eChapter 71 (Part 2): 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 Table 71-2). 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 part 1 of this series). Fourteen of the new drug approvals in 2011 were granted orphan drug status for rare diseases (see Table 71-2, Table 71-3, and part 1 of this series). Two of the new drugs (crizotinib for non-small cell lung cancer 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

Also noteworthy in 2011

"Repurposed" Drugs: 10 established drugs were approved for new purposes or as novel formulations for established purposes (see Table 71-3).

Biocompatible Gels:

BELOTERO BALANCE is an injectable hyaluronic acid-based dermal filler approved for the correction of facial wrinkles and folds. Belotero injections are limited to no more than 6 mL of filler per year and the pre-market adverse effect profile compared favorably to control injections with collagen.3

LEGOO is a temperature-sensitive gel approved for intraoperative injection into small diameter blood vessels to stop blood flow by forming a solid plug in the vessel. LeGoo was licensed by FDA as an alternative to the use of clamps, balloons, or loop devices to facilitate below-the-neck blood vessel grafts during off-pump coronary bypass and other vascular surgery procedures. The gel is contraindicated for use on vessels supplying blood to the brain. LeGoo plugs are dissolved at will within 15 minutes of injection by applying a cold pack or ice directly to the vessel.4

SOLESTA is a bulking agent consisting of dextranomer microspheres in a viscous sodium hyaluronate carrier approved for deep submucosal injection in the high-pressure zone of the anal canal for the outpatient treatment of fecal incontinence. Bowel preparation prior to each treatment is necessary and a course of prophylactic antibiotics is recommended afterward. Efficacy may require repeat treatment and the durability of the response beyond 12 months has not been studied.5

Laboratory Monitoring

Erythropoiesis-Stimulating Agents (ESAs): Clinical trial data has shown an increased risk of death and serious cardiovascular events when epoetin alpha (EPOGEN, PROCRIT) or darbepoetin alpha (ARANESP) are used to manage anemia in patients with chronic kidney disease (CKD) at a dose that causes the hemoglobin level to exceed 11 g/dL.6, 7 FDA has revised the product labels to remove the concept of a target hemoglobin range and replaced it with a recommendation to initiate therapy when the hemoglobin level is below 10 g/dL and use the lowest individually effective dose necessary to reduce red blood cell transfusions.8

Quantative Microsphere System (QMS) Everolimus Immunoassay: FDA has licensed the first laboratory test for routine monitoring of everolimus (ZORTRESS) drug levels in patients who have undergone a kidney transplant.9 The QMS assay measures trough whole-blood everolimus levels, which are therapeutic in the 3-8 ng/mL range.10

Relaxation of Liver Function Monitoring Requirements: Following evaluation of clinical trial and post-marketing safety information, FDA has concluded that the risk of liver injury in patients treated with ambrisentan (LETAIRIS) is low.11 Subsequently, FDA has removed the black box warning related to liver injury from the drug's labeling and monthly drug shipments to patients are no longer contingent on obtaining the results of liver enzyme tests. Ambrisentan is an endothelin receptor antagonist approved in 2007 for the treatment of pulmonary arterial hypertension. It remains under a restricted distribution program with a requirement for monthly pregnancy testing of women with childbearing potential.

FDA Pregnancy Category Changes

Terbutaline (generic): In response to a citizen petition, FDA has reviewed the available data and reclassified terbutaline from FDA Pregnancy Category B to Category C;12 therefore, terbutaline should be used during pregnancy only if the potential benefits are thought to justify the potential risk to the fetus.

Topiramate (TOPAMAX; generic): On the basis of new data from the North American Antiepileptic Drug (NAAED) Pregnancy Registry showing a 20-fold increased risk for the development of cleft lip and/or cleft palate when topiramate monotherapy is used in the first trimester of pregnancy, the drug has been reclassified from Pregnancy Category C to Category D.13 Pregnancy Category D means there is positive evidence of human fetal risk based on human data but the potential benefits of use during pregnancy may outweigh the risks in certain clinical situations. The prevalence of oral clefts associated with topiramate exposures in the NAAED data was 1.4% compared to a prevalence of 0.38 – 0.55% in infants exposed to other antiepileptic drugs, and a prevalence of 0.07% in infants of mothers without epilepsy (Relative Risk: 21.3; 95% CI: 7.9–57.1).13 Similarly, the UK Epilepsy and Pregnancy Register has reported a 16-fold increase in risk of oral clefts among infants exposed to topiramate monotherapy compared to the risk in their background population (3.2% vs. 0.2%).13

Obsolete Indications:

Bevacizumab (AVASTIN) does not prolong survival nor slow disease progression in patients with metastatic breast cancer and the FDA has withdrawn this indication for the drug.14 The drug remains on the market in the US for certain types of colon, lung, kidney and brain cancers.

Terbutaline (generic), a beta-adrenergic agonist indicated for asthma, should no longer be used for prevention or prolonged treatment of premature labor. FDA review revealed that there is no evidence that terbutaline improves infant outcomes and warns that serious adverse events, including maternal death have been reported.15 Injectable terbutaline is used off-label for obstetric purposes (e.g., during imminent preterm delivery in order to effect transport or to allow for antenatal administration of steroids to hasten fetal lung development, to treat uterine hyperstimulation, to facilitate correction of uterine inversion or external version of a breech or transverse fetus).16–20 However, the terbutaline labeling has been revised to contraindicate use of the drug for tocolysis extending longer than 48-72 hours.15

Market Withdrawals/Suspensions:

Drotrecogin alfa (XIGRIS) was withdrawn from the market worldwide following results of the PROWESS-SHOCK study that failed to show a survival benefit for patients with severe sepsis and septic shock.21, 22

Marketed Unapproved and Misbranded Prescription Cough, Cold, and Allergy Drugs: Unapproved and/or misbranded prescription cough, cold, and allergy products were the subject of FDA's 15th notice of enforcement actions against drugs that are not proven to be safe, effective, or of high quality.23 Of primary focus for the action are timed-release formulations, formulations containing tannate salts, and other ingredients that are not generally recognized as safe and effective (GRASE). The 2011 action included antitussives, expectorants, antihistamines, and nasal decongestants, and was a follow-on action to publication of the final Cold, Cough, Allergy, Bronchodilator, and Antiasthmatic Drug Products for Over-the-Counter Human Use monograph (21 CFR part 341).24 See Table 71-4 Summary Table

Vaccine License Extensions

Meningococcal Polysaccharide (Serogroups A, C, Y and W-135) Diphtheria Toxoid Conjugate Vaccine (MENACTRA): License extended to use in children as young as 9 months for the prevention of invasive meningococcal disease caused by Neisseria meningitidis serogroups A, C, Y and W-135. The new labeling allows use in individuals aged 9 months through 55 years.25

Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine, Adsorbed (BOOSTRIX): License extended to use as a single dose booster immunization to prevent tetanus, diphtheria, and pertussis (whooping cough) in people 65 years of age and older. The new license allows use in individuals 10 years of age and older.26

Zoster Vaccine, Live (ZOSTAVAX): License extended to prevent shingles in individuals 50 to 59 years of age. The new labeling allows use in individuals 50 years of age and older.27