinical trial indicate that the observed rash was described as generalized, maculopapular, papular, or pruritic [ 17 ]. A phase II, open-label multicenter study also noted rash as a side effect for 42% of patients taking siltuximab [ 18 ]. Additional case reports have not been published to supplement the clinical trial data. Benznidazole, a nitroimidazole, was approved by the FDA in 2017 for the treatment of Chagas disease in children up to age 12 years. However, it has been utilized since the 1970s in Latin America [ 19 ], and has been available to clinicians in the USA through the Centers for Disease Control and Prevention since 2011 [ 20 ]. Its mechanism of action is unknown. Rashes were seen in 16% of patients taking benznidazole during clinical trials vs 0% of patients taking placebo [ 21 ]. The clinical trial did not offer further characterization of the rash. A prospective descriptive study examining the effects of benznidazole treatment also describes an associated rash in 31.3% of patients and skin peeling in 25% of patients. In 15.6% of the patients, the rash was classified as skin eruptions that culminated in discontinuation of the drug [ 22 ]. Severe cutaneous adverse reactions such as acute generalized exanthematous pustulosis [ 23 ] and Drug Rash with Eosinophilia and Systemic Symptoms (DRESS syndrome) [ 24 ] have also been reported. A prospective study found that dermatitis due to hypersensitivity was seen in 32.4% of patients taking benznidazole [ 25 ], and a supplemental case series describes the induced rash as a classic generalized morbilliform eruption, suggesting that patch testing may be beneficial in the confirmation of hypersensitivity reactions to benznidazole given its necessity in trypanosomiasis [ 26 ]. Interestingly, another nitroimidazole drug, metronidazole, has been reported to be a cross-reactor in several cases [ 26 ]. Additionally, a prospective observational study describes a drug eruption occurring in 38.5% of patients taking benznidazole [ 27 ]. Cannabidiol oral solution was approved in 2018 to treat seizures associated with Lennox–Gastaut syndrome and Dravet syndrome. Its mechanism of action is unknown. Rashes were seen in 13% of patients taking cannabidiol during clinical trials vs 3% of patients taking placebo [ 28 ]. The clinical trial did not elaborate on the exact nature of the rash, but a case report describes an instance of acute generalized exanthematous pustulosis 48 h after self-medicating with over-the-counter oral cannabidiol for hypertension [ 29 ]. Approved in 2013, dimethyl fumarate is a medication used to treat multiple sclerosis. It has also been approved to treat psoriasis in Europe [ 30 ], receiving approval from the European Medicines Agency in 2017 under the brand name Skilarence ® [ 31 ]. Its mechanism of action is thought to involve activation of the nuclear erythroid 2-related factor 2 (nuclear factor erythroid-derived 2-like 2; Nrf2) transcriptional pathway. Rashes were seen in 8% of patients taking dimethyl fumarate during clinical trials vs 3% of patients taking placebo but did not result in treatment discontinuation [ 32 ]. Details of the clinical trial indicate that the observed rash was described as simply a rash. However, flushing was also noted in 40% of patients taking dimethyl fumarate vs 6% of patients taking placebo. It is believed that the flushing reaction described is most likely prostaglandin mediated and may be less visible or likely to develop in non-white populations [ 33 ]. A case report details an instance of erythema nodosum occurring in a woman after 6 years of dimethyl fumarate treatment [ 34 ]. Additional clinical trials have shown high rates of rashes (23%) and pruritus (8%) in children [ 35 ]. Edaravone is a medication used to treat amyotrophic lateral sclerosis that was approved in 2017. Edaravone has also been approved for the treatment of acute ischemic stroke in Japan since 2009 [ 36 ]. It is believed to act as a free radical scavenger, thereby preventing oxidative stress damage to neurons. Rashes were seen in 8% of patients taking edaravone during clinical trials vs 5% of patients taking placebo [ 37 ]. Details of the clinical trial indicate that the observed rash was described as dermatitis or eczema. Fish oil triglycerides as an injectable emulsion are used to treat parenteral nutrition-associated cholestasis. They were approved by the FDA in 2018 and act by providing a biologically utilizable source of calories and essential fatty acids. Rashes were seen in 8% of patients taking fish oil triglycerides during clinical trials [ 38 ]. The clinical trial did not elaborate on the exact nature of the rash and no specific case reports were found to offer further clarification. Approved in 2018, fostamatinib is a medication used to treat immune thrombocytopenic purpura. Its mechanism of action involves inhibition of spleen tyrosine kinase (SYK). Rashes were seen in 9% of patients taking fostamatinib during clinical trials vs 2% of patients taking placebo. Details of the clinical trial indicate that the observed rash was described as a rash, with erythematous and macular features, suggesting a morbilliform reaction [ 39 ]. Isavuconazonium sulfate is a triazole antifungal medication used to treat invasive mucormycosis that was approved in 2015. Its mechanism of action involves inhibition of ergosterol synthesis by inhibiting the cytochrome P450-dependent enzyme, lanosterol 14-alpha-demethylase. Rashes were seen in 8.6% of patients taking isavuconazonium sulfate vs 13.9% of patients taking voriconazole [ 40 ]. Details of the clinical trial indicate that the observed rash was pruritic but without other descriptors. Given the active comparator had a higher rate of cutaneous disease, it is possible that a rash while taking isavuconazonium may be attributable to the high acuity of the treated infection, polypharmacy, or the overall complexity of treated patients who are often immunocompromised rather than the drug itself. Lumacaftor 200 mg/ivacaftor 125 mg, approved in 2015, is a medication used to treat cystic fibrosis in children. This medication utilizes two active ingredients: lumacaftor and ivacaftor. While lumacaftor increases the amount of protein at the cell surface by targeting the defective F508del cystic fibrosis transmembrane conductance regulator protein, ivacaftor (which was approved by the FDA to treat cystic fibrosis in 2012 under the brand name Kalydeco ® ) [ 41 ] enhances the cystic fibrosis transmembrane conductance regulator protein’s function once it reaches the cell surface. Rashes were seen in 7% of patients taking lumacaftor 200 mg/ivacaftor 125 mg during clinical trials vs 2% of patients taking placebo [ 42 ]. The clinical trial did not offer a description of the rash. An article detailing the phase III clinical trial for this medication also comments on the presence of a rash in one patient that resulted in discontinuation of the medication [ 43 ]. However, this article did not offer any further clarification regarding the nature of the rash. Moxidectin, approved in 2018, is a medication used to treat onchocerciasis due to Onchocerca volvulus . It binds to glutamate-gated chloride channels, gamma-aminobutyric acid receptors, and/or ATP-binding cassette transporters. Rashes were seen in 37% of patients taking moxidectin during clinical trials vs 21% of patients taking ivermectin. Details of the clinical trial indicate that the observed rash was described as a papular or urticarial [ 44 ]. A randomized controlled trial comparing moxidectin to ivermectin found that statistically significant higher percentages of participants treated with moxidectin experienced pruritus (87% vs 56%) and rash (63% vs 42%) [ 45 ]. The study did not offer further characterization of the rash. Approved in 2016, obeticholic acid is a medication used to treat chronic liver disease. It is an agonist for farnesoid X receptor, a nuclear receptor expressed in the liver and intestine that regulates bile acid and inflammatory, fibrotic, and metabolic pathways. Rashes were seen in 10% of patients taking obeticholic acid during clinical trials vs 8% of patients taking placebo [ 46 ]. Details of the clinical trial indicate that the observed rash was described as urticarial, macular, papular, maculo-papular, heat rash, and cholinergic urticaria. Ombitasvir, dasabuvir, and paritaprevir are three medications that were approved by the FDA in 2014 to treat hepatitis C virus (HCV). They are used as a combination drug, along with ritonavir, in the commercial formulation “Viekira Pak ® ”. Ombitasvir is an inhibitor of the HCV non-structural protein 5A. Dasabuvir inhibits the action of NS5B palm polymerase, effectively terminating RNA polymerization and stopping the replication of the HCV’s genome. Paritaprevir prevents HCV replication by inhibiting the HCV’s NS3/4A serine protease. Rashes were seen in 16% of patients taking the combination of ombitasvir, dasabuvir, paritaprevir, and ritonavir vs 9% of patients taking placebo during clinical trials [ 47 ]. Details of the clinical trial indicate that the observed rash was described as eczematous, maculo-papular, macular, dermatitis, papular, pruritic, erythematous, generalized, allergic dermatitis, contact dermatitis, exfoliative, dermatitis, photosensitivity reaction, psoriasis, ulcers, and urticarial. A case report describes the development of a generalized maculopapular rash appearing 2 weeks after starting this antiviral treatment [ 48 ]. Approved in 2014, pirfenidone is a medication used to treat idiopathic pulmonary fibrosis; an indication for which it was approved in 2011 by the European Medicines Agency [ 49 ]. It reduces fibroblast proliferation by inhibiting the production of transforming growth factor-beta and reducing the collagen production stimulated by transforming growth factor-beta. Rashes were seen in 30% of patients taking pirfenidone during clinical trials vs 10% of patients taking placebo [ 50 ]. The clinical trial did not offer greater description of the rash, but a case report described the rash as erythematous with edema and noted that it occurred in 32% of patients taking pirfenidone vs 12% of patients taking placebo. A photosensitivity reaction (Fig.  2 ) was also noted in 12% of patients taking pirfenidone vs 2% of patients taking placebo, which was characterized histopathologically as acute dermatitis with focal presence of necrotic keratinocytes [ 51 ]. Fig. 2 Pirfenidone phototoxic drug eruption Pirfenidone phototoxic drug eruption Selexipag is a medication used to treat pulmonary arterial hypertension that was approved in 2015. Selexipag is an oral prostacyclin receptor (IP receptor) agonist that is structurally distinct from prostacyclin. Rashes were seen in 11% of patients taking selexipag during clinical trials vs 8% of patients taking placebo [ 52 ]. The clinical trial described the cutaneous adverse reaction as simply a rash and no case reports offering further clarification were identified. Simeprevir, approved in 2013, is a medication used to treat HCV. It prevents viral maturation through inhibition of the NS3/4A protease. Rashes were seen in 12% of patients taking simeprevir during clinical trials [ 53 ]. The clinical trial described the reaction as a rash that included photosensitivity. A retrospective case series reports that patients taking simeprevir experienced rashes described as eczematous (28.6%), maculopapular (57.1%), and lichenoid (14.3%) [ 54 ]. Sofosbuvir was approved in 2013 as a medication to treat HCV. Sofosbuvir inhibits the HCV NS5B protein, thereby inhibiting viral RNA synthesis. Rashes were seen in 8% of patients taking sofosbuvir during clinical trials [ 55 ]. Details of the clinical trial indicate that the observed rash was described as a rash and pruritus. A case report detailed an instance of Stevens–Johnson syndrome 10 days after initiating sofosbuvir therapy [ 56 ].

Of the 241 medications approved by the FDA between 2013 and 2018, 21 of the non-chemotherapeutic agents were associated with a prominent rate of cutaneous adverse events. Most reactions were classified as morbilliform, macular, popular, or maculopapular. This study was largely limited by the frequently vague and non-specific rash reporting found in the medication package inserts as well as the available case reports. Notably, the lack of specificity in the FDA package inserts highlights the importance of dermatologists reporting adverse events during clinical trials and post-marketing surveillance. Trials should consider engaging with dermatology experts to provide more granular detail of drug reactions when skin toxicities appear common. Fortunately, only a few severe cutaneous adverse reactions have been reported, namely in benznidazole, cannabidiol, and sofosbuvir. When suspicious, careful history taking of any additions or changes to a patient’s medication regimen is an important component of the dermatology assessment. Familiarization with these new therapeutics including understanding their indications and who may be treated should help dermatologists and referring physicians to recognize drug reactions early.

Drugs approved by the FDA between 2013 and 2018 were systematically reviewed directly from the FDA website’s database, and a list of the 241 medications and their approved indications was created (Table 1 ). Subsequently, 61 medications with cancer indications were removed. Then, the prescribing information package inserts for the remaining 180 drugs were reviewed and evaluated for mention of any cutaneous adverse reactions. Medications that produced cutaneous adverse events other than injection-site reactions in more than 5% of patients from pivotal clinical trials or the package insert were included in the study, resulting in the ultimate inclusion of 21 medications (Fig.  1 ). Subsequently, a supplemental literature review was performed using the PubMed search engine and MEDLINE database to better characterize the rash using the search terms: “Drug Name”, AND rash, OR cutaneous, OR dermatitis. The relevant articles were evaluated and any mention of an adverse cutaneous event was extracted and summarized. Of note, the literature review conducted for this study included an emphasis on rashes rather than subjective complaints such as pruritus. References from the articles were cross-checked and additional articles were added if not found in the search strategy. Table 1 All medications approved by the US Food and Drug Administration between 2013 and 2018 Generic Brand Indication 2013  Afatinib Gilotrif Non-small cell lung cancer  Alogliptin Nesina Type 2 diabetes mellitus  Canagliflozin Invokana Type 2 diabetes mellitus  Conjugated estrogens and bazedoxifene Duavee Menopause  Dabrafenib Tafinlar Cancers with BRAF gene mutation  Dimethyl fumarate Tecfidera Multiple sclerosis  Dolutegravir Tivicay HIV  Eslicarbazepine Aptiom Partial-onset seizures  Flutemetamol Vizamyl Alzheimer disease  Fluticasone furoate and vilanterol Breo Ellipta Chronic obstructive pulmonary disease  Gadoteric acid Dotarem Gadolinium-based contrast agent used with MRI  Ibrutinib Imbruvica Mantle cell lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, Waldenstrom macroglobulinemia  luliconazole Luzu Tinea pedis, tinea cruris, and tinea corporis  Macitentan Opsumit Pulmonary arterial hypertension  Mipomersen Kynamro Familial hypercholesterolemia  Obinutuzumab Gazyva Chronic lymphocytic leukemia and follicular lymphoma  Ospemifene Osphena Painful intercourse and vaginal dryness  Pomalidomide Pomalyst Multiple myeloma  Radium-223 Xofigo Prostate cancer  Riociguat Adempas Chronic thromboembolic pulmonary hypertension  Simeprevir Olysio Hepatitis C virus  Sofosbuvir Sovaldi Hepatitis C virus  Technetium Tc 99 m tilmanocept Lymphoseek Lymphatic mapping in patients with solid tumors  Trametinib Mekinist Cancer in people who have a ‘ BRAF ’ gene mutation  Trastuzumab emtansine Kadcyla HER2-positive breast cancer  Umeclidinium bromide Anoro Ellipta Chronic obstructive pulmonary disease  Vortioxetine Brintellix Major depression 2014  Albiglutide Tanzeum Type 2 diabetes mellitus  Apremilast Otezla Arthritis  Belinostat Beleodaq Peripheral T-cell lymphoma  Blinatumomab Blincyto Acute lymphoblastic leukemia  Ceftolozane Zerbaxa Complicated intra-abdominal infections and complicated urinary tract infections  Ceritinib Zykadia Non-small cell lung cancer  Dalbavancin Dalvance Skin infections  Dapagliflozin Farxiga Type 2 diabetes mellitus  Dasabuvir Viekira Pak Hepatitis C virus  Droxidopa Northera Dizziness or a light-headed feeling  Dulaglutide Trulicity Type 2 diabetes mellitus  Efinaconazole Jublia Onychomycosis  Eliglustat Cerdelga Type 1 Gaucher disease  Elosulfase alfa Vimzim Mucopolysaccharidosis IV type A  Empagliflozin Jardiance Type 2 diabetes mellitus  Finafloxacin Xtoro Acute otitis externa  Idelalisib Zydelig Chronic lymphocytic leukemia  Ledipasvir Harvoni Hepatitis C virus  Metreleptin Myalept Leptin deficiency  Miltefosine Impavido Leishmaniasis  Naloxegol Movantik Constipation that is caused by opioids  Netupitant Akynzeo Nausea and vomiting caused by chemotherapy  Nintedanib Ofev Idiopathic pulmonary fibrosis  Nivolumab Opdivo Non-small cell lung cancer  Olaparib Lymparza Ovarian cancer  Olodaterol Striverdi Respimat Chronic obstructive pulmonary disease  Ombitasvir Viekira Pak Hepatitis C virus  Oritavancin Orbactiv Bacterial skin and skin structure infections  Paritaprevir Viekira Pak Hepatitis C virus  Peginterferon beta-1a Plegridy Relapsing forms of multiple sclerosis  Pembrolizumab Keytruda Melanoma  Peramivir Rapivab Influenza  Pirfenidone Esbriet Idiopathic pulmonary fibrosis  Ramucirumab Cyramza Stomach cancer, colorectal cancer, or non-small cell lung cancer  Siltuximab Sylvant Multicentric Castleman disease  Suvorexant Belsomra Insomnia  Tasimelteon Hetlioz Non-24-h sleep–wake disorder  Tavaborole Kerydin Onychomycosis  Tazobactam Zerbaxa Drug-resistant bacteria  Tedizolid Sivextro MRSA infections  Vedolizumab Entyvio Ulcerative colitis and Crohn disease  Vorapaxar Zontivity Lower the risk of stroke or serious heart problems 2015  Alectinib Alecensa Anaplastic lymphoma kinase-positive lung cancer  Alirocumab Praluent High cholesterol  Aripiprazole lauroxil Aristada Schizophrenia  Asfotase alfa Strensiq Perinatal, infantile, and juvenile-onset hypophosphatasia  Brexpiprazole Rexulti Schizophrenia  Cangrelor Kengreal Prevent the formation of harmful blood clots  Cariprazine Vraylar schizophrenia  Ceftazidime-avibactam Avycaz Complicated intra-abdominal infections  Cholic acid Cholbam Bile acid synthesis disorders  Cobimetinib Cotellic Melanoma  Daclatasvir Daklinza Hepatitis C virus  Daratumumab Darzalex Multiple myeloma  Deoxycholic acid Kybella Moderate-to-severe fat below the chin  Dinutuximab Unituxin Neuroblastoma  Edoxaban Savaysa Stroke and dangerous blood clots  Elotuzumab Empliciti Multiple myeloma  Eluxadoline Viberzi Irritable bowel syndrome with diarrhea  Elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide Genvoya HIV  Evolocumab Repatha High cholesterol  Flibanserin Addyi Generalized hypoactive sexual desire disorder  Idarucizumab Praxbind Reverse Pradaxa’s blood-thinning effects  Insulin degludec injection Tresiba Diabetes mellitus  Isavuconazonium sulfate Cresemba Invasive aspergillosis and invasive mucormycosis  Ivabradine Corlanor Heart failure  Ixazomib Ninlaro Multiple myeloma  Lenvatinib Lenvima Differentiated thyroid cancer  Lesinurad Zurampic Gout  Lumacaftor 200 mg/ivacaftor 125 mg Orkambi Cystic fibrosis  Mepolizumab Nucala Asthma  Necitumumab Portrazza Squamous non-small cell lung cancer  Osimertinib Tagrisso Non-small cell lung cancer  Palbociclib Ibrance Breast cancer  Panobinostat Farydak Multiple myeloma  Parathyroid hormone Natpara Hypocalcemia  Patiromer for oral suspension Veltassa Hyperkalemia  Rolapitant Varubi Delayed-phase chemotherapy-induced nausea and vomiting  Sacubitril/valsartan Entresto Heart failure  Sebelipase alfa Kanuma Lysosomal acid lipase deficiency  Secukinumab Cosentyx Plaque psoriasis  Selexipag Uptravi Pulmonary arterial hypertension  Sonidegib Odomzo Basal cell carcinoma  Sugammadex Bridion Reverse effects of neuromuscular blocking drugs  Trabectedin Yondelis Soft-tissue sarcomas  Trifluridine and tipiracil Lonsurf Colorectal cancer  Uridine triacetate Xuriden Hereditary orotic aciduria 2016  Atezolizumab Tecentriq Urothelial carcinoma  Bezlotoxumab Zinplava Clostridium difficile  Brivaracetam Briviact Partial-onset seizures  Crisaborole Eucrisa Mild-to-moderate eczema  Daclizumab Zinbryta Multiple sclerosis  Defibrotide sodium Defitelio Hepatic veno-occlusive disease  Elbasvir and grazoprevir Zepatier Hepatitis C virus  Eteplirsen Exondys 51 Duchenne muscular dystrophy  Fluciclovine F 18 Axumin Prostate cancer  Gallium Ga 68 dotatate NETSPOT Neuroendocrine tumors  Ixekizumab Taltz Plaque psoriasis  Lifitegrast ophthalmic solution Xiidra Dry eye disease  Lixisenatide Adlyxin Glycemic control (blood sugar levels)  Nusinersen Spinraza Spinal muscular atrophy  Obeticholic acid Ocaliva Chronic liver disease  Obiltoxaximab Anthim Anthrax  Olaratumab Lartruvo Soft-tissue sarcoma  Pimavanserin Nuplazid Hallucinations and delusions associated with Parkinson disease  Reslizumab Cinqair Asthma  Rucaparib Rubraca Ovarian cancer  Sofosbuvir and velpatasvir Epclusa Hepatitis C virus  Venetoclax Venclexta Chronic lymphocytic leukemia 2017  Abaloparatide Tymlos Osteoporosis  Abemaciclib Verzenio Breast cancers  Acalabrutinib Calquence Mantle cell lymphoma  Angiotensin II Giapreza Septic or other distributive shock  Avelumab Bavencio Merkel cell carcinoma  Benralizumab Fasenra Asthma  Benznidazole Benznidazole Chagas disease  Betrixaban Bevyxxa Venous thromboembolism  Brigatinib Alunbrig Anaplastic lymphoma kinase-positive metastatic non-small cell lung cancer  Brodalumab Siliq Moderate-to-severe plaque psoriasis  Cerliponase alfa Brineura Batten disease  Copanlisib Aliqopa Relapsed follicular lymphoma  Deflazacort Emflaza Duchenne muscular dystrophy  Delafloxacin Baxdela Bacterial skin infections  Deutetrabenazine Austedo Chorea from Huntington disease  Dupilumab Dupixent Eczema  Durvalumab Imfinzi Urothelial carcinoma  Edaravone Radicava Amyotrophic lateral sclerosis  Emicizumab Hemlibra Hemophilia A  Enasidenib Idhifa Acute myeloid leukemia  Ertugliflozin Steglatro Type 2 diabetes mellitus  Etelcalcetide Parsabiv Secondary hyperparathyroidism  Glecaprevir and pibrentasvir Mavyret Hepatitis C virus  Guselkumab Tremfya Plaque psoriasis  Inotuzumab ozogamicin Besponsa Acute lymphoblastic leukemia  Latanoprostene bunod ophthalmic solution Vyzulta Open-angle glaucoma  Lzetermovir Prevymis Prevent infection after bone marrow transplant  Macimorelin acetate Macrilen Growth hormone deficiency  Meropenem and vaborbactam Vabomere Complicated urinary tract infections  Midostaurin Rydapt Acute myeloid leukemia  Naldemedine Symproic Opioid-induced constipation  Neratinib maleate Nerlynx Breast cancer  Netarsudil Rhopressa Glaucoma  Niraparib Zejula Epithelial ovarian, fallopian tube, or primary peritoneal cancers  Ocrelizumab Ocrevus Relapsing and primary progressive forms of multiple sclerosis  Ozenoxacin Xepi Impetigo  Plecanatide Trulance Chronic idiopathic constipation  Ribociclib Kisqali Breast cancer  Safinamide Xadago Parkinson disease  Sarilumab Kevzara Rheumatoid arthritis  Secnidazole Solosec Bacterial vaginosis  Semaglutide Ozempic Type 2 diabetes mellitus  Sofosbuvir, velpatasvir, and voxilaprevir Vosevi Hepatitis C virus  Telotristat ethyl Xermelo Carcinoid syndrome diarrhea  Valbenazine Ingrezza Tardive dyskinesia  Vestronidase alfa-vjbk Mepsevii Mucopolysaccharidosis type VII also known as Sly syndrome 2018  Amifampridine Firdapse Lambert–Eaton myasthenic syndrome  Apalutamide Erleada Prostate cancer  Avatrombopag Doptelet Thrombocytopenia  Baloxavir marboxil Xofluza Influenza  Baricitinib Olumiant Rheumatoid arthritis  Bictegravir, embitcitabine, tenofovir alafenamide Biktarvy HIV  Binimetinib Mektovi Melanoma  Burosumab-twza Crysvita X-linked hypophosphatemia  Calaspargase pegol-mknl Asparlas Acute lymphoblastic leukemia  Cannabidiol Epidioloex Epilepsy  Cemiplimab-rwlc Libtayo Squamous cell carcinoma  Cenegermin-bkbj Oxervate Neurotrophic keratitis  Dacomitinib Vizimpro Non-small-cell lung cancer  Doravirine Pifeltro HIV  Duvelisib Copiktra Chronic lymphocytic leukemia  Elagolix sodium Orilissa Endometriosis  Elapegademase-lvlr Revcovi Adenosine deaminase severe combined immunodeficiency  Emapalumab-lzsgemapalumab-lzsg Gamifant Hemophagocytic lymphohistiocytosis  Encorafenib Braftovi Melanoma  Eravacycline Xerava Intra-abdominal infections  Erenumab-aooe Aimovig Migraine  Fish oil triglycerides Omegaven Parenteral nutrition  Fosnetupitant and palonosetron Akynzeo Chemotherapy-induced nausea and vomiting  Fostamatinib Tavalisse Chronic immune thrombocytopenia  Fremanezumab-vfrm Ajovy Migraine  Galcanezumab-gnlm Emgality Migraine  Gilteritinib Xospata Acute myeloid leukemia  Glasdegib Daurismo Acute myeloid leukemia  Ibalizumab-uiyk Trogarzo HIV  Inotersen Tegsedi Polyneuropathy of hereditary transthyretin-mediated amyloidosis  Ivosidenib Tibsovo Acute myeloid leukemia  Lanadelumab Takhzyro Hereditary angioedema  Larotrectinib Vitrakvi Cancers with a specific biomarker  Lofexidine hydrochloride Lucemyra Opioid withdrawal  Lorlatinib Lorbrena Non-small cell lung cancer  Lusutrombopag Mulpleta Thrombocytopenia  Lutetium Lu 177 dotatate Lutathera Gastroenteropancreatic neuroendocrine tumors  Migalastat Galafold Fabry disease  Mogamulizumab-kpkc Poteligeo Non-Hodgkin lymphoma  Moxetumomab pasudotox-tdfk Lumoxiti Hairy cell leukemia  Moxidectin Moxidectin Onchocerciasis  Omadacycline Nuzyra Bacterial pneumonia and skin infections  Patisiran Onpattro Hereditary transthyretin-mediated amyloidosis  Pegvaliase-pqpz Palynziq Phenylketonuria  Plazomicin Zemdri Complicated urinary tract infections  Prucalopride Motegrity Chronic idiopathic constipation  Ravulizumab Ultomiris Paroxysmal nocturnal hemoglobinuria  Revefenacin Yupelri Chronic obstructive pulmonary disease  Rifamycin Aemcolo Travelers’ diarrhea  Sarecycline Seysara Acne vulgaris  Segesterone acetate and ethinyl estradiol vaginal system Annovera Contraception  Sodium zirconium cyclosilicate Lokelma Hyperkalemia  Stiripentol Diacomit Dravet syndrome  Tafenoquine Krintafel Plasmodium vivax malaria  Tagraxofusp-erzs Elzonris Blastic plasmacytoid dendritic cell neoplasm  Talazoparib Talzenna Patients with breast cancer with a germline BRCA mutation  Tecovirimat TPOXX Smallpox  Tezacaftor; ivacaftor Symdeko Cystic fibrosis  Tildrakizumab Ilumya Plaque psoriasis HER2 human epidermal growth factor receptor 2, HIV human immunodeficiency virus, MRI magnetic resonance imaging, MRSA methicillin-resistant Staphylococcus aureus Fig. 1 PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) diagram detailing the systematic review process. FDA US Food and Drug Administration All medications approved by the US Food and Drug Administration between 2013 and 2018 HER2 human epidermal growth factor receptor 2, HIV human immunodeficiency virus, MRI magnetic resonance imaging, MRSA methicillin-resistant Staphylococcus aureus PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) diagram detailing the systematic review process. FDA US Food and Drug Administration

In the past 5 years, over 40 new medications or new indications have been approved yearly by the US Food and Drug Administration (FDA), presenting a formidable task for dermatologists to remain current with dermatologic adverse events of these newly FDA-approved therapies. Fortunately, numerous reviews have highlighted adverse events among new therapies with cancer indications [ 1 – 3 ]. However, that represents fewer than 25% of all new approvals or new indications. This article reviews the adverse cutaneous side effects of all non-cancer FDA-approved medications released between 2013 and 2018.