2012 review: New chemical entities, 
drug products labeled for pediatric use

The beginning of a new year is a good time to highlight in this column the latest drugs approved by the FDA. The FDA labeled approximately 45 new chemical entity medications for use in 2012. Most of these are not labeled for use in the pediatric population. However, there are several new chemical entities and new drug products labeled for use in infants and children in 2012.

Inhaled products

Nasally inhaled corticosteroids are commonly used in children to treat allergic rhinitis. Currently, seven corticosteroids agents are available as numerous medication products: beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, mometasone and triamcinolone. Several of these products are labeled for use in children as young as 2 years of age — Veramyst (GlaxoSmithKline), Nasonex (Schering), Nasacort AQ (Sanofi-Aventis) — whereas other products are labeled for use in those aged 4 years and older (Flonase, GlaxoSmithKline) or 6 years and older — Beconase AQ (GlaxoSmithKline), Rhinocort Aqua (AstraZeneca), Omnaris (Sunovion) and flunisolide, available generically.

These products additionally differ by labeled dosing, either once daily or twice daily. Most nasally inhaled corticosteroids products are aqueous based. A potential adverse effect of using an aqueous-based product is post-nasal drip into the throat, which may result in adverse sensations, such as taste. However, two products are available that use HFA (hydrofluoroalkane) propellant, similar to orally inhaled metered-dose inhalers commonly used in asthma therapy. These products include Zetonna by Sunovion (ciclesonide), labeled for those aged 12 years and older, and QNasl by Teva (belcomethasone).

QNasl was approved for use in 2012 and is marketed as a “dry” inhaler, as it is not aqueous based. It is labeled for once daily use in children aged 12 years and older to treat allergic rhinitis. Advantages of QNasl include its potential for fewer adverse sensation effects that may occur with aqueous-based products, and once daily dosing. Disadvantages include its relatively higher cost as compared with other nasally inhaled corticosteroids products, and its lack of FDA labeling for children aged younger than 12 years. Several nasally inhaled corticosteroids products are available generically, including flunisolide and fluticasone propionate.

Another inhaled product, Asthmanefrin (Nephron Pharmaceuticals), was labeled for use in 2012 that also can be used to treat asthma. This over-the-counter orally inhaled product, however, should not be used in children, in my opinion, and clinicians should recommend that their patients with asthma not use this product. Asthmanefrin is a racemic mixture of epinephrine, a sympathomimetic agent with potent alpha- and beta-adrenergic receptor stimulating effects. When orally inhaled, racepinephrine results in bronchial smooth muscle relaxation and bronchodilation. Because it is less specific than beta2-receptor agonists, such as albuterol, it may also result in cardiac stimulatory adverse effects.

What is most concerning with the use of this product, however, is its OTC availability. Readers may recall a similar OTC product, Primatene Mist (Armstrong Pharmaceuticals), which was also available with a prescriber’s prescription. When chlorofluorocarbons were banned from inhaled products in 2011, Primatene was discontinued. Asthmanefrin is labeled for use in those aged 4 years and older and is available as an atomizer, to create a mist to be inhaled. The product can be difficult to use and clean and can require multiple steps. A major reason not to recommend use of Asthmanefrin is the ability of children and families to self-treat asthma or other pulmonary conditions with a bronchospastic component, conditions that most likely would require assessment and therapy by a pediatric clinician. Clinicians should ask if patients with these conditions are using Asthmanefrin, and if so, should discourage its use. Short-acting beta2-receptor agonists are the preferred medications to use.

Cystic fibrosis agent

Perhaps the most exciting medication to be approved for use in 2012 was ivacaftor (Kalydeco, Vertex). Ivacaftor represents a significant step forward in the treatment of cystic fibrosis, as it is a new chemical entity and has a unique mechanism of action. Additionally, ivacaftor targets the underlying abnormality in cystic fibrosis, the chloride channel located in epithelial cells. No other FDA-labeled medications are currently available that act as a transmembrane conductance regulator (CFTR) potentiator. However, ivacaftor is only clinically effective and indicated for use when a specific mutation (G551D) of the CFTR gene is present.

G551D affects approximately 4% to 5% of the cystic fibrosis population. Thus, it is helpful to determine the genotype of patients with cystic fibrosis, and the availability of ivacaftor has resulted, in part, in more patients with cystic fibrosis becoming genotyped to determine their specific mutations. Ivacaftor does not provide efficacy in patients with cystic fibrosis who do not have the G551D mutation. Other similar agents, however, are currently being evaluated that may have efficacy in more common cystic fibrosis mutations. An important characteristic of ivacaftor that primary care clinicians should be familiar with includes its propensity for significant drug-drug interactions. Drugs such as antifungals (eg, fluconazole, ketoconazole), some anticonvulsants (eg, phenobarbital, phenytoin), and some antibiotics (eg, rifampin, clarithromycin) may adversely interact with ivacaftor. Pharmacists can assist physicians with assessing the potential for drug-drug interactions with ivacaftor when other drugs are prescribed.

Infectious disease products

Several new medications and products with new, lower age indications that target infectious diseases became available in 2012. Although not a new medication, new age labeling was approved by the FDA last year for oseltamivir (Tamiflu, Genentech). On Dec. 21, the FDA announced it had approved labeling for oseltamivir’s use in the treatment of influenza in infants (with symptoms no longer than 48 hours) as young as 2 weeks of age. Previously, oseltamivir was labeled for use in children aged 1 year and older. Data supporting the efficacy and safety of oseltamivir in young infants came from extrapolated clinical and pharmacokinetic data from previous studies of older infants and children.

Dosing for infants aged younger than 12 months is specifically weight-based (3 mg/kg, twice daily), as compared with fixed dosing regimens for older infants and children (30 mg, 45 mg, 60 mg or 75 mg, twice daily). There are several practical considerations that clinicians should be aware of when prescribing oseltamivir. This drug is available as capsules (30 mg, 45 mg and 75 mg) and a liquid suspension (6 mg/mL). The liquid formulation was recently reformulated as a 6-mg/mL strength product and is available with a 10 mL oral dosing syringe.

It is most helpful if prescribers express patient-specific orders as both volume and milligram doses to avoid confusion, ie, 18-mg (3 mL) dose for a 6-kg infant. Smaller volume doses prescribed for younger infants should be given smaller oral dosing syringes (eg, 3 mL) by pharmacy staff. Package labeling for oseltamivir includes a recipe for a compounded suspension using 75-mg capsules, if supplies of the commercially available liquid product become depleted. The most common adverse effects that may occur in younger infants are similar to those reported in children: vomiting and diarrhea. Food does not alter the absorption of oseltamivir, and it may be given with food to lessen the potential for vomiting.

Varicella zoster immune globulin (VZIG; Varizig, Cangene Corp.) was also approved for use last year. This product was available previously, but was discontinued in 2004. Varizig is the only FDA-labeled VZIG product readily available and is indicated to reduce the severity of varicella in high-risk individuals when given within 96 hours of exposure. Until last year, VZIG was available only as an investigational expanded access protocol. High-risk individuals are considered to be immunocompromised children and adults, newborns, pregnant women, premature infants, children aged younger than 12 months, and adults with no immunity to varicella zoster virus. Varizig is administered intramuscularly and is manufactured from pooled human plasma of individuals with high titers of antibodies to varicella zoster virus. Varizig is an immune globulin product, and therefore it may interfere with a clinical response to live viral vaccines. These vaccines should be deferred for 3 months after Varizig use.

Last year saw the approval of FluMist Quadrivalent (MedImmune), which is another product that is likely to have broad application and use in pediatrics. This live viral intranasal influenza vaccine was approved for use in 2012, although it is likely that it will not be used extensively until the 2013-2014 influenza season. The currently available FluMist product is a trivalent influenza vaccine, as are the other labeled vaccine products. FluMist Quadrivalent vaccine product contains a total of two B virus lineages (Yamagata and Victoria). Its labeling is similar to the current FluMist product: for use in otherwise healthy children and adults aged 2 to 49 years to prevent influenza infection and disease.

For more information:

Edward A. Bell, PharmD, BCPS, is a professor of clinical sciences at Drake University College of Pharmacy, Blank Children’s Hospital, in Des Moines, Iowa. He is also a member of the Infectious Diseases in Children Editorial Board. He can be reached at: Drake University College of Pharmacy, 2507 University Ave, Des Moines, IA 50311; email: ed.bell@drake.edu.

Disclosure: Bell reports no relevant financial disclosures.