eChapter 68: The Goodman & Gilman Year in Review: 2014 New and Noteworthy FDA Approvals

The FDA approved 54 new drugs and biologics of note in 2014. Thirty-four new drugs are pharmacologically similar to others already marketed (see Part 2 of this chapter). The remaining 20 represent first-in-class agents indicated for the management of cancers, cardiovascular risk, hepatitis C virus (HCV) infection, insomnia, inflammatory bowel disease, leishmaniasis, lipodystrophy, mucopolysaccharidosis, onychomycosis, and pulmonary fibrosis, and for immunization against serogroup B meningococcal disease (eTable 68–1).

Fourteen drugs were approved under the FDA’s “breakthrough therapy” designation (eTable 68–1).^{1, 2, 3} Among the breakthrough therapy drugs are the first new biologic agent to receive accelerated approval via this designation (the meningococcal group B vaccine trumenba; see eTable 68–1) and four marketed drugs granted approval as breakthrough therapies for new indications [eltrombopag (promacta) for cytopenias associated with aplastic anemia;^{4, 5} ivacaftor (kalydeco) for eight (additional) rare gene mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene;⁶ and ibrutinib (imbruvica)^{7, 8} and ofatumumab (arzerra),⁹ both for chronic lymphocytic leukemia]. Established by the FDA in 2012, the “breakthrough therapy” designation is reserved for drugs exhibiting superior efficacy against serious diseases.¹⁰ At the end of 2014, a total of 17 agents had been approved as breakthrough therapy drugs.

Also in 2014, 21 of the 54 new drugs were approved for the management of a rare disease, qualifying them for orphan drug status (see eTable 68–1, eTable 68–2, and 2014 Biologic Licenses in Part 2 of this chapter). An additional 13 marketed drugs won approval for an orphan indication in 2014 (eTable 68–3).

In conjunction with olaparib (lynparza) approval in 2014, the FDA also licensed the BRACAnalysis CDx companion diagnostic test for marketing. The test detects BRCA variants eligible for olaparib treatment in patients with ovarian cancer.¹¹ In a related action, the FDA announced its intent to begin regulating laboratory-developed diagnostic tests.^{12, 13} FDA oversight of laboratory tests as “medical devices” is expected to be phased in over a decade, with the highest-risk tests subject to FDA review one year after the final rule is published in the Federal Register.^{14, 15, 16, 17} Other 2014 noteworthy FDA regulatory activities are summarized in Part 2 of this chapter. Brief first-in-class drug monographs follow eTable 68–1.

First-in-Class New Drug Monographs (^†orphan drug; ^$breakthrough drug)

In the drug monographs below, lists of drugs that are known to be cytochrome P450 enzyme inducers and inhibitors can be found in Preissner S, Kroll K, Dunkel M, et al. SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res, 2010, 38(Database issue): D237–D243. The searchable database is available at http://bioinformatics.charite.de/supercyp.

Ceritinib^$† (zykadia) is an anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor that blocks the growth of ALK-dependent cancer cells. Significantly more potent than crizotinib against ALK,²⁰ ceritinib also has activity against insulin-like growth factor 1 receptor (IGF-1R), insulin receptor (InsR), and ROS1.²¹ ALK is described as a member of the insulin receptor family of tyrosine kinases that can act as an oncogenic driver when disregulated.²² Oncogenic ALK mutations are known to occur in 4% to 6% of patients with non–small cell lung cancer (NSCLC).²² Designated as a breakthrough therapy, ceritinib is indicated for the salvage treatment of ALK-positive metastatic NSCLC in patients who have progressed on or are intolerant to crizotinib. The accelerated FDA approval was based on tumor response rate [43.6% as assessed by a blinded independent review committee (BIRC)] and duration of response (7.1 months as assessed by BIRC) among 163 patients studied during an expanded phase I trial.^{21, 23, 24} No survival benefit with ceritinib has been established. Ceritinib is administered orally at a dose of 750 mg daily, with hyperglycemia and cardiac (bradycardia and QT prolongation), gastrointestinal, and hepatic toxicities being dose-limiting. The use of ceritinib may also be limited by life-threatening pulmonary toxicity. Ceritinib is a cytochrome P450 (CYP) 3A4 and P-glycoprotein (P-gp) substrate and is presumed to be a CYP3A4 and CYP2D6 inhibitor. Ceritinib should be taken on an empty stomach because administration with food increases systemic exposure and thereby increases toxicity risk. The absorption of ceritinib is pH dependent, and it is not known what effect concurrent use of proton-pump inhibitors may have on its bioavailability. Ceritinib has a median terminal elimination half-life of 41 hours, and with once-daily dosing, 15 days are necessary to reach steady-state plasma levels. A number of ongoing clinical trials are underway to better discern the safety and efficacy of ceritinib for ALK-dependent NSCLC.²² The chemical structure of ceritinib is shown in eFigure 68–1.

Elosulfase alfa^† (vimizim) is a recombinant form of the human lysosomal enzyme N-acetylgalactosamine-6-sulfatase produced in Chinese hamster ovary cells.²⁵ This sulfatase enzyme is required for the catabolism of glycosaminoglycans and is responsible for preventing the accumulation of keratan sulfate and chondroitin-6-sulfate in the lysosomal compartments of cells throughout the body. Characterized as a very rare, autosomal-recessive, lysosomal storage disorder, a deficiency of this sulfatase leads to widespread cellular, tissue, and organ dysfunction and the disease known as mucopolysaccharidosis IVA (MPS IVA). Approximately 3000 people worldwide (800 in the U.S.) suffer from MPS IVA.²⁶ Elosulfase is the first FDA-approved treatment for patients with this disorder. The enzyme replacement is administered weekly as a slow intermittent intravenous infusion. Administration requires healthcare supervision due to the risk of life-threatening hypersensitivity reactions. The annual cost of therapy is estimated to be $380,000.²⁶ See reference 27 for a clinical summary of the milestones leading to the approval of elosulfase alfa.²⁷

Ledipasvir in combination with sofosbuvir^$ (harvoni) is the first FDA-approved regimen for the treatment of chronic HCV genotype 1 infection that does not require administration with either interferon or ribavirin. harvoni is a fixed-dose combination tablet for once-daily oral administration containing an NS5A inhibitor (ledipasvir, 90 mg) and a nucleotide analog NS5B polymerase inhibitor (sofosbuvir, 400 mg).²⁸ Sofosbuvir is a prodrug converted to its pharmacologically active form (GS-461203). It was first approved in 2013 (under the brand name sovaldi) for the treatment of HCV genotypes 1-4 in combination with ribavirin and/or pegylated interferon. Ledipasvir is one of two first-in-class NS5A inhibitors approved for marketing in 2014 (see also Ombitasvir in combination with paritaprevir, ritonavir, and dasabuvir). Rapid development of viral resistance precludes the use of either new NS5A inhibitor as monotherapy.²⁹ The chemical structure of ledipasvir is shown in eFigure 68–2. Ledipasvir is largely excreted unchanged in the feces through biliary excretion, with a median terminal elimination half-life of 47 hours. Ledipasvir is an inhibitor of the drug transporters P-gp and breast cancer resistance protein (BCRP); therefore, concurrent use with P-gp inducers is not recommended with harvoni. Fatigue and headache are reported to be the main side effects of ledipasvir in combination with sofosbuvir. The recommended dose of harvoni is 1 tablet daily for 8, 12, or 24 weeks, depending on prior treatment exposure and hepatic disease. FDA approval for harvoni was granted on the basis of three controlled trials comprising 1952 patients with a combined sustained virologic response of 97% and a relapse rate of 2%.³⁰ Refer to Liang and Ghany for a comprehensive summary of the phase III trial efficacy results demonstrated for ­harvoni and other new interferon-free regimens for the treatment of chronic HCV infections.³¹

Meningococcal group B vaccine^$ (trumenba) is composed of two recombinant lipidated factor H binding protein (fHBP) variants from N. meningitidis serogroup B. It has activity against four serogroup B strains prevalent in the U.S. and is indicated for active immunization of individuals 10 through 25 years of age to prevent invasive disease.³² trumenba is administered intramuscularly as a 3-dose series according to a 0-, 2-, and 6-month schedule. The most common adverse reactions are reported to be pain at the injection site (≥85%), fatigue (≥40%), headache (≥35%), muscle pain (≥30%), and chills (≥15%). While there is no public health recommendation for the routine use of this vaccine, FDA approval was targeted at streamlining access for at-risk populations, particularly those arising during outbreaks on college campuses.³³

Metreleptin^† (myalept) is recombinant methionyl-human leptin indicated as replacement therapy to manage the complications of leptin deficiency in patients with congenital or acquired generalized lipodystrophy.³⁴ Affecting less than 200 people in the U.S.,³⁵ generalized lipodystrophy is an orphan indication in which adipocyte dysfunction leads to hypertriglyceridemia, ectopic fat deposits, and leptin deficiency. Metreleptin binds to the human leptin receptor (ObR) and is thought to signal satiety through the JAK/STAT transduction pathway. Metreleptin is administered as a once-daily subcutaneous injection. Clinical experience among a limited number of patients (median age at baseline = 15 years) enrolled in an open-label, single-arm study suggests that metreleptin is associated with reductions in food intake and improvements in measurements of HbA1c (35 patients), fasting glucose (37 patients), and fasting triglycerides (36 patients).³⁴ The FDA has restricted the prescribing and distribution of metreleptin to a risk evaluation mitigation strategy (REMS) program because of the possible association with the development of lymphomas and serious metabolic consequences associated with the development of neutralizing antibodies against endogenous leptin. These potential consequences include difficult to control or reverse metabolic derangements associated with weight gain, increases in HbA1c and triglycerides, glucose intolerance, diabetes mellitus, and infections.

Miltefosine (impavido) is an oral medicine that is FDA-approved to treat visceral, cutaneous, and mucosal leishmaniasis. Leishmaniasis is a tropical disease caused by the Leishmania parasite, which is transmitted to humans through sand fly bites. The disease occurs primarily in the tropics and subtropics, and most U.S. patients acquire leishmaniasis overseas. As leishmaniasis is considered a rare disease, miltefosine was granted orphan drug status by the FDA for this indication. Among 547 patients enrolled in four clinical trials, the most common side effects were abdominal pain, decreased appetite, diarrhea, dizziness, drowsiness, headache, itching, nausea, vomiting, and elevated serum liver enzymes and creatinine.³⁶ Parasite resistance and relapse after apparent cure have both been reported.³⁷ Miltefosine is fetotoxic, and women are advised to use effective contraception during and for 5 months after therapy. Renal function must be monitored weekly during therapy and for 4 weeks after therapy. During therapy patients should also be monitored for the development of hepatic dysfunction, thrombocytopenia, and Stevens Johnson syndrome. The chemical structure of miltefosine is shown in eFigure 68–3. Its mechanism of action is presumed to involve lipid interactions, inhibition of mitochondrial function, and apoptosis-like cell death. Miltefosine is administered at a dose of 50 mg, taken 2 or 3 times daily with food for 28 days. With a half-life longer than 6 days, steady-state serum levels are not reached before the end of therapy. Miltefosine undergoes slow metabolic breakdown in hepatocytes to choline and palmitic acid. The therapy is contraindicated in patients with defective fatty aldehyde dehydrogenase activity because of their inability to clear palmitic acid.

Nintedanib^$† (ofev) and pirfenidone^$† (esbriet) are two breakthrough therapy antifibrotic drugs both FDA- approved for the treatment of idiopathic pulmonary fibrosis (IPF) on October 15, 2014. IPF is a rare disease qualifying both new agents for an orphan drug designation. IPF is characterized as a progressive and fatal disease with a complex pathogenesis and unpredictable natural history.³⁸ Nintedanib and pirfenidone are the first two drugs to be FDA-approved for the treatment of IPF and the first antifibrotic drugs to be licensed in the U.S. At least 27 other antifibrotic agents are in development for IPF or other fibrotic diseases.³⁹ Nintedanib and pirfenidone both modestly and measurably slow the 1-year rate of decline in lung function in IPF, but neither confers an overall survival benefit.^{40, 41, 42} The National Institute of Health and Care Excellence (NICE) issued a technical guideline for pirfenidone in 2013, recommending antifibrotic therapy for patients with a forced vital capacity (FVC) between 50% and 80% of predicted, along with discontinuation of antifibrotic therapy if FVC declines 10% or more within any 12-month period.^{43, 44} A NICE guideline for the use of nintedanib for IPF is scheduled to be published in January 2016.⁴⁵

Nintedanib. Nintedanib acts as a multiple nonreceptor and receptor tyrosine kinase inhibitor.^{40, 46} Nintedanib inhibits the Lck, Lyn, and Src nonreceptor tyrosine kinases (nRTKs). In addition, nintedanib inhibits the following receptor tyrosine kinases (RTKs): platelet-derived growth factor receptor (PDGFR) α and β, fibroblast growth factor receptors (FGFRs) 1-3, vascular endothelial growth factor receptors (VEGFRs) 1-3, and Fms-like tyrosine kinase-3 (FLT3). Relevant to the therapy of IPF, nintedanib binds competitively to the adenosine triphosphate (ATP) binding pocket of FGFR, PDGFR, and VEGFR to block the intracellular signaling necessary for the proliferation, migration, and transformation of fibroblasts.^{40, 46} The contribution of FLT3 and of nRTK inhibition to the efficacy of nintedanib against IPF is unknown. In placebo-controlled clinical trials, treatment with nintedanib over 52 weeks was associated with a statistically significant reduction in the annual rate of decline in FVC and a mixed impact on risk of first acute IPF exacerbation.^{40, 46} The recommended dose of nintedanib is 150 mg taken twice daily with food. It is necessary to monitor ALT, AST, and bilirubin before and during treatment. Temporary dosage reductions or discontinuation of therapy may be necessary due to anorexia, arterial thromboembolic events [including myocardial infarction (MI)], bleeding, gastrointestinal toxicity (including perforation), headache, hypothyroidism, liver enzyme elevations, or weight loss. Nintedanib is a substrate of P-gp and CYP3A4 and a weak inhibitor of BCRP, organic cation transporter-1 (OCT-1), and P-gp. Coadministration of P-gp and CYP3A4 inhibitors are expected to increase nintedanib exposure, and smoking is noted to significantly decrease exposure. The half-life of nintedanib is 9.5 hours. Its chemical structure is shown in eFigure 68–4. Biotransformation and elimination of nintedanib are mainly via hydrolytic cleavage by esterases with subsequent biliary/fecal elimination. Glucuronidation by UDP-glucuronosyltransferase (UGT) enzymes (1A1, 1A7, 1A8, and 1A10) and cytochrome P450 pathways (mainly CYP3A4) appear to be minor contributors to the biotransformation of nintedanib. Women of childbearing potential should be advised to use adequate contraception during treatment and for at least 3 months after the last dose of nintedanib.

Pirfenidone^$†. While the precise pharmacological mechanism of action against IPF is unknown, pirfenidone has been shown to (1) reduce fibroblast proliferation; (2) inhibit transforming growth factor beta–stimulated collagen production; (3) reduce the production of fibrogenic mediators such as transforming growth factor beta; and (4) reduce the production of inflammatory mediators such as tumor necrosis factor alpha and interleukin-1 beta.⁴¹ The dose of pirfenidone is 267 mg taken 3 times daily with food and titrated up over 14 days to the full dose of 2403 mg, taken as 3 801-mg doses daily. Liver enzyme and bilirubin elevations requiring dosage reduction or discontinuation have occurred during therapy with pirfenidone. Liver function tests are required prior to therapy, monthly for the first 6 months of therapy, and every 3 months thereafter. Pirfenidone is associated with photosensitivity, so patients must use a sunscreen with an SPF of 50 or higher and wear protective clothing to minimize exposure to sunlight. Other adverse reactions have included abdominal pain, agranulocytosis, angioedema, anorexia, arthralgia, diarrhea, dizziness, dyspepsia, fatigue, gastroesophageal reflux, headache, insomnia, nausea, rash, sinusitis, upper respiratory tract infection, vomiting, and weight loss. Pirfenidone is metabolized primarily by CYP1A2 and excreted predominantly as the 5-carboxy-pirfenidone metabolite, mainly in the urine. In addition to CYP1A2, pirfenidone is a substrate of CYP2C9, -2C19, -2D6, and -2E1 and an inhibitor of CYP1A2, -2C9, -2C19, -2D6, -3A4, and P-gp. CYP1A inhibitors should be avoided during pirfenidone therapy as they can significantly increase toxicity risk. Smoking and CYP1A inducers should also be avoided during pirfenidone therapy as they can reduce its therapeutic efficacy. The mean terminal half-life of pirfenidone is approximately 3 hours. The efficacy of pirfenidone versus placebo was evaluated in 1247 patients with IPF in three phase III, randomized, double-blind, placebo-controlled, multicenter trials.^{41, 42} The mean difference in “change in forced vital capacity from baseline” was193 mL at 52 weeks in one study (statistically significant), 157 mL at 72 weeks in one study (statistically significant), and not statistically significant at 72 weeks in one study.⁴¹ The chemical structure of pirfenidone is shown in eFigure 68–5.

Nivolumab^$† (opdivo) and pembrolizumab^$† (keytruda) are both humanized monoclonal antibodies that bind to anti–programmed death receptor 1 (PD-1) on T cells to prevent PD-1 ligands (PD-L1 and PD-L2) from inhibiting normal T-cell anti-tumor surveillance activities.⁴⁷ Blockade of this “immune checkpoint” pathway by nivolumab, pembrolizumab, and other compounds in development restores anti-tumor T-cell immune surveillance activities and is associated with tumor shrinkage.⁴⁷ Pembrolizumab was approved as a breakthrough therapy drug and orphan drug product in September 2014, with nivolumab following in December 2014. Both monoclonal antibodies are indicated for the treatment of patients with unresectable or metastatic melanoma and disease progression following therapy with ipilimumab [a cytotoxic T-lymphocyte antigen 4 (CTLA-4)-type “immune checkpoint” inhibitor].^{47, 48, 49} Consistent with the mechanism of action of immune checkpoint inhibitors, both nivolumab and pembrolizumab are associated with serious immune-mediated adverse effects.

Nivolumab. The efficacy of nivolumab was established in a single-arm, non-comparative, planned interim analysis of the first 120 patients who received nivolumab for a minimum duration of 6 months.⁴⁸ The confirmed objective response rate (ORR), as measured by blinded independent central review, was 32% (95% confidence interval: 23, 41), including 38 patients with complete or partial response and 13 patients with ongoing response of 6 months or longer.⁴⁸ Nivolumab is administered as a 3-mg/kg intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity occurs. The administration of nivolumab has been associated with severe immune-mediated colitis, hepatitis, nephritis, pneumonitis, and thyroid dysfunction. Other serious adverse reactions have included edema, erythema multiforme, exfoliative dermatitis, infusion-related reactions, increased amylase, increased lipase, iridocyclitis, dizziness, peripheral and sensory neuropathy, psoriasis, ventricular arrhythmia, and vitiligo. The mean elimination half-life of nivolumab is 26.7 days, and 12 weeks of continuous dosing are required to reach steady-state concentrations.

Pembrolizumab. The efficacy of pembrolizumab was established in a multicenter, open-label, randomized, dose-comparative, activity-estimating cohort consisting of 89 patients.⁴⁹ Confirmed ORR, as assessed by blinded independent central review, was 24% (95% confidence interval: 15, 34), including 21 patients with complete or partial response and 8 patients with ongoing response of 6 months or longer.⁴⁹ Pembrolizumab is administered as a 3-mg/kg intravenous infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity occurs. Administration is associated with severe immune-mediated adrenal insufficiency, arthritis, colitis, exfoliative dermatitis, hemolytic anemia, hepatitis, hypophysitis, myasthenic syndrome, myositis, nephritis, optic neuritis, pancreatitis, pneumonitis, rhabdomyolysis, seizures (arising from inflammatory foci in brain parenchyma), thyroid dysfunction, and uveitis. Other adverse reactions have included abdominal pain, anemia, arthralgia, back pain, chills, constipation, cough, decreased appetite, diarrhea, dizziness, dyspnea, elevated liver enzymes, extremity pain, fatigue, headache, hyperbilirubinemia, hyperglycemia, hypertriglyceridemia, hypoalbuminemia, hypocalcemia, hyponatremia, insomnia, myalgia, nausea, peripheral edema, pruritus, pyrexia, rash, upper respiratory tract infection, sepsis, vitiligo, and vomiting. The mean elimination half-life of pembrolizumab is 26 days, and 18 weeks of continuous dosing are required to reach steady-state concentrations.

Olaparib (lynparza) is a polyadenosine 5’-diphosphoribose polymerase (PARP) inhibitor that blocks enzymes (PARP1, PARP2, and PARP3) involved in repairing damaged DNA.^{50, 51} The FDA approved olaparib as monotherapy for patients with germline BRAC-mutated advanced ovarian cancer who have previously been treated with chemotherapy. Olaparib was granted accelerated approved by the FDA in conjunction with approval of the BRACAnalysis CDx companion diagnostic to aid in accurately identifying patients with germline BRAC mutations eligible for therapy.⁵² Approval of olaparib was based on the detection of a 34% ORR and a 7.9-month median duration of response among 137 patients investigated in a single-arm study.⁵⁰ The recommended dose of olaparib is 400 mg (eight 50-mg capsules) taken twice daily, for a total daily dose of 800 mg. Therapy is continued until disease progression or unacceptable toxicity occurs. Olaparib has a mean terminal plasma half-life of 11.9 hours. It is primarily metabolized by CYP3A, and the concomitant use of CYP3A4 inducers or inhibitors should be avoided. Olaparib is a weak inhibitor and inducer of CYP3A4 and CYP2B6; a substrate for P-gp; and an inhibitor of BCRP, organic anion-transporting protein 1B1 (OATP1B1), organic cation transporters (OCT1 and OCT2), organic anion transporter 3 (OAT3), and multidrug and toxin extrusion (MATE1 and MATE2K) transporters. Serious side effects associated with olaparib include acute myeloid leukemia, anemia, dermatitis, fatigue, headache, gastrointestinal toxicity, infection, lymphopenia, musculoskeletal pain, myelodysplastic syndrome, neutropenia, pneumonitis, rash, and renal dysfunction. Monthly complete blood counts are required, and women of reproductive potential should be advised to use effective contraception during treatment and for at least one month after receiving the last dose of olaparib. The chemical structure of olaparib is shown in eFigure 68–6.

Ombitasvir in combination with paritaprevir, ritonavir and co-packaged with dasabuvir (viekira pak) consists of a fixed-dose combination tablet containing 12.5 mg of ombitasvir, 75 mg of paritaprevir, and 50 mg of ritonavir for once-daily dosing (administered as two tablets taken once daily with food), packaged together with 250-mg tablets of dasabuvir for twice-daily dosing (administered as one tablet taken twice daily with food).⁵³ viekira pak is approved for the treatment of patients with genotype 1 chronic HCV infection and contains three new-to-market HCV antivirals: ombitasvir, one of two NS5A inhibitor “firsts” to be approved by the FDA in 2014 (see also Ledipasvir in combination with sofosbuvir); paritaprevir, an NS3/4A protease inhibitor; and dasabuvir, a non-nucleoside NS5B (palm domain)⁵⁴ polymerase inhibitor. Ritonavir is included in the fixed-dose tablet component of the regimen to boost the serum levels of paritaprevir. Mathematical modeling was employed in the design of the viekira pak drug regimen to predict the cocktail of direct-acting antivirals necessary to achieve astonishingly high response rates (all about 96%) without selecting for viral resistance during the course of therapy.³¹ For all except noncirrhosis patients infected with HCV subgenotype 1b, the viekira pak multidrug regimen requires concomitant ribavirin administration to meet this objective.⁴⁹ Depending on viral subtype and hepatic disease status (positive or negative for compensated cirrhosis), the recommended duration of therapy for the viekira pak regimen is either 12 or 24 weeks. Refer to Liang and Ghany for a comprehensive summary of the phase III trial efficacy results demonstrated for viekira pak and other interferon-free regimens for the treatment of HCV.³¹ viekira pak is contraindicated for use with ethinyl estradiol–containing medications and with drugs that are highly dependent on CYP3A for clearance, strong inducers of CYP3A and CYP2C8, and strong inhibitors of CYP2C8. Common adverse reactions to viekira pak include ALT elevations, asthenia, fatigue, insomnia, nausea, and pruritus. For the best possible outcome for patients, prescribers of viekira pak must be mindful of potential drug-drug interactions. Select characteristics of each of the three new-to-market components contained in viekira pak are summarized below.

• Ombitasvir (NS5A inhibitor): Ombitasvir is metabolized primarily via amide hydrolysis followed by oxidative metabolism, with elimination mainly through feces. CYP enzymes play a minor role in its biotransformation. Ombitasvir is an inhibitor of UGT1A1 and a substrate of P-gp and BCRP. Its mean elimination half-life is approximately 21-25 hours. The chemical structure of ombitasvir is shown in eFigure 68–7.

• Paritaprevir (NS3/4A protease inhibitor): Paritaprevir is predominantly metabolized by CYP3A4 and to a lesser extent by CYP3A5. Elimination is mainly through feces. Paritaprevir is a substrate of P-gp; a substrate and inhibitor of BCRP, OATP1B1, and OATP1B3; and an inhibitor of UGT1A1. Paritaprevir has a half-life of approximately 5.5 hours. The chemical structure of paritaprevir is shown in eFigure 68–8.

• Dasabuvir (NS5B polymerase inhibitor): Dasabuvir is predominantly metabolized by CYP2C8 and to a lesser extent by CYP3A. Approximately 95% of dasabuvir is eliminated through feces. Dasabuvir is a substrate of P-gp, a substrate and inhibitor of BCRP, and an inhibitor of UGT1A1. The mean plasma half-life of dasabuvir is approximately 5.5-6 hours. Based on drug resistance mapping studies of HCV genotypes 1a and 1b, dasabuvir targets the palm domain⁵⁴ of the NS5B polymerase and is therefore referred to as a non-nucleoside NS5B-palm polymerase inhibitor. The chemical structure of dasabuvir is shown in eFigure 68–9.

Ramucirumab^† (cyramza) is a human VEGFR2 antagonist that acts as an angiogenesis inhibitor to block microvascular growth in all tissues, including tumors.⁵⁵ Blockade of VEGFR2 prevents VEGFR ligands (VEGF-A, VEGF-C, and VEGF-D) from activating VEGFR2, thereby inhibiting one pathway leading to the proliferation and migration of endothelial cells.⁵⁶ VEGFR2 inhibition by ramucirumab results in reduced tumor vascularity and growth. The downstream activity of ramucirumab overlaps with the activity of other FDA-approved angiogenesis inhibitors: axitinib, bevacizumab, pazopanib, regorafenib, and ziv-aflibercept.⁵⁶ Ramucirumab is indicated as salvage therapy for advanced gastric or gastro-esophageal junction adenocarcinoma and NSCLC. Therapy with ramucirumab is continued until disease progression or unacceptable toxicity occurs. For gastric cancer, the recommended dose of ramucirumab is 8 mg/kg every 2 weeks. For NSCLC, the dose is 10 mg/kg on day 1 of a 21-day cycle prior to docetaxel. Ramucirumab is a fully humanized IgG1 monoclonal antibody, and its administration requires premedication with an antihistamine alone or in combination with dexamethasone and acetaminophen to reduce the risk of severe infusion-related reactions. Consistent with its pharmacology, ramucirumab is labeled with a black box warning about the risk of severe and potentially fatal hemorrhagic events. Concomitant use of anticoagulants or antiplatelet agents is presumed to increase this risk and should be avoided. Other serious adverse events include arterial thromboembolic events (including MI and cerebrovascular accident), clinical deterioration in patients with cirrhosis, hypertension, impaired wound healing, gastrointestinal perforation, proteinuria, and posterior leukoencephalopathy syndrome. Other common adverse reactions include diarrhea, fatigue, headache, hypoalbuminemia, hyponatremia, increased lacrimation, intestinal obstruction, neutropenia, peripheral edema, rash, stomatitis/mucosal inflammation, sepsis, and thrombocytopenia. Blood pressure should be monitored at least every 2 weeks during treatment with ramucirumab. The mean elimination half-life of ramucirumab is 15-23 days. FDA approval of ramucirumab was based on a small progression-free interval and overall survival benefits demonstrated among patients with prior disease progression despite previous chemotherapy enrolled in 3 multinational, double-blind, multicenter, placebo-controlled studies: (1) ramucirumab plus best supportive care (238 patients with gastric cancer randomized to receive ramucirumab); (2) ramucirumab plus paclitaxel (330 patients with gastric cancer randomized to receive ramucirumab); and (3) ramucirumab plus docetaxel (628 patients with NSCLC randomized to receive ramucirumab). Patients treated with ramucirumab achieved median progression-free intervals of 2.1, 4.4, and 4.5 months, respectively, and survived a median of 5.2, 9.6, and 10.5 months, respectively. In comparison, both outcome measures for ramucirumab were better than placebo, and both reached statistical significance in all three pivotal studies.

Siltuximab^† (sylvant) is a human-mouse chimeric monoclonal antibody that binds interleukin-6 (IL-6) to prevent it from binding to IL-6 receptors (IL-6Rs).⁵⁷ Siltuximab is indicated for the treatment of patients with multicentric Castleman’s disease (MCD) who are human immunodeficiency virus (HIV) and human herpesvirus-8 (HHV-8) negative. MCD is a rare lymphoproliferative disorder caused by dysregulated IL-6 production. Siltuximab has a different mechanism but shares the same pharmacological activity as tocilizumab, a monoclonal antibody targeted against the IL-6 receptor.⁵⁸ The results of hematology tests (absolute neutrophil count, platelet count, and hemoglobin) are used to guide therapy with siltuximab during the first 12 months and every 3 dosing cycles thereafter. On the basis of these results, siltuximab is administered as an 11-mg/kg dose given over one hour by intravenous infusion every three weeks until treatment failure. The drug must be administered in a setting capable of providing resuscitation. Siltuximab must not be administered to patients with severe infections, and the administration of live vaccines to patients receiving siltuximab should be avoided. Therapy with siltuximab should be permanently discontinued in patients who experience severe infusion-related reactions, anaphylaxis, severe allergic reactions, or cytokine release syndromes. Other adverse reactions have included abdominal pain, arthralgia, constipation, decreased appetite, dehydration, diarrhea, dry skin, eczema, fatigue, gastrointestinal perforation, headache, hypercholesterolemia, hypertriglyceridemia, hyperuricemia, hypotension, increased weight, infection, oropharyngeal pain, pain in extremities, pruritus, psoriasis, rash, renal impairment, skin hyperpigmentation, and thrombocytopenia. Therapy with siltuximab may normalize the production of IL-6-suppressed CYP liver enzymes to alter the biotransformation of CYP substrates, including some potent drugs with a narrow therapeutic index. Patients should be monitored for changes in the therapeutic effect of concomitant drugs metabolized by CYP enzymes when co-administered with siltuximab and for several weeks after siltuximab therapy is discontinued. Women of childbearing potential should be advised to use effective contraception during siltuximab therapy and for 3 months after treatment. The terminal half-life of siltuximab ranges from 14.2 to 29.7 days. The efficacy of siltuximab was established in a single phase II, multinational, double-blind, placebo-controlled study that achieved a 34% durable response (defined as tumor and symptomatic response that persisted for a minimum of 18 weeks) among 53 patients randomized to siltuximab plus best supportive care. No patients (0%) randomized to the comparator (placebo) group exhibited a durable response. Soumerai et al. have published a treatment algorithm for Castleman’s disease.⁵⁹ A table listing the ongoing clinical trials of siltuximab for a variety of conditions has been compiled by Markham.⁶⁰

Suvorexant (belsomra) is a dual orexin-1 and orexin-2 receptor antagonist indicated for the treatment of insomnia.⁶¹ The orexin neuropeptide signaling system in the brain has been linked to circadian rhythms and wakefulness, as well as the neural regulation of reward, emotion, stress, appetite, and autonomic control.⁶² Blocking the binding of wake-promoting neuropeptides orexin A and orexin B to receptors OX1R and OX2R is thought to suppress the wake drive, and the loss of orexin neurons has been reported in humans with narcolepsy. The U.S. Drug Enforcement Administration (DEA) classifies suvorexant as a Schedule IV Controlled Substance and judges its abuse potential to be about equal to that of zolpidem.⁶³ The recommended dose is 10 mg (reduced for patients using concurrent CYP34 inhibitors), taken within 30 minutes of going to bed when there are at least 7 hours remaining before the planned time of awakening. Consistent with the elimination half-life of approximately 12 hours, impaired daytime wakefulness is the most frequent unwanted effect. To minimize the risk of impaired mental alertness and lack of coordination while under the influence of suvorexant, the lowest effective dose should be used, patients should avoid concurrent central nervous system (CNS) depressants, and patients at risk should be cautioned regarding activities requiring mental alertness. Patients particularly at risk include those taking the maximum dose (20 mg) and those with higher than “normal” systemic exposures (e.g., women, obese patients, patients receiving concurrent CYP3A inhibitors). Suvorexant is a CNS depressant and has additive effects with other CNS depressants. It is contraindicated in patients with narcolepsy.

The main warnings associated with the use of suvorexant include “sleep-driving” and other complex behaviors while out of bed but not fully awake (with amnesia for the event), falling asleep while driving, worsening of depression, an increase in suicidal thinking, possible respiratory function compromise [particularly in patients with chronic obstructive pulmonary disease (COPD) or sleep apnea], sleep paralysis (an inability to move or speak for up to several minutes during sleep-wake transitions), hallucinations during the transitions between wakefulness and sleep, and cataplexy-like symptoms. Other adverse effects associated with suvorexant include abnormal dreams, cough, diarrhea, dry mouth, elevated serum cholesterol, headache, and upper respiratory tract infection. Retinal atrophy has been observed in long-term animal studies. Suvorexant is a substrate for CYP3A and CYP2C19 and an inhibitor of P-gp. The concomitant use of suvorexant with strong CP3A inhibitors is not recommended, and a reduced dose of suvorexant (5 mg) is recommended for patients taking moderate CYP3A inhibitors. CYP3A inducers may lower the efficacy of suvorexant. The primary route of elimination of suvorexant is through feces. The chemical structure of suvorexant is shown in eFigure 68–10.

Tavaborole (kerydin) is an oxaborole antifungal protein synthesis inhibitor that acts through inhibition of aminoacyl–transfer ribonucleic acid (tRNA) synthetase (AARS). Tavaborole is indicated for the topical treatment of onychomycosis of the toenails due to Trichophyton rubrum or T. mentagrophytes.⁶⁴ A small boron-containing molecule (eFigure 68–11), tavaborole penetrates the nail plate in concentrations well above the minimum necessary to inhibit T. rubrum and T. mentagrophytes with negligible systemic absorption.⁶⁵ In the treatment of onychomycosis, mycological cure can be expected in 31-36% of patients treated with a once-daily application of tavaborole for 48 weeks.⁶⁴ Adverse effects include ingrown toenail and application site reactions (e.g., exfoliation, erythema, dermatitis).

Vedolizumab (entyvio) is a humanized IgG1 monoclonal antibody that acts as a gut-specific integrin receptor antagonist by selectively inhibiting the interaction of α4β7 integrin with mucosal addressin cell adhesion molecule-1 (MAdCAM-1).^{66, 67, 68} Vedolizumab is considered gut-specific because MAdCAM-1 is mainly expressed on gut endothelial cells and α4β7 integrin is expressed on the surface of memory T lymphocytes that preferentially migrate into the gastrointestinal tract.^{67, 68} Vedolizumab is a more selective integrin receptor antagonist than natalizumab and is thought to be less likely than natalizumab to trigger progressive multifocal leukoencephalopathy (PML).^{67, 68, 69} Unlike natalizumab, vedolizumab does not bind to or inhibit function of the α4β1 integrin and does not antagonize the interaction of α4 integrins with vascular cell adhesion molecule-1 (VCAM-1) at the blood-brain barrier.^{67, 68, 69} Integrins serve as the primary mediators of inflammation in the gastrointestinal tract, and blockade by vedolizumab has been proven to reduce gastrointestinal inflammation.^{66, 67} Vedolizumab is indicated for the treatment of ulcerative colitis and Crohn’s disease. The dose of vedolizumab is 300 mg infused intravenously over 30 minutes at 0, 2, and 6 weeks, then every 8 weeks thereafter. Vedolizumab should be discontinued in patients who do not show evidence of therapeutic benefit by week 14 and in patients who develop serious hypersensitivity reactions or evidence of liver injury. Serious hypersensitivity reactions have occurred up to several hours post-infusion. Clinical experience suggests that patients who develop persistently positive antivedolizumab antibodies are less likely to benefit from therapy. Vedolizumab therapy should not be administered concurrently with natalizumab or tumor necrosis factor (TNF) blockers. Prior to beginning vedolizumab therapy, patients should be up to date with all immunizations, and therapy should be withheld for patients with severe infections. Tuberculosis screening prior to therapy should also be considered. The most common adverse reactions of vedolizumab include arthralgia, back pain, bronchitis, cough, fatigue, headache, influenza, nasopharyngitis, nausea, oropharyngeal pain, pain in extremities, pruritus, pyrexia, rash, sinusitis, and upper respiratory tract infection. A pregnancy registry has been established. The efficacy of vedolizumab for ulcerative colitis was established in a 52-week, randomized, double-blind trial. One hundred twenty-two patients with a demonstrated response during 6 weeks of therapy received vedolizumab and achieved an overall 26% better clinical response rate, a 32% better rate of improvement in mucosal appearance, and an 18% better rate of corticosteroid-free clinical remission than the 126 patients randomized to placebo.⁶⁶ Under a similar study strategy, 154 vedolizumab responders with Crohn’s disease randomized to vedolizumab had an overall 17% better clinical remission rate, a 13% better clinical response rate, and a 16% better rate of corticosteroid-free remission than the 153 patients randomized to placebo.⁶⁶ All efficacy end points in these two studies were statistically significant. Several theories have been proposed to explain the differences in responsiveness to vedolizumab between patients with ulcerative colitis versus Crohn’s Disease.^{68, 69, 70}

Vorapaxar (zontivity) is a small-molecule, long-acting, clinically irreversible, platelet-aggregation inhibitor that acts as a protease-activated receptor-1 (PAR-1) antagonist.⁷¹ PAR-1 is a the primary receptor for thrombin on platelets, and vorapaxar competitively and selectively prevents thrombin-induced and thrombin receptor agonist peptide (TRAP)-induced platelet activation by blocking the interaction between PAR-1 and thrombin.^{72, 73, 74} Vorapaxar achieves more than 80% inhibition of TRAP-induced platelet aggregation within 1 week of therapy initiation, and significant residual platelet inhibition lasts for 4 weeks after discontinuation of therapy.⁷¹ The pharmacodynamic effect of vorapaxar on PAR-1 expressed on vascular endothelial and smooth muscle cells, leukocytes, neurons, cardiomyocytes, and cardiac fibroblasts is not known.^{71, 74} Vorapaxar does not interfere with the thrombin-mediated conversion of fibrinogen to fibrin and does not affect the coagulation cascade.⁷² However, consistent with its targeted mechanism of action, vorapaxar is associated with an increased risk of bleeding. Therefore, prior to initiation of therapy with vorapaxar, risk factors for bleeding (including old age; body weight <60 kg; renal or hepatic dysfunction; and the concomitant use of fibrinolytic therapy, nonsteroidal anti-inflammatory drugs, or serotonin reuptake inhibitors) should be weighed against the potential benefit of therapy.⁷⁵ Due to an elevated risk, vorapaxar is contraindicated in patients with active bleeding and in patients with a history of stroke, transient ischemic attacks (TIAs), or intracranial hemorrhage. Vorapaxar should not be used concurrently with anticoagulants or in the acute phase of MI in patients receiving aggressive antithrombotic therapy.^{71, 75} Vorapaxar is indicated in combination with aspirin or clopidogrel for secondary risk reduction in patients with a history of MI or with peripheral arterial disease (PAD). In patients with PAD, vorapaxar was shown to reduce limb ischemia and the requirement for peripheral vascularisation.^{71, 72, 73, 74} Vorapaxar is not indicated as monotherapy, and in premarket trials, vorapaxar was associated with an unfavorable risk-benefit ratio in the setting of acute coronary syndrome.⁷³ The dose of vorapaxar is one 2.08-mg tablet taken orally once daily. Vorapaxar is eliminated primarily by metabolism by CYP3A4 and CYP2J2 with excretion mainly in the feces. Its terminal elimination half-life ranges from 5 to 13 days. Vorapaxar should not be used with strong CYP3A inhibitors or inducers. In clinical trials, when patients with a history of stroke or TIA were excluded from analysis, vorapaxar in combination with aspirin or clopidogrel was associated with an 18% reduction in first occurrence of cardiovascular death, MI, stroke, or urgent coronary revascularization procedure (hazard ratio, 0.86; 95% confidence interval: 0.79, 0.94; P<0.001).⁷³ The efficacy of vorapaxar is driven largely by a lower rate of acute MI (5.2% versus 6.1%; hazard ratio, 0.83; 95% confidence interval: 0.74, 0.93; P=0.001).^{73, 74, 75} Baker calculated that the number needed to treat to prevent one cardiovascular death, MI, or ischemic stroke versus the number needed to harm due to severe bleeding per 10,000 patient years is 140 versus 1798, suggesting that vorapaxar is 12 times more likely to result in benefit than harm.⁷³ The chemical structure of vorapaxar is shown in eFigure 68–12.

Among the remaining new drugs and biologics of note to be FDA approved in 2014 are 26 newly approved drugs (eTable 68–2) and 8 biologics that are pharmacologically similar to others already marketed. Although draft guidance for biosimilar product development in the U.S. was established in 2012, to date there have been no “follow-on biologics” approved by the FDA under the new rules.⁷⁶ Also in 2014, the FDA Safety and Innovation Act of 2012 again had a dramatic impact on pediatric labeling.^{77, 78} As of November 21, 2014, pediatric labeling had been approved for 21 new and existing drugs and biologics.⁷⁹ Thirteen marketed drugs won approval for an orphan drug indication in 2014 (eTable 68–3; see also Part 1 of this chapter), and 3 marketed drugs were “repurposed” or significantly reformulated in 2014 (eTable 68–4). Other 2014 noteworthy FDA regulatory activities are summarized below.

2014 Biologic Licenses (^†orphan drug; ^$breakthrough drug)

• Antihemophilic factor (recombinant), Fc fusion protein^† (eloctate). Licensed for the treatment of adults and children with hemophilia A (congenital factor VIII deficiency) for:

  • The control and prevention of bleeding episodes;

  • Routine prophylaxis to prevent or reduce the frequency of bleeding episodes; and

  • Perioperative management (surgical prophylaxis).⁸⁰

• Antihemophilic factor (recombinant), porcine sequence^† (obizur): Licensed for the treatment of bleeding episodes in adults with acquired hemophilia A (i.e., acquired inhibitory antibodies to factor VIII).⁸¹

• C1 esterase inhibitor (recombinant)^† (ruconest): Licensed for the treatment of acute attacks of hereditary angioedema (HAE).^{82, 83}

• Coagulation factor IX (recombinant), Fc fusion protein^† (alprolix): Licensed for the treatment of hemophilia B for:

  • The control and prevention of bleeding episodes;

  • Routine prophylaxis to prevent or reduce the frequency of bleeding episodes; and

  • Peri-operative management (surgical prophylaxis).⁸⁴

• Immune globulin infusion (human), 10% with recombinant human hyaluronidase (hyqvia): Licensed for the treatment of humoral immune defects in adults with primary immunodeficiency.⁸⁵

• Meningococcal group B vaccine^$ (trumenba): Licensed for active immunization to prevent invasive meningococcal disease caused by N. meningitidis serogroup B in individuals 10 through 25 years of age.⁸⁶ (See also see Part 1 of this chapter.)

• Short ragweed pollen allergen extract (ragwitek): Licensed as immunotherapy (sublingual administration) for the treatment of short ragweed pollen–induced allergic rhinitis, with or without conjunctivitis, confirmed by positive skin test or in vitro testing for pollen-specific IgE antibodies against short ragweed pollen.⁸⁷

• Sweet vernal, orchard, perennial rye, timothy, and Kentucky blue grass mixed-pollen allergen extract (oralair): Licensed as immunotherapy (sublingual administration) for the treatment of grass pollen–induced allergic rhinitis, with or without conjunctivitis, confirmed by positive skin test or in vitro testing for pollen-specific IgE antibodies for any of the five grass species contained in this product.⁸⁸

• Timothy grass pollen allergen extract (grastek): Licensed as immunotherapy (sublingual administration) for the treatment of grass pollen–induced allergic rhinitis, with or without conjunctivitis, confirmed by positive skin test or in vitro testing for pollen-specific IgE antibodies for Timothy grass or cross-reactive grass pollens.⁸⁹

Inhaled insulin. An inhaled insulin product (afrezza) was FDA approved in 2014.⁹⁰ In 2006-2007, the first FDA-approved inhaled insulin product, exubra, was briefly available on the U.S. market.⁹¹ A commercial disappointment, exubra was discontinued by its distributor after less than a full year of marketing.⁹¹ The next-generation inhaled insulin, afrezza, is described as an inhalation powder of recombinant human insulin adsorbed onto proprietary microsphere carrier particles consisting of fumaryl diketopiperazine.⁹² The afrezza inhalation device is described as “thumb-sized.” Compared to the subcutaneous administration of rapid-acting insulin analogs, the pharmacodynamic profile of orally inhaled afrezza is characterized as more rapid “on and off” [quicker onset (~15 minutes) and shorter duration (~3 hours)].^{92, 93} afrezza received initial FDA approval for prandial administration and must be used in combination with long-acting (basal) insulin injections or oral antidiabetic medications for sustained glucose control.^{93, 94}

Marketed, unapproved drugs. Potassium chloride oral solution,⁹⁵ 1% atropine sulfate ophthalmic solution,⁹⁶ epinephrine IV infusion solution (1mg/mL),⁹⁷ and vasopressin infusion solution (20 units/mL)⁹⁸ were all licensed in 2014. FDA approval of “marketed, unapproved” drugs establishes the good manufacturing practices necessary to assure their batch-to-batch reliability.⁹⁹

Medical device approvals. Four noteworthy agents licensed as medical devices were approved by FDA in 2014:

• gel-syn: An artificial material containing sodium hyaluronate for injection into osteoarthritic knee joints for the purpose of relieving pain by providing lubrication and shock absorption.^{100, 101}

• monovisc: A hyaluronic acid viscosupplement derived from bacteria for injection into osteoarthritic knee joints to improve joint mobility and reduce pain.¹⁰²

• restylane silk: A transparent hyaluronic acid gel for injection into patients’ lips and wrinkles around the mouth to increase lip volume and smooth wrinkles, respectively.^{103, 104}

• resure sealant: A combination of polyethylene glycol and a trilysine amine in solution for topical application to the cornea to prevent leakage from surgical incisions.^{105, 106}

Pregnancy, lactation, and fertility labeling changes. In 2014, the FDA issued a final rule directing changes to the pregnancy and lactation labeling information for prescription and biological products. Effective June 15, 2015, the new rule abolishes the old letter system (A, B, C, D, X) of the FDA Pregnancy Categories and replaces it with 3 new descriptive subsections in the product labeling containing information about the benefits and risks related to “Pregnancy,” “Lactation,” and “Females and Males of Reproductive Potential.”¹⁰⁷

Prescription (R_X) to over-the-counter (OTC) switches. The FDA authorized the R_X-to-OTC switch of two drug products in 2014:

• Fluticasone propionate (flonase allergy relief); and

• Esomeprazole magnesium (nexium 24hr).¹⁰⁸

Reduction in recommended starting dose of eszopiclone (lunesta). As a follow-on action to the FDA’s 2013 decision to reduce the approved starting dose of zolpidem (ambien),¹⁰⁹ in 2014, the FDA lowered the labeled starting dose of eszopiclone from 2 mg to 1 mg for both men and women.³⁵ The reduction in dose for both sleep drugs is thought to be necessary to minimize the risk associated with severe next-morning psychomotor and memory impairment.^{109, 110} The reductions were based on the post-marketing discovery of lower than expected nocturnal clearance paired with the disturbing dissociation between patient perception of drowsiness and impairment.^{109, 110} Due to the heightened risk of patients being unaware of their impairment and a possible risk “signal” suggestive of excessive traffic accidents, the FDA is continuing to evaluate the risks of impaired next-morning mental alertness for the entire class of R_x and OTC sleep drugs.^{109, 110} If the adverse signal can be validated, further regulatory control of the class is to be expected.