The objective of this 2-part review is to provide information about drugs that have been recently approved by the US Food and Drug Administration. Part 1 reviewed recently approved drugs with pediatric indications. Part 2 reviews drugs recently approved only in adults and have published or ongoing studies in children.

This is the second article in a 2-part series that reviews recently approved drugs. The first article reviewed drugs that when approved by the US Food and Drug Administration (FDA) contained labeling for use in children. This second part reviews drugs that have been approved for use only in adults and have published or ongoing clinical studies in children as reported in ClinicalTrials.gov.

This review is divided into 2 sections. The first section includes new drugs with potential for use in children. Oncology drugs are discussed separately in the second section because they present a unique problem: children often have different types of cancer than those found in adults. Currently, the Pediatric Research Equity Act only requires drug companies to perform studies in children for the approved adult indication. A proposed solution would be to require newly approved drugs in adults to be studied in children with similar disease pathways or gene mutations.

Tables 1 and 2 provide a summary of select adult trials that contributed to drug approval and pediatric published and ongoing studies for each drug.

Table 1.

New Drugs With Active Pediatric Trials

New Drugs With Active Pediatric Trials
New Drugs With Active Pediatric Trials
Table 1.

New Drugs With Active Pediatric Trials (cont.)

New Drugs With Active Pediatric Trials (cont.)
New Drugs With Active Pediatric Trials (cont.)
Table 1.

New Drugs With Active Pediatric Trials

New Drugs With Active Pediatric Trials
New Drugs With Active Pediatric Trials
Table 2.

New Oncology Drugs With Active Pediatric Trials

New Oncology Drugs With Active Pediatric Trials
New Oncology Drugs With Active Pediatric Trials
Table 2.

New Oncology Drugs With Active Pediatric Trials (cont.)

New Oncology Drugs With Active Pediatric Trials (cont.)
New Oncology Drugs With Active Pediatric Trials (cont.)
Table 2.

New Oncology Drugs With Active Pediatric Trials (cont.)

New Oncology Drugs With Active Pediatric Trials (cont.)
New Oncology Drugs With Active Pediatric Trials (cont.)

Deferiprone (Ferriprox)

Iron is an essential element in many physiologic functions including oxygen transport, energy production, oxidative metabolism, DNA synthesis, and oxygen storage in muscle. Iron can also cause harm by catalyzing the formation of free radicals that attack cell membranes, DNA, and proteins. These harmful effects are increased in states of iron overload. The concern for iron overload is important in patients with thalassemias because ineffective hemoglobin synthesis can result in chronic anemias that are treated with multiple blood transfusions. Repeated blood transfusions can cause iron overload, which can then result in cardiac toxicity, liver fibrosis and cirrhosis, and endocrinopathies.1 

Deferoxamine was the first iron chelator approved for human use. It requires parenteral administration and is typically given as a sub-cutaneous or intravenous infusion for 8 to 12 hours for 5 to 7 days per week. The first oral chelator approved for human use, deferasirox, is administered once daily and is approved for use in children 2 years of age and older. A second oral iron chelator, deferiprone (Ferriprox, ApoPharma USA, Inc, Rockville, MD), was approved for human use on October 14, 2011.

Indication(s)

Deferiprone is indicated for the treatment of adults with transfusion iron overload due to thalassemias when current chelation therapy is inadequate.2 Deferiprone has been studied in children 1 to 10 years of age (n=100) for 6 months who received 50 to 100 mg/kg/day,3 but it is not currently approved for pediatric patients. Deferiprone use was associated with a significant decrease in serum ferritin concentrations and a toxicity profile similar to that of adult studies.3 

Clinical Pharmacology

Deferiprone is a chelating agent with affinity for ferric ion (Fe+++) forming a 3:1 chelator to iron complex (Figure 1). No clinical studies have assessed the relationship between the dose of deferiprone and the amount of iron eliminated from the body. Following oral administration, the peak serum concentration occurs about 1 hour after dosing in fasted individuals and 2 hours in fed individuals. Food decreases the maximum concentration about 40% and the area under the concentration curve by 10%. Deferiprone is rapidly eliminated predominately by metabolism via glucuronidation with an elimination half-life of 1.9 hours. Protein binding is less than 10%.2 

Figure 1.

Iron chelation by deferiprone. DFP, deferiprone; Fe, iron.

Figure 1.

Iron chelation by deferiprone. DFP, deferiprone; Fe, iron.

Close modal

Dosage and Administration

Deferiprone is available as a 500-mg scored, film-coated tablet. The initial recommended dose is 25 mg/kg (rounded to the nearest 250 mg, half tablet), orally three times daily for a total of 75 mg/kg/day. The dose can be increased every 2 to 3 months to a maximum dose of 33 mg/kg, three times daily for a total of 99 mg/kg/day. Although deferiprone does not carry pediatric labeling, the dosing chart provided in the product label goes down to a dosing weight of 20 kg.2 In the pediatric study by ElAlfy et al,3 a dose of 50 to 100 mg/kg/day (in 3 divided doses) was used. In addition, a liquid formulation was given, but this product is not commercially available in the United States.3 The ongoing pediatric studies4,5 report daily dosing ranges between 20 to 75 mg/kg/day.

Comments

Deferiprone has a boxed warning of agranulocytosis/neutropenia. The absolute neutrophil count (ANC) should be measured before beginning therapy and weekly during therapy. Deferiprone therapy should be interrupted for an ANC < 1.5 × 109/L or symptoms of an infection. For an ANC < 0.5 × 109/L consider hospitalization and do not resume therapy without a careful assessment of the risks and benefits. Avoid the concurrent use of other drugs that are associated with neutropenia.2 

Although studies assessing the effect of deferiprone on QT interval have not been conducted, deferiprone should be used with caution in patients at risk for QT prolongation. One patient with a documented history of QT prolongation experienced torsades de pointes during deferiprone treatment.2 

The most common adverse reactions occurring in greater than 5% of patients include neutropenia, nausea, abdominal pain/discomfort, vomiting, elevated alanine aminotransferase, arthralgia, and chromaturia. Other less common side effects include agranulocytosis, diarrhea, dyspepsia, weight gain, elevated aspartate aminotransferase, changes in appetite, back pain, arthropathy, and headache.2 

Although not studied, deferiprone should not be given within 4 hours of ingesting foods, mineral supplements, and antacids that contain polyvalent cations (iron, aluminum, and zinc).2 

Ezogabine (Potiga)

The search for new, more effective, and better-tolerated antiepileptic drugs for the treatment of inadequately controlled seizures remains a major therapeutic quest. Current antiepileptic drugs target voltage-dependent sodium or calcium channels, enhance γ-aminobutyric acid (GABA), antagonize T-type calcium channels, or reduce glutamate-induced receptor excitation. Ezogabine (Potiga, GlaxoSmithKline, Research Triangle Park, NC) was approved June 10, 2011. It has a novel mechanism in which it binds to voltage-gated potassium channels to regulate neuronal excitability.

Indication(s)

Ezogabine (retigabine) is indicated for adjunctive treatment of partial-onset seizures in patients 18 years of age and older. Safety and efficacy of ezogabine were established in adults in 3 multi-center clinical studies.6–8 Ezogabine, is currently being investigated in 2 open-label studies in pediatric patients to evaluate the pharmacokinetics9 and safety and tolerability9,10 in patients with uncontrolled partial-onset seizures or Lennox-Gastaut syndrome.

Clinical Pharmacology

The mechanism of action of ezogabine is not completely understood, but in vitro studies suggest that it may enhance transmembrane potassium currents by activating KCNQ channels (a type of ion channel), which are thought to stabilize the resting membrane potential to reduce brain excitability.11,12 Other studies11 indicate ezogabine may also augment GABA-mediated channels. Ezogabine is rapidly absorbed after oral administration, with an oral bioavailability of about 60%. High-fat meals can increase peak concentrations but do not affect the extent of absorption. Studies suggest ezogabine is 80% bound to plasma protein, but this does not appear to be clinically significant with respect to displacement of other medications. Ezogabine is well distributed throughout the body and is extensively metabolized by glucuronidation and acetylation.11 

Dosage and Administration

In adults, the recommended starting dose is 100 mg three times daily (300 mg/day) for the first week. The dose should be titrated weekly by no more than 150 mg/day to a goal dosage between 200 and 400 mg three times daily (600–1200 mg/day). Little improvement has been observed with doses between 900 mg/day and 1200 mg/day, and the larger dose was associated with an increase in adverse events and drug discontinuation. No dose adjustment is needed for mild renal or hepatic impairment but is required with moderate or severe changes in renal or hepatic function. When ezogabine is discontinued, the dose should be reduced slowly over a period of at least 3 weeks to minimize the potential for withdrawal or increased seizure frequency. Ezogabine is available as 50-mg, 200-mg, 300-mg, and 400-mg tablets and it may be taken with or without food.11 

Comments

Several warnings and precautions should be considered in patients taking ezogabine. In clinical trials, ezogabine was associated with urinary retention (approximately 2%), so urologic symptoms should be monitored closely, especially in patients with other risk factors for urinary retention. Confusion (4%), psychosis (<1%), and hallucinations (<1%) were also reported in trials more commonly than with placebo. The effects were dose related and often presented within the first 8 weeks of therapy. Also, rapid titration was associated with an increased risk of neuropsychiatric symptoms. Dizziness (23%) and somnolence (22%) were reported and these effects also appeared to be dose related. Most of these effects were mild or moderate in nature, most commonly occurred in the titration phase, and diminished with continued use. Ezogabine has also been shown to cause QT prolongation, so QT interval should be monitored in high-risk patients. As with other antiepileptic medications, ezogabine may increase the risk of suicidal thoughts or behavior, so patients should be informed of this risk and advised to seek medical attention if signs or symptoms of depression or mood changes develop.11 

Other reported adverse reactions include diplopia, blurred vision, gastrointestinal disturbances, fatigue, infection (specifically influenza), and weight gain. Most of these reactions appear to be dose related.11 

The safety and efficacy of ezogabine in patients younger than 18 years have not been established, but in animal studies, young rats appear to have increased sensitivity to urinary retention and neurotoxicity, compared to adult rats.11 

Fidaxomicin (Dificid)

Clostridium difficile is one of the most common infectious causes of antibiotic-associated diarrhea and typically occurs after broad-spectrum antibiotic use.13 Illness severity varies greatly, but severe disease can be associated with ileus, toxic megacolon, and even death.14 In children, there is an increasing trend in incidence of C difficile infection, but in contrast to adults, there does not appear to be an increasing trend in severity of illness.15 According to the Infectious Diseases Society of America, first-line treatment options include metronidazole and oral vancomycin.16 ,In vitro, fidaxomicin (Dificid, Optimer Pharmaceuticals, Inc, San Diego, CA), which was previously referred to as OPT-80, has been shown to be 8 times more potent than vancomycin against clinical isolates of C difficile.17 It was approved May 27, 2011.

Fidaxomicin has been shown to be non-inferior to vancomycin for C difficile infection18,19 and was associated with a significantly lower rate of recurrence with some strains.19 

Indication(s)

Fidaxomicin has been approved for treatment of C difficile–associated diarrhea (CDAD) in adults (18 years of age or older). Fidaxomicin has been studied in patients 16 years of age and older,18,19 and there are currently 2 ongoing studies in children. In a phase 2 open-label study,20 investigators are assessing the safety, tolerability, and the pharmacokinetics of fidaxomicin in patients aged 6 months to 18 years. Fidaxomicin is also being investigated for possible use in neonates with CDAD in an observational, noninterventional feasibility study.21 

Clinical Pharmacology

Fidaxomicin is a macrolide antibiotic and is bactericidal against C difficile in vitro. It acts locally in the gastrointestinal tract and has minimal systemic absorption at therapeutic doses. Metabolism is not dependent on cytochrome P450 enzymes but occurs through hydrolysis, and an active metabolite is formed (OP-1118). Fidaxomicin and its active metabolite are mainly excreted through feces. In controlled trials, renal impairment did not affect plasma concentrations, so no adjustment is recommended based on renal function. The effects of hepatic impairment have not been evaluated, but because fidaxomicin is not significantly metabolized through the liver, dose adjustment does not appear to be necessary based on hepatic function.22 

Dosage and Administration

Fidaxomicin is available as a 200-mg oral tablet and the recommended adult dose is 200 mg orally twice daily. It may be administered with or without food.22 Fidaxomicin 32 mg/kg/day in 2 divided doses (maximum of 400 mg/day) is currently being studied in pediatric patients.20 In this study an oral suspension is being used in patients younger than 6 years, but this product is not commercially available in the United States.

Comments

In clinical trials, there was no significant difference in safety between fidaxomicin and vancomycin. The most commonly reported adverse events associated with fidaxomicin were mild gastrointestinal symptoms (nausea, vomiting, diarrhea, and abdominal pain).18,19 Other adverse events that have rarely been reported with use of fidaxomicin are gastrointestinal hemorrhage, anemia, and neutropenia.22 

Icatibant (Firazyr)

Hereditary angioedema (HAE) is a rare autosomal dominant disease presenting with recurrent self-limiting episodes of skin and mucosal swelling/edema. This edema is caused by the absence (type I HAE) or decreased (type II HAE) function of C1-esterase inhibitor, which plays a major role in regulation of the factor XII/kallikrein proteolytic cascade that results in bradykinin production.23–25 

Indication(s)

Icatibant (Firazyr, Shire Orphan Therapies, Inc, Lexington, MA) was approved August 25, 2011, for acute attacks of HAE in adults (18 years of age or older)26–28 and is currently being studied in a phase 3 clinical trial for use in pediatric patients with HAE.29 

Clinical Pharmacology

Icatibant is a competitive bradykinin B2 receptor antagonist (Figure 2). Bradykinin is a vasodilator thought to be responsible for the characteristic HAE symptoms of localized swelling, inflammation, and pain. Icatibant inhibits bradykinin from binding the B2 receptor, which results in resolution of the clinical symptoms of an acute HAE attack.28 

Figure 2.

Icatibant inhibition of the bradykinin cascade.

Figure 2.

Icatibant inhibition of the bradykinin cascade.

Close modal

Icatibant intravenous doses of 0.4 and 0.8 mg/kg infused for a period of 4 hours elicited an inhibition response to bradykinin challenge for 6 to 8 hours after the end of the infusion time. From this analysis, icatibant 30 mg injected subcutaneously is thought to be effective for at least 6 hours. Effect on QTc interval was evaluated by using 30- and 90-mg subcutaneous dosing and was found to be below the threshold for concern. The dose of 90 mg represented the maximum dosing to be administered in a 24-hour period.28 

Intravenous and subcutaneous administrations have been evaluated to determine the pharmacokinetic profile of icatibant. The absolute bio-availability of a single 30-mg subcutaneous dose of icatibant is approximately 97%. In 96 healthy subjects, this dose produced a mean maximum concentration (Cmax) of 974 ng/mL after approximately 45 minutes, an elimination half-life of 1.4 ± 0.4 hours, and a volume of distribution of 29.0 L. There was no accumulation noted after 3 doses given 6 hours apart.28 

Icatibant is extensively metabolized to inactive metabolites, with primary excretion in the urine. There is no need to adjust dosing due to hepatic or renal impairment. Icatibant does not appear to inhibit cytochrome P450 isoenzymes (CYP) and does not induce CYP1A2 or 3A4. However, there is a potential concern for drug interaction when administered concurrently with an angiotensin-converting enzyme (ACE) inhibitor. Icatibant may attenuate the antihypertensive effect of ACE inhibitors. There are no clinical data to support this as current trials have excluded patients taking ACE inhibitors.28 

Dosage and Administration

The recommended dosage for adults is 30 mg subcutaneously every 6 hours with a maximum of 3 doses in a 24-hour period. Icatibant is available in single-use, prefilled syringes containing icatibant 30 mg in 3 mL and is packaged with a 25-gauge needle. Pediatric dosing has not been currently established, but a phase 3 clinical trial is underway, evaluating a dose of 0.4 mg/kg up to a maximum of 30 mg subcutaneously as a 1-time dose.29 

Comments

Three controlled trials in adults provided safety data evaluating 223 patients who received icatibant (n=113), placebo (n=75), or comparator (n=38). The most commonly reported adverse event is related to injection site reactions (97% vs 33%) in patients receiving icatibant vs placebo. Other reported adverse events in greater than 1% of treated patients included pyrexia, transaminase increases, dizziness, tiredness, and rash.

The safety of self-administered icatibant was also evaluated in an open-label trial including 56 patients with HAE. There was no difference in the safety profile of icatibant when comparing patients who self-administered vs patients who received icatibant from a health care professional. Patients experiencing laryngeal edema should still seek additional medical treatment after self-administration of icatibant.28 

Linagliptin (Tradjenta)

The incidence of type 2 diabetes mellitus in children is increasing dramatically. Rates are higher in non-white groups, with American Indian youths having the highest reported incidence (4.5 per 1000 for all US American Indians and 50.9 per 1000 for Pima Indians from Arizona). Retrospective studies have reported an incidence of 7.2 per 100,000 for African Americans and whites aged 10 to 19 years in 1994. Type 2 diabetes also accounted for 8% to 46% of all new cases of diabetes (regardless of type) in pediatric center referrals.30 During 2002–2005, there were 3600 newly diagnosed cases of type 2 diabetes annually among youths. However, type 2 diabetes is still extremely rare in children younger than 10 years.31 

Indication(s)

Linagliptin (Tradjenta, Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, CT) was approved May 2, 2011, for adults as an adjunct to diet and exercise to improve glycemic control in patients diagnosed with type 2 diabetes mellitus.32 A phase 2 dose-finding study is currently underway in pediatric patients aged 10 to 17 years with type 2 diabetes mellitus.33 

Clinical Pharmacology

Linagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor, which ultimately inhibits the degradation of incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). GLP-1 and GIP increase insulin release in a glucose-dependent manner and decrease circulating concentrations of glucagon. These incretin hormones regulate glucose homeostasis and are secreted at low basal concentrations with an immediate increase in production in response to a meal. In the presence of both euglycemia and hyperglycemia, GLP-1 and GIP increase insulin production and secretion from pancreatic beta cells. In addition to the effect on pancreatic beta cells, GLP-1 decreases glucagon secretion from pancreatic alpha cells, which reduces glucose output from the liver and decreases fasting plasma glucose and glycosylated hemoglobin (HbA1c). Improvements were also noted in 2-hour postprandial glucose measurements when compared to measurements for patients taking placebo.32 

Oral bioavailability is approximately 30% and is not affected by administration with food. The volume of distribution at steady state is approximately 1110 L and protein binding is concentration-dependent, decreasing from 99% to from 75% to 89% at 1 nmol/L and ≥30 nmol/L, respectively. This is due to saturation of binding to DPP-4. Protein binding is not affected by renal or hepatic impairment. Linagliptin is primarily excreted unchanged and elimination occurs via the enterohepatic system (80%) or urine (5%). Renal clearance is approximately 70 mL/min. There is no dosage adjustment necessary in patients with hepatic or renal impairment.32 

Linagliptin is a weak to moderate inhibitor of CYP3A4 and a P-glycoprotein (P-gp) substrate. There is no recommendation for dosage adjustment of linagliptin when given concomitantly with other medications. Inducers of CYP3A4 or P-gp decrease exposure to linagliptin, and alternative therapy is recommended.32 

Dosage and Administration

Linagliptin is available as a 5-mg oral tablet and the recommended dosage in adults is currently 5 mg once daily to be taken with or without food.32 Dosing in pediatric patients has not yet been established, but dosing regimens of 1 mg and 5 mg once daily are currently being evaluated.33 

Comments

Linagliptin is not indicated for use in patients diagnosed with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis. This oral agent has not been studied in combination with insulin. Nasopharyngitis was reported in 5% or more of patients. Other less common adverse events reported include pancreatitis and hypoglycemia. If a patient is receiving an insulin secretagogue, one should consider lowering the dose of the insulin secretagogue as the risk for hypoglycemia was reported more often in combination with a sulfonylurea than for those patients treated with sulfonylurea and placebo.32 

Rivaroxaban (Xarelto)

Venous thromboembolism rates in the hospitalized pediatric population have risen by 70% from 2001 to 2007.34 Enoxaparin is a viable option but is not available orally and requires monitoring. Rivaroxaban (Xarelto, Janssen Pharmaceuticals, Inc, Titusville, NJ) was approved July 1, 2011. It is an oral agent that does not require extensive monitoring.

Indication(s)

Rivaroxaban is indicated in adults for prophylaxis of deep vein thrombosis (DVT) in patients undergoing knee or hip replacement surgery35 and in patients with non-valvular atrial fibrillation36 to reduce the risk of stroke and systemic embolism.37 Two clinical trials38,39 are currently underway, evaluating the use of rivaroxaban in children with venous thromboembolism.

Clinical Pharmacology

Rivaroxaban is an orally bioavailable factor Xa inhibitor (Figure 3). It selectively blocks factor Xa (activation of factor X to factor Xa is central in the coagulation cascade) and does not require a cofactor, such as antithrombin III, for activity. This drug exhibits dose-dependent absolute bioavailability. Systemic exposure does not increase further in doses >50 mg. Due to the dose-dependent nature of rivaroxaban, the 10-mg tablet can be taken with or without food, whereas the 15-mg and 20-mg tablets are recommended to be taken with the evening meal.37 

Figure 3.

Rivaroxaban is a competitive reversible antagonist of activated factor X (Xa).

Figure 3.

Rivaroxaban is a competitive reversible antagonist of activated factor X (Xa).

Close modal

Rivaroxaban is a substrate of CYP3A4/5, CYP2J2, and P-gp. Avoidance of concomitant administration with rivaroxaban and drugs with combined P-gp and strong CYP3A4 inhibitor activity is recommended, as this may increase bleeding risk. Patients with renal impairment (creatinine clearance [CrCL] < 80 mL/min) taking P-gp and weak to moderate CYP3A4 inhibitors may also have increased bleeding risks owing to increase in exposure.

Dosage and Administration

Rivaroxaban is available as an oral tablet in 3 strengths: 10 mg, 15 mg, and 20 mg. For non-valvular atrial fibrillation, the recommended adult dose is 20 mg orally once daily with the evening meal. In patients receiving rivaroxaban for DVT prophylaxis, the recommended adult dose is 10 mg daily with or without food.37 Dosage adjustment in renal impairment is recommended and is based on indication and CrCL. Rivaroxaban should be avoided in patients with moderate to severe hepatic impairment (Child-Pugh B or C, respectively).37 Two ongoing pediatric studies38,39 are evaluating a weight-adjusted dose with equivalent exposure, compared to 10-mg or 20-mg dosing in adults.

A preliminary study showed better comparability in prolonging activated partial thromboplastin time values between neonatal cord and adult samples than with heparin, suggesting that establishing a rivaroxaban dose in neonates may be relatively easy. This is likely due to rivaroxaban's anticoagulant effect independent of antithrombin III activity.40 

Comments

Rivaroxaban does increase the risk of bleeding, which can be serious or fatal, and there is no known antidote. The most commonly observed adverse reactions were bleeding complications. When used for prophylaxis, most major bleeding complications (≥60%) were noted during the first week postoperatively. Non-hemorrhagic complications reported in ≥1% of treated patients included surgical wound secretion, extremity pain, muscle spasms, syncope, pruritus, and blisters. Also, one study in acute medically ill patients reported cases of pulmonary hemorrhage and pulmonary hemorrhage with bronchiectasis. Postmarketing surveillance has also identified Stevens-Johnson syndrome, anaphylaxis, cholestasis, and agranulocytosis, but incidence of these adverse events has not been established.37 

Roflumilast (Daliresp)

Chronic obstructive pulmonary disease (COPD) can be a very debilitating disease characterized by chronic bronchitis or emphysema, primarily caused by smoking. Several medications used for the treatment of COPD are also used in the treatment of bronchial asthma. Since asthma is prevalent in children, roflumilast (Daliresp, Forest Pharmaceuticals Inc, St Louis, MO) has been studied in pediatrics for this condition.41–43 It was approved on March 1, 2011.

Indication(s)

Roflumilast is indicated in adults for the treatment of severe COPD associated with chronic bronchitis to reduce the risk of exacerbations.44 Although roflumilast is not FDA approved for the treatment of asthma, several studies have been completed, assessing the safety and efficacy of roflumilast in adolescent and adults with chronic stable asthma.41,42,45 

Clinical Pharmacology

Roflumilast and its active metabolite are selective phosphodiesterase-4 inhibitors, which cause an increase in intracellular cyclic adenosine monophosphate (cAMP) (Figure 4). The exact mechanism of action is unknown, but it is thought the therapeutic effect is related to this increase in cAMP. Oral bioavailability is approximately 80%; therefore, it can be taken with or without food. There is no need for adjustment in renal failure, but dosing is contraindicated in moderate to severe hepatic impairment (Child-Pugh B or C).44 

Figure 4.

Roflumilast-selective phosphodiesterase 4 inhibition increases intracellular cyclic adenosine monophosphate concentration, decreasing inflammatory activity, [adenosine triphosphate (ATP)].

Figure 4.

Roflumilast-selective phosphodiesterase 4 inhibition increases intracellular cyclic adenosine monophosphate concentration, decreasing inflammatory activity, [adenosine triphosphate (ATP)].

Close modal

Dosage and Administration

Roflumilast is available as a 500-mcg white round tablet. The recommended adult dosage is 500 mcg orally daily. It can be taken with or without food.44 A dose of 500 mcg orally once daily has been evaluated in two phase 3 clinical trials in asthmatic persons, which included pediatric patients 12 years of age and older.41,42 In addition, an open-label, single-dose pharmacokinetic study evaluated the use of 100 mcg and 250 mcg in asthmatic children aged 6 to 16 years. They reported pharmacokinetic parameters similar to those reported in adults.43 

Comments

In adult clinical trials, sputum neutrophil and eosinophil reduction occurred in patients with COPD, as well as increases in FEV1. In addition, there were significant reductions in the number of COPD exacerbations.46 Roflumilast is not to be used for relief of acute bronchospasm as it does not cause bronchodilation. There is a warning that advises about the risk of psychiatric events, including suicidality, in patients treated with roflumilast. It is recommended that the risks and benefits be carefully weighed before prescribing this medication to someone with a history of depression or suicidal thoughts. Weight should be monitored regularly, as weight loss has been associated with its use. The most commonly reported adverse reactions (≥2%) include diarrhea, weight loss, nausea, headache, back pain, influenza, insomnia, dizziness, and anorexia. Adverse reactions occurring at a rate of 1% to 2% and greater when compared to placebo include, but are not limited to, abdominal pain, vomiting, muscle spasms, sinusitis, urinary tract infection, tremor, anxiety, and depression.44,47 

Brentuximab vedotin (Adcetris)

Anaplastic large cell lymphoma (ALCL) and Hodgkin lymphoma tumor cell membranes highly express the protein CD30, which is a cell membrane protein of the tumor necrosis factor receptor family. Monoclonal antibodies directed against specific tumor antigens have become an important class of chemotherapy drugs, since they can bind to both the primary tumor and any metastases.48 These antibodies exert their antitumor effect either directly by cell-mediated cytotoxicity or indirectly by delivery of radiation or toxins to the tumor cell. CD30 monoclonal antibodies have demonstrated limited activity in clinical studies,49,50 but the potency has been enhanced by the development of an antibody-drug conjugate, brentuximab vedotin (Adcetris, Seattle Genetics, Inc, Bothell, WA), which was approved August 19, 2011.

Indication(s)

Brentuximab vedotin is indicated for the treatment of ALCL in adults after failure of at least 1 multiagent chemotherapy regimen. It is also approved for the treatment of Hodgkin lymphoma in adults after failure of either autologous stem cell transplant or 2 prior multiagent chemotherapy regimens. Table 2 summarizes the important characteristics of the adult51,52 and pediatric53–57 studies evaluating brentuximab.

Clinical Pharmacology

Brentuximab vedotin is an antibody-drug conjugate comprising the anti-CD30 monoclonal antibody conjugated to a small molecule, monomethyl auristatin E (vedotin).58 Vedotin is a tubulin polymerization inhibitor that blocks cell division. The conjugate is stable in the bloodstream but releases vedotin when it is internalized into CD30-expressing tumor cells. CD30 cells are highly expressed in hematologic malignancies including Hodgkin lymphoma and ALCL.59 

The brentuximab vedotin conjugate has a multiexponential decline in serum concentrations with a terminal half-life of 4 to 6 days. There is no accumulation of the antibody-conjugate with multiple dosing every 3 weeks. The time to maximum concentration for vedotin was 1 to 3 days. Vedotin exposures decreased with continued administration of brentuximab vedotin, with 50% to 80% of the exposure of the first dose being observed on subsequent doses.60 

Dosage

Brentuximab vedotin is available as a lyophilized powder in single-use vials containing 50 mg. The contents of the vial are reconstituted with 10.5 mL of Sterile Water for Injection to yield a single-use solution of 5 mg/mL. The vial is gently swirled to aid dissolution. The recommended dose is 1.8 mg/kg as an intravenous infusion for 30 minutes every 3 weeks for a maximum of 16 cycles or until disease progression or unacceptable toxicity.60 For patients weighing more than 100 kg, the dose should be calculated from a weight of 100 kg. If patients experience grade 2 or 3 neuropathy or grade 3 or 4 neutropenia, the dose should be held until recovery and then restarted at 1.2 mg/kg. The calculated dose should be added to an infusion bag containing a minimum volume of 100 mL of 0.9% sodium chloride, 5% dextrose, or Lactated Ringers Injection to achieve a final concentration of 0.4 mg/mL. After dilution, brentuximab should be infused immediately or stored under refrigeration for up to 24 hours. The solution should not be frozen.60 

Comments

Brentuximab vedotin has a boxed warning for John Cunningham virus infection resulting in progressive multifocal leukoencephalopathy and death. In addition, brentuximab is contraindicated with concurrent use of bleomycin owing to increased pulmonary toxicity.60 The most common side effects reported in ≥20% of treated patients include neutropenia, anemia, thrombocytopenia, peripheral sensory neuropathy, fatigue, pyrexia, upper respiratory tract infection, nausea, vomiting, diarrhea, abdominal pain, rash, and cough. Other serious adverse events are infusion-related reactions and the potential for tumor lysis syndrome with rapidly proliferating tumor and high tumor burden.60 

Crizotinib (Xalkori)

Gene mutations that lead to the proliferation of cancer cells have become the targets for therapeutic interventions. Tyrosine kinases have been an important target because of their role in modulating cell proliferation. Anaplastic lymphoma kinase (ALK) plays an important role in the pathogenesis of solid and hematologic tumors. It was first discovered in ALCL, but ALK has also been found in subsets of B-cell non-Hodgkin lymphoma, neuroblastoma, breast cancer, inflammatory myofibroblastic tumor, and non–small cell lung cancer. Rearrangements of the ALK gene can be detected by using fluorescence in situ hybridization technology. Several tyrosine kinase inhibitors have been previously developed, including imatinib, gefitinib, erlotinib, lapatinib, sorafenib, and sunitinib.61 

Indication(s)

Crizotinib (Xalkori, Pfizer Inc, New York, NY) was approved August 26, 2011, and is indicated for the treatment of adults with locally advanced or metastatic non–small cell lung cancer that is ALK positive.62 ,Table 2 summarizes the established efficacy of crizotinib in adults62,63 and describes the active pediatric open-labeled trials.64 

Clinical Pharmacology

ALK is part of a superfamily of leukocyte tyrosine kinase receptors. Translocations in the ALK gene result in the expression of fusion oncogenic proteins. Crizotinib is a tyrosine kinase inhibitor that has more selective activity towards ALK than other tyrosine kinases.65 

Following oral administration, peak crizotinib concentration occurred in 4 to 6 hours, the mean bioavailability was 43%, and the terminal elimination half-life was 42 hours. Steady-state concentration was achieved within 15 days after taking 250 mg dosed twice daily. Elimination is predominately through CYP3A4 metabolism with subsequent conjugation. Coadministration with a strong CYP3A4 inhibitor increases systemic exposure, whereas coadministration with CYP3A4 inducers reduces systemic exposure. Crizotinib is also a moderate inhibitor of CYP3A4.62 

Dosage

Crizotinib is available as 200- and 250-mg hard gelatin capsules. The recommended adult dose is 250 mg taken orally twice daily. Treatment is continued for as long as the patient is deriving clinical benefit from therapy. If a dose reduction is required because of excessive toxicities, the dose can be reduced to 200 mg orally twice daily or to 250 mg once daily.62 The optimal pediatric dose is not yet known, but several investigators are currently conducting pediatric dose escalation studies.66–68 In these studies, there is no information related to the dosage form that is being used. This is an important consideration in young children who are unable to swallow capsules. This further illustrates the need for pediatric-friendly dosage forms and contributes to the difficulty in studying these medications in pediatric patients.

Comments

Adverse events have been evaluated in 255 patients from the 2 safety and efficacy trials.62 Dosing interruptions occurred in about 40% of patients and lasted greater than 2 weeks in about 15% of patients. Dosage reduction was required in 29% to 44% of patients. The most common adverse events, occurring in ≥20% of treated patients, included vision disorder, nausea, diarrhea, vomiting, edema, fatigue, and constipation.62 Also, QT prolongation has been reported in patients receiving crizotinib.62 

Ipilimumab (Yervoy)

Melanoma is the most severe type of malignant skin cancer and the incidence continues to increase each year. Although melanoma is fairly rare in children, with about 400 new cases per year, the number of newly diagnosed children is increasing.69 The treatment options for unresectable or metastatic melanoma are limited. Standard treatment options such as dacarbazine and high-dose interleukin-2 have not prolonged survival.

Cytotoxic T-lymphocyte–associated antigen-4 (CTLA-4) is a cell surface molecule located on T cells. CTLA-4 functions as a natural brake on T lymphocyte activation, which causes immune system impairment. Ipilimumab is a monoclonal antibody targeted to inhibit CTLA-4 activity.70 

Indication(s)

Ipilimumab (Yervoy, Bristol-Myers Squibb, Princeton, NJ) was approved March 25, 2011, for the treatment of adult patients with unresectable or metastatic melanoma.71,72 Ipilimumab is being investigated in 2 ongoing clinical studies in children with advanced or refractory solid tumors73 and stage III or IV malignant melanoma.74 

Clinical Pharmacology

Ipilimumab binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands on antigen-presenting cells (Figure 5).75 Blockage of CTLA-4 augments T-lymphocyte activation and proliferation. The effect of ipilimumab on melanoma is thought to be indirect through T-lymphocyte–mediated antitumor activity.

Figure 5.

Ipilimumab blocks the immune inhibitory molecule cytotoxic T-lymphocyte antigen-4 (CTLA-4) on activated T cells. Ag, antigen; B7, B7 receptor; CD28 receptor, cluster of differentiation 28 receptor; MHC, major histocompatibility complex; TCR, T-cell receptor.

Figure 5.

Ipilimumab blocks the immune inhibitory molecule cytotoxic T-lymphocyte antigen-4 (CTLA-4) on activated T cells. Ag, antigen; B7, B7 receptor; CD28 receptor, cluster of differentiation 28 receptor; MHC, major histocompatibility complex; TCR, T-cell receptor.

Close modal

The terminal half-life is 14.7 days and steady-state concentrations are achieved after 3 doses when administered at 3-week intervals with minimum systemic accumulation.

Dosage

Ipilimumab is available in 50 mg/10 mL and 200 mg/40 mL single-use vials that should be stored under refrigeration (2°C to 8°C) and protected from light. The required volume of ipilimumab is withdrawn from the vial and further diluted with normal saline to a final concentration of 1 mg/mL or 2 mg/mL. The diluted solution should be stored for no more than 24 hours under refrigeration (2°C to 8°C) or room temperature (20°C to 25°C). The recommended adult dose is 3 mg/kg injected intravenously for 90 minutes every 3 weeks for a total of 4 doses.71 Pediatric dosing has not been established, but is currently being investigated in a phase 1 open-label dose escalation study in patients aged 1 to 21 years.73 Also, in a phase 2 open-label study including children aged 12 to 17 years with stage III or IV malignant melanoma, ipilimumab 10 mg/kg every 3 weeks for 4 doses, then every 12 weeks, is being assessed.74 

Comments

The most severe adverse and fatal reactions (black box warning) are immune mediated and include enterocolitis, hepatitis, dermatitis (toxic epidermal necrolysis), neuropathy, and endocrinopathy. Ipilimumab should be permanently discontinued and high-dose systemic corticosteroids initiated. Other reported side effects include diarrhea, pruritus, and fatigue.71 

Vandetanib (Caprelsa)

Medullary thyroid cancer is a rare form of cancer, representing about 4% to 5% of all thyroid cancers. The disease has a high cure rate if surgery is performed at an early stage. Children represent about 5% of all thyroid cancer cases and commonly present with widespread disease. Thyroid cancer is the third most common solid tumor malignancy and is the most common endocrine neoplasm in children. There are few treatment options for individuals with progressive or unresectable medullary thyroid cancer. Tyrosine kinase inhibitors can be combined with chemotherapy or radiation therapy, and they have the advantages of oral administration and a favorable safety profile. Rearranged during transfection (RET) mutations are important pathways in the development of medullary thyroid cancer and are the target of the tyrosine kinase inhibitor vandetanib.76 

Indication(s)

Vandetanib (Caprelsa, AstraZeneca Pharmaceuticals LP, Wilmington, DE) was approved April 11, 2011, and is indicated for the treatment of symptomatic or progressive, unresectable medullary thyroid cancer in adults.77,78 Vandetanib is being investigated in 2 open-label studies in children with medullary thyroid cancer79 and brainstem glioma.80 

Clinical Pharmacology

Vandetanib is an orally active drug that inhibits the activity of several tyrosine kinases including epidermal growth factor receptor, vascular endothelial cell growth factor, and RET kinase– dependent signaling. These tyrosine kinases play an important role in cellular signaling that promotes tumor proliferation, angiogenesis, and metastasis.81 

Dosage

Vandetanib is available in 100-mg and 300-mg film-coated tablets. The recommended adult dose is 300 mg orally once daily. For individuals with difficulty swallowing tablets, the tablet can be added to a glass with 2 oz of water and stirred for about 10 minutes until the tablet is dispersed. The tablet should not be crushed. The dispersed drug should be swallowed immediately and any residue in the glass should be mixed again with an additional 4 oz of water and swallowed. Patients with renal impairment (CrCL < 50 mL/min) should have the dose reduced to 200 mg. The dose should also be reduced to 200 mg and then to 100 mg if the patient experiences grade 3 or greater toxicity (Common Terminology Criteria for Adverse Events includes QT prolongation, skin reactions, diarrhea, and hypertension).77 In one pediatric ongoing study,79 vandetanib 150 mg/m2 once daily in 28-day cycles is being evaluated in patients with medullary thyroid carcinoma. A dose-escalation study in patients aged 2 to 21 years with brainstem glioma is currently underway to determine the maximum tolerated dose in this patient population.80 

Comments

The two most common reported adverse events, diarrhea and rash, have been reported in more than 50% of treated patients. Other frequent adverse events occurring in 20% to 50% of treated patients include acne, nausea, hypertension with progression to hypertensive crisis, headache, fatigue, decreased appetite, and abdominal pain. Vandetanib has a block box warning for the potential to cause prolonged QT interval and sudden death.77 Because of this risk, vandetanib is available only through a restricted distribution program (CAPRELSA Risk Evaluation and Mitigation Strategy) whereby only physicians and pharmacies that are certified with the program are able to prescribe and dispense vandetanib.82 

Vemurafenib (Zelboraf)

Melanoma has one of the highest frequencies (>65%) of the BRAF gene mutation. BRAF is a proto-oncogene for which acquired mutations are associated with cancer.83 More than 30 mutations of the BRAF gene have been identified that are associated with human cancer. About 90% of BRAF mutations are V600E-mutated kinase and involve the substitution of glutamic acid (E) for valine (V) at position V600 in the B-raf protein. B-raf protein is involved in cell signaling and growth. There is an FDA-approved test to detect the BRAF V600E mutation.84 

Indication(s)

Vemurafenib (Zelboraf, Genentech USA, Inc, San Francisco, CA) was approved on August 17, 2011, for the treatment of adults with unresectable or metastatic melanoma with BRAF V600E gene mutation.85–87 Vemurafenib is also being investigated in children with advanced solid tumors88 and with BRAF V600–positive melanoma.89 

Clinical Pharmacology

Vemurafenib is an orally active selective inhibitor of mutated B-raf V600E kinase (Figure 6). The V600E mutation leads to a B-raf protein that is constitutively active, resulting in excessive cell proliferation and resistance to apoptosis. It has no antitumor effect against wild-type B-raf.

Figure 6.

Vemurafenib inhibits BRAF V600E kinase activity in the melanoma cell, blocking growth factor signals that process from the tyrosine kinase receptor. ERK, extracellular signal–regulated kinase; MEK, mitogen-activated protein kinase.

Figure 6.

Vemurafenib inhibits BRAF V600E kinase activity in the melanoma cell, blocking growth factor signals that process from the tyrosine kinase receptor. ERK, extracellular signal–regulated kinase; MEK, mitogen-activated protein kinase.

Close modal

Dosage

Vemurafenib is available in 240-mg film-coated tablets. The recommended adult dose is 960 mg orally twice daily. The dose can be taken with or without meals. Dose modification for adverse events or QT prolongation can be made, but it is not recommended to reduce the dose below 480 mg twice daily.85 Vemurafenib 480 mg twice daily is being evaluated in pediatric patients older than 12 years.88 

Comments

The most common adverse events occurring in >30% of patients include arthralgia, rash, photosensitivity, pruritus, fatigue, nausea, alopecia, and skin papilloma. Other frequent adverse events include hyperkeratosis, dry skin, headache, diarrhea, vomiting, and loss of appetite. Cutaneous squamous cell carcinoma occurred in 24% of treated patients, usually occurring early in therapy (median time to appearance, 7 to 8 weeks). Serious adverse events include hypersensitivity reaction, 1 case of Stevens Johnson syndrome, and 1 case of toxic epidermal necrolysis, and QT prolongation.85 

ACE

angiotensin-converting enzyme

ALCL

anaplastic large cell lymphoma

ALK

anaplastic lymphoma kinase

ANC

absolute neutrophil count

cAMP

cyclic adenosine monophosphate

CDAD

Clostridium difficile–associated diarrhea

Cmax

mean maximum plasma concentration

COPD

chronic obstructive pulmonary disease

CrCL

creatinine clearance

CTLA-4

cytotoxic T-lymphocyte antigen-4

CYP

cytochrome P450 isoenzymes

DPP-4

dipeptidyl peptidase-4

DVT

deep vein thrombosis

FDA

US Food and Drug Administration

GABA

γ-aminobutyric acid

GIP

glucose-dependent insulinotropic peptide

GLP-1

glucagon-like peptide 1

HAE

hereditary angioedema

HbA1c

glycosylated hemoglobin

P-gp

P-glycoprotein

RET

rearranged during transfection

1.
Kwiatkowski
JL.
Oral iron chelators
.
Hematol Oncol Clin North Am
.
2010
;
24
(
1
):
229
248
.
2.
US Food and Drug Administration
.
FDA labeling information—Ferriprox
;
2011
. .
3.
ElAlfy
MS
,
Sari
TT
,
Lee
CL
,
et al
.
The safety, tolerability, and efficacy of a liquid formulation of deferiprone in young children with transfusional iron overload
.
J Pediatr Hematol Oncol
.
2010
;
32
(
8
):
601
605
.
4.
Children's Hospital of Philadelphia
.
Compassionate use of deferiprone for patients with thalassemia and iron-induced heart disease. ClinicalTrials.gov Web site
.
Bethesda, MD
:
National Library of Medicine
;
2006
.
NLM identifier: NCT00293098. http://clinicaltrials.gov/ct2/show/NCT00293098?term=00293098&rank=1. Accessed October 10, 2012
.
5.
ApoPharma
.
A study investigating the long-term safety and efficacy of deferiprone in patients with Friedreich's ataxia. ClinicalTrials.gov Web site
.
Bethesda, MD
:
National Library of Medicine
;
2009
.
NLM identifier: NCT00897221. http://clinicaltrials.gov/ct2/show/NCT00897221?term=00897221&rank=1. Accessed October 10, 2012
.
6.
Gil-Nagel
A
,
Brodie
MJ
,
Leroy
R
,
et al
.
Safety and efficacy of ezogabine (retigabine) in adults with refractory partial-onset seizures: interim results from two ongoing open-label studies
.
Epilepsy Res
.
2012
;
102
(
1–2
):
117
121
.
7.
Porter
RJ
,
Partiot
A
,
Sachdeo
R
,
et al
.
Randomized, multicenter, dose-ranging trial of retigabine for partial-onset seizures
.
Neurology
.
2007
;
68
(
15
):
1197
1204
.
8.
French
JA
,
Abou-Khalil
BW
,
Leroy
RF
,
et al
.
Randomized, double-blind, placebo-controlled trial of ezogabine (retigabine) in partial epilepsy
.
Neurology
.
2011
;
76
(
18
):
1555
1563
.
9.
GlaxoSmithKline
.
Open-label, multiple dose study to evaluate the pharmacokinetics, safety, and tolerability of ezogabine/retigabine as adjunctive treatment in subjects aged from 12 years to less than 18 years with partial onset seizures or Lennox-Gastaut syndrome. ClinicalTrials.gov Web site
.
Bethesda, MD
:
National Library of Medicine
;
2011
.
NLM identifier: NCT01494584. http://clinicaltrials.gov/ct2/show/NCT01494584?term=NCT01494584. Accessed March 8, 2012
.
10.
GlaxoSmithKline
.
RTG113388, a long-term, open-label safety extension study of retigabine/ezogabine in pediatric subjects with partial onset seizures (≥12 years old) and subjects with Lennox-Gastaut syndrome (≥12 years old). ClinicalTrials.gov Web site
.
Bethesda, MD
:
National Library of Medicine
;
2012
.
NLM identifier: NCT01668654. http://clinicaltrials.gov/ct2/show/NCT01668654?term=01668654&rank=1. Accessed October 11, 2012
.
11.
US Food and Drug Administration
.
FDA labeling information—Potiga
;
2012
. .
12.
Gunthorpe
MJ
,
Large
CH
,
Sankar
R.
The mechanism of action of retigabine (ezogabine), a first-in-class K+ channel opener for the treatment of epilepsy
.
Epilepsia
.
2012
;
53
(
3
):
412
424
.
13.
Baxter
R
,
Ray
GT
,
Fireman
BH.
Case-control study of antibiotic use and subsequent Clostridium difficile-associated diarrhea in hospitalized patients
.
Infect Control Hosp Epidemiol
.
2008
;
29
(
1
):
44
50
.
14.
Gerding
DN.
Disease associated with Clostridium difficile infection
.
Ann Intern Med
.
1989
;
110
(
4
):
255
257
.
15.
Nylund
CM
,
Goudie
A
,
Garza
JM
,
et al
.
Clostridium difficile infection in hospitalized children in the United States
.
Arch Pediatr Adolesc Med
.
2011
;
165
(
5
):
451
457
.
16.
Cohen
SH
,
Gerding
DN
,
Johnson
S
,
et al
.
Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the society for healthcare epidemiology of America (SHEA) and the infectious diseases society of America (IDSA)
.
Infect Control Hosp Epidemiol
.
2010
;
31
(
5
):
431
455
.
17.
Karlowsky
JA
,
Laing
NM
,
Zhanel
GG.
In vitro activity of OPT-80 tested against clinical isolates of toxin-producing Clostridium difficile
.
Antimicrob Agents Chemother
.
2008
;
52
(
11
):
4163
4165
.
18.
Cornely
OA
,
Crook
DW
,
Esposito
R
,
et al
.
Fidaxomicin versus vancomycin for infection with Clostridium difficile in Europe, Canada, and the USA: a double-blind, non-inferiority, randomised controlled trial
.
Lancet Infect Dis
.
2012
;
12
(
4
):
281
289
.
19.
Louie
TJ
,
Miller
MA
,
Mullane
KM
,
et al
.
Fidaxomicin versus vancomycin for Clostridium difficile infection
.
New Engl J Med
.
2011
;
364
(
5
):
422
431
.
20.
Optimer Pharmaceuticals
.
A phase 2A, multi-center, open-label, uncontrolled study to determine the safety, tolerability, and pharmacokinetics of fidaxomicin oral suspension or tablets in pediatric subjects with Clostridium difficile-associated diarrhea (CDAD). ClinicalTrials.gov Web site
.
Bethesda, MD
:
National Library of Medicine
;
2012
.
NLM identifier: NCT01591863. http://clinicaltrials.gov/ct2/show/NCT01591863?term=01591863&rank=1. Accessed October 10, 2012
.
21.
Astellas Pharma Inc.
An observational, non-interventional study to determine the role of Clostridium difficile in the pathogenesis of disease observed in neonates and to investigate the feasibility of a potential study to evaluate safety, efficacy and pharmacokinetics of fidaxomicin oral suspension in neonates with Clostridium difficile associated disease (CDAD). ClinicalTrials.gov Web site
.
Bethesda, MD
:
National Library of Medicine
;
2012
.
NLM identifier: NCT01533844. http://clinicaltrials.gov/ct2/show/NCT01533844?term=NCT01533844. Accessed March 8, 2012
.
22.
US Food and Drug Administration
.
FDA labeling information–Dificid
;
2011
. .
23.
Maurer
M
,
Magerl
M.
Hereditary angioedema: an update on available therapeutic options
.
J Dtsch Dermatol Ges
.
2010
;
8
(
9
):
663
672
.
24.
Ebo
DG
,
Verweij
MM
,
De Knop
KJ
,
et al
.
Hereditary angioedema in childhood: an approach to management
.
Paediatr Drugs
.
2010
;
12
(
4
):
257
268
.
25.
Sardana
N
,
Craig
TJ.
Recent advances in management and treatment of hereditary angioedema
.
Pediatrics
.
2011
;
128
(
6
):
1173
1180
.
26.
Cicardi
M
,
Banerji
A
,
Bracho
F
,
et al
.
Icatibant, a new bradykinin-receptor antagonist, in hereditary angioedema
.
New Engl J Med
.
2010
;
363
(
6
):
532
541
.
27.
Lumry
WR
,
Li
HH
,
Levy
RJ
,
et al
.
Randomized placebo-controlled trial of the brady-kinin B(2) receptor antagonist icatibant for the treatment of acute attacks of hereditary angioedema: the FAST-3 trial
.
Ann Allergy Asthma Immunol
.
2011
;
107
(
6
):
529
537
.
28.
US Food and Drug Administration
.
FDA labeling information—Firazyr
;
2011
. .
29.
Shire Human Genetic Therapies, Inc
.
A multicenter, open-label, non-randomized study to assess the pharmacokinetics, tolerability, and safety of a single subcutaneous administration of icatibant in children and adolescents with hereditary angioedema. ClinicalTrials.gov Web site
.
Bethesda, MD
:
National Library of Medicine
;
2011
.
NLM identifier: NCT01386658. http://clinical-trials.gov/ct2/show/NCT01386658. Accessed May 29, 2012
.
30.
CDC
.
More information—children and diabetes: projects, diabetes DDT
. .
31.
National Diabetes Statistics
.
National Diabetes Information Clearinghouse
;
2011
. .
32.
US Food and Drug Administration
.
FDA labeling information—Tradjenta
;
2011
. .
33.
Boehringer Ingelheim Pharmaceuticals
.
A randomized, double-blind, placebo-controlled, parallel group dose-finding study of linagliptin (1 and 5 mg administered orally once daily) over 12 weeks in children and adolescents, from 10 to 17 years of age, with type 2 diabetes and insufficient glycaemic control despite treatment with diet and exercise alone. ClinicalTrials. gov Web site
.
Bethesda, MD
:
National Library of Medicine
;
2012
.
NLM identifier: NCT01342484. http://clinicaltrials.gov/ct2/show/NCT01342484. Accessed May 30, 2012
.
34.
Raffini
L
,
Huang
YS
,
Witmer
C
,
Feudtner
C.
Dramatic increase in venous thromboembolism in children's hospitals in the United States from 2001 to 2007
.
Pediatrics
.
2009
;
124
(
4
):
1001
1008
.
35.
Eriksson
BI
,
Borris
LC
,
Friedman
RJ
,
et al
.
Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty
.
New Engl J Med
.
2008
;
358
(
26
):
2765
2775
.
36.
Patel
MR
,
Mahaffey
KW
,
Garg
J
,
et al
.
Rivaroxaban versus warfarin in nonvalvular atrial fibrillation
.
New Engl J Med
.
2011
;
365
(
10
):
883
891
.
37.
US Food and Drug Administration
.
FDA labeling information—Xarelto
;
2011
. .
38.
Bayer
.
Single-dose pilot study of oral rivaroxaban in pediatric subjects with venous thromboembolism. ClinicalTrials. gov Web site
.
Bethesda, MD
:
National Library of Medicine
;
2012
.
NLM identifier: NCT01145859. http://clinicaltrials.gov/ct2/show/NCT01145859. Accessed May 30, 2012
.
39.
Bayer
.
30-Day, open-label, active-controlled, randomized study of the safety, eficacy and the pharmacokinetic and pharmaco-dynamic properties of oral rivaroxaban in children with various manifestations of venous thrombosis. ClinicalTrials.gov Web site
.
Bethesda, MD
:
National Library of Medicine
;
2012
.
NLM identifier: NCT01684423. http://clinicaltrials.gov/ct2/show/study/NCT01684423?term=01684423&rank=1. Accessed October 6, 2012
.
40.
Novak
M
,
Schlagenhauf
A
,
Bernhard
H
,
et al
.
Effect of rivaroxaban, in contrast to heparin, is similar in neonatal and adult plasma
.
Blood Coagul Fibrinolysis
.
2011
;
22
(
7
):
588
592
.
41.
Takeda Global Research & Development Center, Inc
.
The MOVE-study: morning versus evening administration of 500 mcg roflumilast once daily for 6 weeks in patients with asthma. ClinicalTrials.gov Web site
.
Bethesda, MD
:
National Library of Medicine
;
2005
.
NLM identifier: NCT00163475. http://clinicaltrials.gov/ct2/show/NCT00163475?term=NCT00163475. Accessed March 8, 2012
.
42.
Takeda Global Research & Development Center, Inc
.
A 24-week, double-blind, parallel group, placebo and active controlled study to investigate the efficacy and safety of daily oral roflumilast taken with low dose inhaled corticosteroids in patients with chronic asthma. ClinicalTrials.gov Web site
.
Bethesda, MD
:
National Library of Medicine
;
2005
.
NLM identifier: NCT00163527. http://clinicaltrials.gov/ct2/show/NCT00163527?term=NCT00163527. Accessed March 8, 2012
.
43.
Neville
KA
,
Szefler
SJ
,
Abdel-Rahman
SM
,
et al
.
Single-dose pharmacokinetics of roflumilast in children and adolescents
.
J Clin Pharmacol
.
2008
;
48
(
8
):
978
985
.
44.
US Food and Drug Administration
.
FDA labeling information—Daliresp
;
2011
. .
45.
Bateman
ED
,
Izquierdo
JL
,
Harnest
U
,
et al
.
Efficacy and safety of roflumilast in the treatment of asthma
.
Ann Allergy Asthma Immunol
.
2006
;
96
(
5
):
679
686
.
46.
Grootendorst
DC
,
Gauw
SA
,
Verhoosel
RM
,
et al
.
Reduction in sputum neutrophil and eosinophil numbers by the PDE4 inhibitor roflumilast in patients with COPD
.
Thorax
.
2007
;
62
(
12
):
1081
1087
.
47.
Rabe
KF
,
Bateman
ED
,
O'Donnell
D
,
et al
.
Roflumilast—an oral anti-inflammatory treatment for chronic obstructive pulmonary disease: a randomised controlled trial
.
Lancet
.
2005
;
366
(
9485
):
563
571
.
48.
Ross
JS
,
Gray
K
,
Gray
GS
,
et al
.
Anticancer antibodies
.
Am J Clin Pathol
.
2003
;
119
(
4
):
472
485
.
49.
Ansell
SM
,
Horwitz
SM
,
Engert
A
,
et al
.
Phase I/II study of an anti-CD30 monoclonal antibody (MDX-060) in Hodgkin's lymphoma and anaplastic large-cell lymphoma
.
J Clin Oncol
.
2007
;
25
(
19
):
2764
2769
.
50.
Forero-Torres
A
,
Leonard
JP
,
Younes
A
,
et al
.
A Phase II study of SGN-30 (anti-CD30 mAb) in Hodgkin lymphoma or systemic anaplastic large cell lymphoma
.
Br J Haematol
.
2009
;
146
(
2
):
171
179
.
51.
Pro
B
,
Advani
R
,
Brice
P
,
et al
.
Brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large-cell lymphoma: results of a phase II study
.
J Clin Oncol
.
2012
;
30
(
18
):
2190
2196
.
52.
Younes
A
,
Gopal
AK
,
Smith
SE
,
et al
.
Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin's lymphoma
.
J Clin Oncol
.
2012
;
30
(
18
):
2183
2189
.
53.
National Cancer Institute
.
A study of brentuximab vedotin (SGN-35) in pediatric patients with relapsed or refractory systemic anaplastic large-cell lymphoma or Hodgkin lymphoma. ClinicalTrials. gov Web site
.
Bethesda, MD
:
National Library of Medicine
;
2012
.
NLM identifier: NCT01492088. http://clinicaltrials.gov/ct2/show/NCT01492088. Accessed May 18, 2012
.
54.
National Cancer Institute
.
A study of brentuximab vedotin in patients with CD30-positive non-Hodgkin lymphoma. Clinical-Trials.gov Web site
.
Bethesda, MD
:
National Library of Medicine
;
2011
.
NLM identifier: NCT01421667. http://clinicaltrials.gov/ct2/show/NCT01421667. Accessed May 18, 2012
.
55.
Seattle Genetics, Inc
.
A phase 2, open-label study of brentuximab vedotin in patients with CD30-positive nonlymphomatous malignancies. ClinicalTrials.gov Web site
.
Bethesda, MD
:
National Library of Medicine
;
2011
.
NLM identifier: NCT01461538. http://clinicaltrials.gov/ct2/show/NCT01461538?term=01461538&rank=1. Accessed October 6, 2012
.
56.
Seattle Genetics, Inc
.
A phase 2, a treatment-option study of brentuximab vedotin in patients with progression of Hodgkin lymphoma or systemic anaplastic large cell lymphoma. ClinicalTrials.gov Web site
.
Bethesda, MD
:
National Library of Medicine
;
2010
.
NLM identifier: NCT01196208. http://clinicaltrials.gov/ct2/show/NCT01196208?term=01196208&rank=1. Accessed October 6, 2012
.
57.
Seattle Genetics, Inc
.
Treatment with SGN-35 in patients with CD30-positive hematologic malignancies who have previously participated in an SGN-35 study. Clinical-Trials.gov Web site
.
Bethesda, MD
:
National Library of Medicine
;
2009
.
NLM identifier: NCT00947856. http://clinicaltrials.gov/ct2/show/NCT00947856?term=00947856&rank=1. Accessed October 6, 2012
.
58.
Younes
A
,
Bartlett
NL
,
Leonard
JP
,
et al
.
Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas
.
New Engl J Med
.
2010
;
363
(
19
):
1812
1821
.
59.
Younes
A.
CD30-targeted antibody therapy
.
Curr Opin Oncol
.
2011
;
23
(
6
):
587
593
.
60.
US Food and Drug Administration
.
FDA labeling information—Adcetris
;
2011
. .
61.
Arora
A
,
Scholar
EM.
Role of tyrosine kinase inhibitors i n cancer therapy
.
J Pharmacol Exp Ther
.
2005
;
315
(
3
):
971
979
.
62.
US Food and Drug Administration
.
FDA labeling information—Xalkori
;
2011
. .
63.
Kwak
EL
,
Bang
YJ
,
Camidge
DR
,
et al
.
Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer
.
New Engl J Med
.
2010
;
363
(
18
):
1693
1703
.
64.
National Cancer Institute
.
Crizotinib in treating young patients with relapsed or refractory solid tumors or anaplastic large cell lymphoma. ClinicalTrials.gov Web site
.
Bethesda, MD
:
National Library of Medicine
;
2012
.
NLM identifier: NCT00939770. http://clinicaltrials.gov/ct2/show/NCT00939770. Accessed May 18, 2012
.
65.
Ou
SH.
Crizotinib: a novel and first-in-class multitargeted tyrosine kinase inhibitor for the treatment of anaplastic lymphoma kinase rearranged non-small cell lung cancer and beyond
.
Drug Des Devel Ther
.
2011
;
5
:
471
485
.
66.
Children's Oncology Group
.
A phase I/II study of PF-02341066, an oral small molecule inhibitor of anaplastic lymphoma kinase (ALK) and c-Met, in children with relapsed/refractory solid tumors, primary CNS tumors, and anaplastic large cell lymphoma. ClinicalTrials.gov Web site
.
Bethesda, MD
:
National Library of Medicine
;
2009
.
NLM identifier: NCT00939770. http://clinicaltrials.gov/ct2/show/NCT00939770?term=00939770&rank=1. Accessed October 6, 2012
.
67.
Children's Oncology Group
.
Phase 1 study of crizotinib in combination with conventional chemotherapy for relapsed or refractory solid tumors or anaplastic large cell lymphoma. ClinicalTrials.gov Web site
.
Bethesda, MD
:
National Library of Medicine
;
2012
.
NLM identifier: NCT01606878. http://clinicaltrials.gov/ct2/show/NCT0 1606878?term=01606878&rank=1. Accessed October 6, 2012
.
68.
St. Jude Children's Research Hospital
.
Phase I study of the combination of crizotinib and dasatinib in pediatric research participants with diffuse pontine glioma (DIPG) and high-grade glioma (HGG). ClinicalTrials.gov Web site
.
Bethesda, MD
:
National Library of Medicine
;
2012
.
NLM identifier: NCT01644773. http://clinicaltrials.gov/ct2/show/NCT01644773?term=01644773&rank=1. Accessed October 6, 2012
.
69.
Ducharme
EE
,
Silverberg
NB.
Pediatric malignant melanoma: an update on epidemiology, detection, and prevention
.
Cutis
.
2009
;
84
(
4
):
192
198
.
70.
Ascierto
PA
,
Marincola
FM
,
Ribas
A.
Anti-CTLA4 monoclonal antibodies: the past and the future in clinical application
.
J Transl Med
.
2011
;
9
:
196
.
71.
US Food and Drug Administration
.
FDA labeling information—Yervoy
;
2011
. .
72.
Hodi
FS
,
O'Day
SJ
,
McDermott
DF
,
et al
.
Improved survival with ipilimumab in patients with metastatic melanoma
.
New Engl J Med
.
2010
;
363
(
8
):
711
723
.
73.
National Cancer Institute
.
Phase I study of ipilimumab (anti-CTLA-4) in children and adolescents with treatment-resistant cancer. ClinicalTrials.gov Web site
.
Bethesda, MD
:
National Library of Medicine
;
2012
.
NLM identifier: NCT01445379. http://clinicaltrials.gov/ct2/show/NCT01445379. Accessed May 18, 2012
.
74.
Bristol-Myers Squibb
.
Phase 2 study of ipilimumab in children and adolescents (12 to <18 years) with previously treated or untreated, unresectable stage III or stage IV malignant melanoma. ClinicalTrials.gov Web site
.
Bethesda, MD
:
National Library of Medicine
;
2012
.
NLM identifier: NCT01696045. http://clinicaltrials.gov/ct2/show/NCT01696045?term=01696045&rank=1. Accessed October 6, 2012
.
75.
Cameron
F
,
Whiteside
G
,
Perry
C.
Ipilimumab: first global approval
.
Drugs
.
2011
;
71
(
8
):
1093
1104
.
76.
Langmuir
PB
,
Yver
A.
Vandetanib for the treatment of thyroid cancer
.
Clin Pharmacol Ther
.
2012
;
91
(
1
):
71
80
.
77.
US Food and Drug Administration
.
FDA labeling information—Caprelsa
;
2011
. .
78.
Wells
SA
Jr
,
Robinson
BG
,
Gagel
RF
,
et al
.
Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial
.
J Clin Oncol
.
2012
;
30
(
2
):
134
141
.
79.
National Cancer Institute
.
Vandetanib to treat children and adolescents with medullary thyroid cancer. ClinicalTrials. gov Web site
.
Bethesda, MD
:
National Library of Medicine
;
2011
.
NLM identifier: NCT00514046. http://clinicaltrials.gov/ct2/show/NCT00514046. Accessed May 18, 2012
.
80.
St. Jude Children's Research Hospital
.
Phase I trial of vandetanib (ZD6474, ZACTIMA) with concurrent radiation in treatment of newly diagnosed brainstem glioma. ClinicalTrials.gov Web site
.
Bethesda, MD
:
National Library of Medicine
;
2007
.
NLM identifier: NCT00472017. http://clinicaltrials.gov/ct2/show/NCT00472017?term=00472017&rank=1. Accessed October 6, 2012
.
81.
Cakir
M
,
Grossman
AB.
Medullary thyroid cancer: molecular biology and novel molecular therapies
.
Neuroendocrinology
.
2009
;
90
(
4
):
323
348
.
82.
Caprelsa REMS Program
.
http://www.caprelsarems.com. Accessed May 18, 2012
.
83.
Curtin
JA
,
Fridlyand
J
,
Kageshita
T
,
et al
.
Distinct sets of genetic alterations in melanoma
.
New Engl J Med
.
2005
;
353
(
20
):
2135
2147
.
84.
Anderson
S
,
Bloom
KJ
,
Vallera
DU
,
et al
.
Multisite analytic performance studies of a real-time polymerase chain reaction assay for the detection of BRAF V600E mutations in formalin-fixed paraffin-embedded tissue specimens of malignant melanoma
.
Arch Pathol Lab Med
.
2012
;
136
(
11
):
1385
1391
.
85.
US Food and Drug Administration
.
FDA labeling information—Zelboraf
;
2011
. .
86.
Chapman
PB
,
Hauschild
A
,
Robert
C
,
et al
.
Improved survival with vemurafenib in melanoma with BRAF V600E mutation
.
New Engl J Med
.
2011
;
364
(
26
):
2507
2516
.
87.
Sosman
JA
,
Kim
KB
,
Schuchter
L
,
et al
.
Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib
.
New Engl J Med
.
2012
;
366
(
8
):
707
714
.
88.
M.D. Anderson Cancer Center
.
Phase I study of the combination of vemurafenib with carboplatin and paclitaxel in patients with advanced malignancy. ClinicalTrials.gov Web site
.
Bethesda, MD
:
National Library of Medicine
;
2012
.
NLM identifier: NCT01636622. http://clinicaltrials.gov/ct2/show/NCT01636622?term=01636622&rank=1. Accessed October 6, 2012
.
89.
National Cancer Institute
.
A study of vemurafenib in pediatric patients with stage IIIC or stage IV melanoma harboring BRAFV600 mutations. ClinicalTrials. gov Web site
.
Bethesda, MD
:
National Library of Medicine
;
2012
.
NLM identifier: NCT01519323. http://clinicaltrials.gov/ct2/show/NCT01519323. Accessed May 18, 2012
.

DISCLOSURE The authors declare no conflicts or financial interest in any product or service mentioned in the manuscript, including grants, equipment, medications, employment, gifts, and honoraria.