PEDIATRIC PHARMACOTHERAPY A Monthly Newsletter for Health Care Professionals from the University of Virginia Children’s Hospital Volume 19 Number 3 March 2013 Alternative Forms of Oral Drug Delivery for Pediatric Patients Marcia L. Buck, Pharm.D., FCCP, FPPAG he lack of an appropriate dosage form the concentration versus time curve (AUC) of T limits the use of many medications that 45% for lopinavir and 47% for ritonavir (p = may potentially benefit children. While this has 0.003 and 0.006, respectively). been a long-standing problem for pediatric healthcare providers, little attention has been Cutting tablets, another common practice, may paid to remedying it until recently. In 2005 the be acceptable for some drugs, however this Eunice Kennedy Shriver National Institute for practice can introduce considerable variability Child Health and Human Development, joined between doses. In drugs with a narrow by representatives from the Food and Drug therapeutic index, such as levothyroxine, this Administration (FDA), academic medicine, and variability may be enough to produce clinically the pharmaceutical industry, formed the United significant changes in clinical response.7 When States (US) Pediatric Formulations Initiative in cutting a tablet is necessary, family members an effort to stimulate research in pediatric should receive specific instructions on the formulation technology.1 Similar work by the process, including the proper use of a tablet European Medication Agency (EMA) led to the splitter. Family members involved in dose development of the European Pediatric preparation should also understand how to Formulation Initiative.2 In addition, the World dispose of unused drug and the need to avoid Health Organization launched a global initiative repeated exposure to drugs that have in 2007 entitled “Make Medicines Child Size” to carcinogenic or teratogenic properties. foster development of pediatric dosage formulations.3 These groups continue to guide Having a pharmacist prepare an extemporaneous research in the field of pediatric drug delivery oral suspension or solution can minimize these and champion technologic advances. issues, but even a relatively simple change in the process, such as conversion to a sugar-free Limitations with Current Products suspending agent, addition of a flavoring, or use One of the greatest challenges in pediatric of a different brand, may alter the stability of the pharmacology has been optimization of oral drug final product or the absorption characteristics of delivery. Although most children over 6 years the drug. While the availability of of age can be taught to swallow solid dosage extemporaneous formulations is widespread in forms, many remain uncomfortable with it until most developed countries, it may be limited in adolescence. In a recent study 54% of children parts of the world lacking necessary resources between 6 and 11 years told study investigators such as a source of clean water.5 that they were unable to easily swallow a tablet.4 While altering oral tablets to create formulations Commercially available oral liquid medications suitable for children has long been a part of provide a more reliable, ready-to-use preparation pediatric healthcare, it is clearly a less than ideal for infants and children, but bioequivalence with option.5 solid oral dosage forms is still not assured. In 2012, Kasirye and colleagues published the Crushing tablets to mix them with food or water results of a pharmacokinetic study comparing may change the rate or extent of drug absorption. oral solutions and solid dosage forms of three Best and colleagues recently found that crushing antiretrovirals in 19 children between 1 and 4 lopinavir/ritonavir (Kaletra®) tablets, a common years of age.8 Oral solutions of zidovudine and practice for children with HIV-1 infection, abacavir produced similar AUC values to tablets, resulted in a significant change in drug but lamivudine AUC values were 45% lower bioavailability.6 The authors conducted a with the solution. The authors concluded that pharmacokinetic study in 12 children between 10 administration of lamivudine solution based on and 16 years of age after administration of whole dosing guidelines developed for the tablets may and crushed tablets. The use of crushed tablets result in subtherapeutic serum concentrations. resulted in a median decrease in the area under A new oral liquid formulation of levothyroxine methylphenidate suspension in children with available in Europe was recently shown to attention-deficit/hyperactivity disorder produce lower rates of normalization of thyroid (ADHD).12 Forty-five children between 6 and 12 function than a tablet given at the same dose.9 years of age were enrolled. Following an open- Levothyroxine, digoxin, hydrocodone, and label dose optimization period, patients were phenobarbital are just a few examples of drugs randomized to receive either active drug or that cannot be easily formulated as liquids placebo for 1 week, followed by the alternative. because of their relative insolubility in water. Use of the extended release methylphenidate The traditional method of preparing liquid suspension resulted in improvement in scores on formulations of these drugs has been as alcohol- ADHD rating scales and a standardized math test based elixirs. The concentration of alcohol in similar to that reported with methylphenidate in elixirs varies from 5% to as much as 40%. The other studies. The new suspension has not yet long-term effects of repeated exposure to the been evaluated in a comparison study with other alcohol in these products, particularly in infants extended release methylphenidate dosage forms. and toddlers, are not known. Orally Disintegrating Tablets The problems encountered with currently Orally disintegrating, or orodispersible, tablets available formulations highlight the need for the (ODTs) are designed to dissolve in the presence development of new products that are both easy of saliva within one minute. The primary to administer and capable of providing reliable advantage of ODTs is that no external source of serum drug concentrations. Several alternatives liquid is needed for consumption.13 For patients to traditional dosage formulations have been with dysphagia or children too young to swallow introduced in the US over the past decade that tablets or capsules, ODTs provide a useful may fill this need. Extended release oral alternative. There are a variety of methods for suspensions, as well as orally disintegrating preparing ODTs, including freeze drying, tablets and films are ideally suited for children molding, compaction, granulation, spray drying, unable to swallow tablets and capsules. flash heat processing, sublimation to increase porosity, and direct compression. Disintegrating Extended Release Oral Liquids aids, binding agents, and sweeteners are added to One of the disadvantages of oral liquid the active drug moiety during production to preparations has been the need to give multiple improve the feel of the product in the mouth, doses throughout the day. Until recently, making the dissolved drug smooth and creamy. extended release products have been available Several companies have patented technologies only as tablets, capsules, or sprinkles. On June for manufacturing ODTs, such as Zydis® 10, 2005 the first extended release oral (Catalent, Inc.) Flashtab® (Prographarm), suspension, Pfizer’s azithromycin product Orasolv® (Cima), and Wowtab® (Yamanouchi (Zmax®), was approved by the FDA for the Pharma Technologies).1,13 treatment of community acquired pneumonia in adults and children over 6 months of age and Although the development of ODTs began in the acute bacterial sinusitis in adults.10 It is 1970s, the first product to reach the US market, administered as a single 60 mg/kg dose (with an Claritin® Reditabs, was not approved by the FDA adult dose of 2 grams). until December 1996. Since that time the number of ODT products has grown rapidly to include On September 27, 2012, the FDA approved an more than two dozen prescription and non- extended release oral suspension of prescription drugs (Table). methylphenidate (Quillivant XRTM) developed by NextWave Pharmaceuticals, a subsidiary of Table. Examples of Drugs Available as ODTs Pfizer.11 The suspension consists of cationic Acetaminophen Loratadine polymer matrix particles that bind racemic Alprazolam Metoclopramide methylphenidate via ion exchange. Variation in Aripiprazole Mirtazapine the thickness of the coating applied to the Carbidopa-levodopa Olanzapine particles results in 20% of the drug being Cetirizine Ondansetron released immediately, with the remaining 80% of Citalopram Prednisolone the drug released over 12 hours. It is shipped as Clonazepam Risperidone a powder to be reconstituted with water prior to Clozapine Rizatriptan dispensing to make a 5 mg/mL suspension. Desloratadine Selegiline Diphenhydramine Tramadol In the February 2013 issue of the Journal of Donepezil Vardenafil Child and Adolescent Psychopharmacology, Fexofenadine Zolmitriptan Wigal and colleagues published the results of a Lansoprazole Zolpidem two-week double-blind, randomized, placebo- Lamictal controlled trial of extended release While most currently available ODTs have been single strength, often one that is too large for use designed for adolescents and adults, some have in younger children. Because of their fragility, been formulated specifically for younger breaking, cutting, or splitting ODTs is not patients, such as Children’s Tylenol® Meltaways. recommended.