eChapter 71 (Part 1): The Goodman & Gilman Year in Review: 2011 New and Noteworthy FDA Approvals

The FDA approved 33 drugs and biologics of note in 2011. Most are pharmacologically similar to others already marketed (see part 2 of this series). Among the remainder are 18 "first-in-class" agents for acute coronary syndrome, angioedema, chronic obstructive pulmonary disease, congenital factor XIII deficiency, depression, head lice, hepatitis C infection, lupus, lymphoma, melanoma, myelofibrosis, prostate cancer, seizures, diagnosis of Parkinsonian syndromes, and vaccination of military personnel against adenovirus (see Table 71-1). Fourteen of the new drug approvals in 2011 were granted orphan drug status for rare diseases (see Table 71-1 and part 2 of this series). Two of the new drugs (crizotinib for non-small cell lung cancer (see part 2 of this series) and vemurafenib for melanoma) were approved in conjunction with diagnostic genetic tests and represent a breakthrough in the field of personalized medicine.1 In addition, one new approval, HEMACORD, is the first cord blood therapy approved in the US.2

• Abiraterone acetate (ZYTIGA) is a CYP17 inhibitor that blocks the production of testosterone precursors (dehydroepiandrosterone (DHEA) and androstenedione).3, 4 It is indicated in combination with prednisone for the treatment of metastatic castration-resistant prostate cancer in patients who have received prior therapy with docetaxel. Abiraterone is administered once a day on an empty stomach in combination with twice daily prednisone to suppress ACTH secretion in response to the increased mineralocorticoid levels that accompany CYP17 inhibition. Adrenocortical insufficiency, hepatotoxicity, hypertension, hypokalemia, fluid overload, and heart failure are potentially serious adverse effects associated with abiraterone therapy that require intensive monitoring. The drug is a CYP3A4 substrate and an inhibitor of both p-glycoprotein and CYP2D6. Abiraterone is classified as FDA Pregnancy Category X and the chemical structure of abiraterone acetate is shown in Figure 71-1.

• Belimumab (), a monoclonal antibody against soluble B-lymphocyte stimulator (BLyS) cytokine, is licensed as an adjunct to standard therapy for the treatment of autoantibody-positive, systemic lupus erythematosus (SLE).5 By inhibiting soluble BLyS, a B-cell survival factor, from binding to B cells, belimumab shortens their survival and reduces their differentiation into immunoglobulin-producing plasma cells (see Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12e,). Belimumab is administered as a monthly IV infusion following three initial doses given at 2-week intervals. A subcutaneous formulation is under development.6 The terminal half-life of the drug is approximately 19 days. Deaths, serious infections, psychiatric events, hypersensitivity, and infusion reactions were reported during pre-marketing clinical trials with belimumab. Live vaccines should be avoided in patients receiving belimumab and a pregnancy registry has been established. The efficacy and safety of belimumab was evaluated in three randomized, double blind, placebo-controlled studies involving 2133 patients with SLE. Patients with severe nephritis or active CNS disease were excluded. Belimumab or placebo was added to traditional therapy with corticosteroids, antimalarials, NSAIDs, and immunosuppressives (but not other biologics or). The majority of the patients studied were receiving two or more traditional therapies. Predictive biomarker data from disappointing Phase II studies were used to narrow the focus of Phase III studies to autoantibody-positive SLE test subjects. Drug efficacy assessment compared to placebo was based on a composite disease activity index (the SLE Responder Index) derived from four previously published instruments of disease activity: the Safety of in Lupus Erythematosus: National Assessment (SELENA), the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), the British Isles Lupus Assessment Group (BILAG), and the Physician's Global Assessment (PGA).7 Belimumab was judged to be statistically superior to placebo, as well as demonstrating steroid sparing and disease flare-reduction effects.7 Subgroup analysis suggests that belimumab is inferior to traditional therapy for black patients.5, 6 At a price of $2,806 (US) per infusion,6 therapy with the drug is expected to add over $36,000 to the annual cost of treating a patient with SLE.

• Boceprevir (VICTRELIS) is a hepatitis C virus (HCV) NS3/4A protease inhibitor indicated, in combination with peginterferon alfa and ribavirin, for the treatment of chronic hepatitis C genotype 1 infection. The mechanism of action of boceprevir is the same as for telaprevir (see below). Boceprevir and telaprevir reversibly bind to the NS3/4A protease active site serine (S139) though an α-ketoamide function group.8 Inhibition of NS3/4A protease prevents the manufacture of mature forms of four proteins essential for viral replication: NS4A, NS4B, NS5A, and NS5B.8 Emergence of HCV resistance during treatment with boceprevir has been reported.9 The chemical structure of boceprevir is shown in Figure 71-2.

Boceprevir, taken orally at a dose of 800 mg three times daily with food, is added to dual therapy with peginterferon alfa and ribavirin after four weeks of treatment. This triple-drug therapy is administered for up to 44 weeks using a response-based approach guided by periodic HCV-RNA level monitoring and patient tolerability. Among treatment-naïve patients, boceprevir triple therapy is associated with nearly twice the rate of sustained viral response that previously could be achieved from peginterferon/ribavirin dual therapy (66% compared with 38%).10, 11 In addition, triple-drug therapy with boceprevir is associated with a 44% rate of sustained viral response by 28 weeks of therapy.11 Among patients who had previously relapsed following interferon-based therapy and among patients categorized as partial responders to previous interferon-based therapy, triple therapy with boceprevir is associated with a sustained viral response of 69-75% and 40-52%, respectively.10, 11 Discontinuation of boceprevir at week 12 of therapy is recommended for any patient with HCV-RNA levels >100 IU/mL and at week 23 for any patient with confirmed detectable HCV-RNA levels.8

Boceprevir is associated with anemia that may require the use of an erythropoiesis-stimulating agent (e.g., epoetin alfa or darbepoetin alfa), and with worsening of dual therapy neutropenia.8 Routine CBC monitoring with WBC differential counts is necessary. Among the other most common adverse effects of triple-drug therapy are fatigue, nausea, headache, and dysgeusia. Precluding concomitant therapy with many other commonly prescribed medications that increase the risk of serious adverse effects (e.g, QT prolongation), boceprevir is both a substrate for and inhibitor of CYP3A4/5 and a potential inhibitor of p-glycoprotein (P-gp).8 Consult the drug labeling prior to coadministering medications that are dependent on CYP3A4 for clearance (e.g., warfarin, sildenafil, tadalafil, vardenafil, antiarrhythmics, calcium channel blockers, benzodiazepines, bosentan, colchicine, contraceptives, corticosteroids, HIV-protease inhibitors, immunosuppressants, opioids, and others) or substrates of P-gp (e.g., digoxin). Boceprevir is contraindicated in pregnancy and therapy requires monthly pregnancy tests for female patients and female partners of male patients during treatment and for 6 months after discontinuation of therapy.

• Spinosad (NATROBA) is a pediculicide indicated for the treatment of head lice (Pediculosis capitis). Spinosad is a fermentation product of Saccharopolyspora spinosa that contains of a mixture of two tetracyclic macrolides, spinosyn A (see Figure 71-3) and spinosyn D (see Figure 71-4), in a ratio of approximately 5:1.12 Spinosyn compounds were first isolated from soil samples taken from an abandoned Caribbean rum distillery and spinosad was first licensed by EPA as a "reduced-risk" (low mammalian toxicity) agricultural insecticide.13 Spinosad causes neuronal excitation in insects mediated by a toxic effect on nicotinic and GABA-gated ion channels that is thought to be unique to insects.13 After periods of hyperexcitation, head lice become paralyzed and die. During pre-market studies of human head lice infestations, the efficacy of 0.9% topical spinosad was approximately twice that of 1% permethtrin solution as measured by the percentage of lice-free patients 14 days after treatment (85% vs. 43%).12, 14 Spinosad is applied topically to dry hair and rinsed off after 10 minutes in conjunction with thorough cleaning of contaminated clothing and personal care items. If necessary, treatment can be repeated in 7 days.

• Telaprevir (INCIVEK) is a hepatitis C virus (HCV) NS3/4A protease inhibitor indicated, in combination with peginterferon alfa and ribavirin, for the treatment of chronic hepatitis C genotype 1 infection. The mechanism of action of telaprevir is the same as for boceprevir (see above). Telaprevir and boceprevir reversibly bind to the NS3/4A protease active site serine (S139) though an α-ketoamide functional group.15 Inhibition of NS3/4A protease prevents the manufacture of mature forms of four proteins essential for viral replication: NS4A, NS4B, NS5A, and NS5B.14 During pre-market study, treatment-emergent resistance developed in a high proportion of subjects who did not achieve a sustained viral response to telaprevir or who relapsed after telaprevir discontinuation.9, 15 Virologic failure during telepravir treatment was more frequent in subjects with genotype 1a and more frequent among prior null responders to interferon-based therapies.9, 15 Available evidence suggests that telaprevir-resistant HCV strains are likely to be resistant to boceprevir and other (investigational) HCV NS3/4A protease inhibitors.9, 15 The chemical structure of telaprevir is shown in Figure 71-5.

Telaprevir, taken orally at a dose of 750 mg three times daily with food that is not low-fat, is combined as triple therapy with peginterferon alfa and ribavirin for the first 12 weeks of treatment followed by a response-guided regimen of either 12 or 36 additional weeks of dual therapy consisting of only peginterferon and ribavirin. The specific regimen is determined on the basis of periodic HCV-RNA level monitoring, prior response status, and patient tolerability.

Among treatment-naïve patients, telaprevir triple therapy is associated with nearly twice the rate of sustained viral response that previously could be achieved from peginterferon/ribavirin dual therapy (72-75% compared with 44%).11 In addition, triple-drug therapy with telaprevir is associated with a 65% rate of sustained viral response by 24 weeks of therapy.11 Among patients who had previously relapsed following interferon-based therapy and among patients categorized as partial or null responders to previous interferon-based therapy, triple therapy with telaprevir is associated with a sustained viral response of 54-59% (relapsed), 83-88% (partial responders), and 31% (null responders), respectively.11 Discontinuation of therapy at week 4 or 12 of therapy is recommended for any patient with HCV-RNA levels >1000 IU/mL and at week 24 for any patient with confirmed detectable HCV-RNA levels.15

Triple therapy containing telaprevir is associated with anemia and routine periodic monitoring of hemoglobin levels with WBC differential counts is necessary. Telaprevir is associated with serious skin reactions including Stevens-Johnson Syndrome. More than ½ of patients exposed to telaprevir will develop a mild-moderate rash that can be managed with topical corticosteroid cream.16 However, these patients should be carefully monitored for rash progression with therapy discontinued immediately if clinically warranted. Among the other most common adverse effects of telaprevir triple-drug therapy are pruritus, nausea, hemorrhoids, diarrhea, anorectal discomfort, dysgeusia, fatigue, vomiting, anal pruritus, and elevations in serum bilirubin and uric acid levels. Telaprevir administration is not recommended for patients with moderate or severe hepatic impairment or for patients with decompensated liver disease.

Telaprevir is both a substrate and inhibitor of CYP3A4 and p-glycoprotein (P-gp).15 Telaprevir drug-drug interactions have been studied extensively. Telaprevir is contraindicated in combination with many other commonly prescribed narrow therapeutic index medications that are highly dependent on CYP3A4 for clearance, and telaprevir is contraindicated in combination with drugs that induce CYP3A4. Consult the drug labeling prior to coadministering substrates of P-gp (e.g., digoxin) or medications that are dependent on CYP3A4 for clearance (e.g., warfarin, sildenafil, tadalafil, vardenafil, antiarrhythmics, antifungals, bosentan, calcium channel blockers, benzodiazepines, colchicine, contraceptives, corticosteroids, immunosuppressants, macrolide antibiotics, opioids, and others). Telaprevir (FDA pregnancy category B), in combination with pegineterferon and ribavirin, is contraindicated in pregnancy. Triple-drug therapy with telaprevir requires monthly pregnancy tests for female patients and female partners of male patients during treatment and for 6 months after treatment discontinuation.

• Vilazodone (VIIBRYD) is both a selective serotonin reuptake inhibitor and a 5HT1A receptor partial agonist with the chemical structure. It is the first 5HT1A partial agonist to be marketed in the US. Vilazodone is indicated for the treatment of major depressive disorder and was shown to be superior to placebo, as measured by the mean change from baseline in the Montgomery-Asberg Depression Rating Scale total score, during two 8-week clinical trials.17 Efficacy beyond 8 weeks of therapy has not been studied, nor has use in patients with seizure disorders. Despite a dual mechanism of action, patient response rates of approximately 40% to vilazodone therapy appear to be similar to other marketed antidepressants and so far, efforts to identify genetic biomarkers predictive of therapeutic efficacy and toxicity have been disappointing.18 Likewise, the theoretical advantage of a potentially quicker antidepressant onset through 5HT1A receptor partial agonist activity was not reliably demonstrated during pre-market clinical trials with vilazodone.18

Vilazodone administration is contraindicated for 14 days before or after administration of an MAOI (e.g., isocarboxazid, phenelzine, tranylcypromine, rasagiline, selegiline, furazolidone, isoniazid, methylene blue, procarbazine, St. John's wort). Caution is also advised when vilazodone is administered in conjunction with other drugs that affect serotonergic neurotransmission (e.g., SSRIs, SNRIs, triptans, buspirone, tramadol, tryptophan, and others) To improve gastrointestinal tolerability, the initial 10 mg daily dose of vilazodone should be doubled at 7 day intervals to the final recommended dose of 40 mg daily.18 Failure to take vilazodone with food results in a 50% reduction in systemic exposure and may result in drug levels that are insufficient to achieve a therapeutic effect. The terminal half-life of vilazodone is approximately 25 hours and the drug is over 90% protein-bound. Metabolism of vilazodone is mainly through CYP3A4 with CYP2C19, CYP2D6, and other CYP enzymes representing minor pathways for elimination. Viladozone is a moderate inhibitor of CYP2C19, CYP2D6, and CYP2C8. To avoid potential toxicity, the dose of vilazodone should be reduced when coadministered with CYP3A4 inhibitors. Caution is also warranted when vilazodone is administered in conjunction with highly protein-bound drugs. The most common side effects of vilazodone are diarrhea, nausea, vomiting, and insomnia. Other noteworthy consequences of therapy with vilazodone may include: sexual dysfunction, seizures, serotonin syndrome (0.1% in premarket trials), neuroleptic malignant-like syndrome, bleeding, activation of mania or hypomania (0.1% in premarket trials), and syndrome of inappropriate antidiuretic hormone secretion. Use caution in patients receiving anticoagulants and in patients with a family history of bipolar disorder, mania, or hypomania. Prescriptions for vilazodone should be written for the smallest quantity consistent with good patient management and abrupt discontinuation of therapy is not recommended.

Vilazodone has been assigned to FDA Pregnancy Category C and neonates exposed late in the third trimester of pregnancy should be monitored for signs of a drug discontinuation syndrome. There is limited clinical experience with vilazodone human overdosage; five patients that ingested doses up to 280 mg during all recovered. QTc interval prolongation was found to be below the threshold for clinical concern at doses up to 80 mg. It is unknown whether the negative QTc finding will hold during higher clinical exposures.