Pediatric use of topical ophthalmic drugs

Transcription

1 Pediatric use of topical ophthalmic drugs Rachel Anastasia Coulter, O.D. Nova Southeastern University. College of Optometry, Ft Lauderdale, Florida Background: Changes in the policies of the Food and Drug Administration (FDA) have resulted in a rapid increase in the number of drugs now labeled for pediatric use. In topical ophthalmic drugs, there are pharmaceuticals approved for use in children in the treatment of allergy, inflammation, and bacterial and viral infection. Clinicians should anticipate that this trend will continue into the future. Overview: This article reviews the history of FDA oversight of drugs used to treat children. Recent shifts in policies and approach are emphasized. Pediatric issues associated with ophthalmic drug use are discussed, including important differences regarding dosage, instillation, distribution, systemic toxicity, and metabolism. A summary of topical ophthalmic drugs approved for pediatric use, including age considerations, is provided. Conclusions: Clinicians should be aware of the increasing number of topical ophthalmic drugs that are approved for pediatric use. Social, regulatory, and economic factors suggest this trend will continue. When prescribing these drugs for use in children, clinicians should remember to refer to details of labeling for Pediatric Use, including the age of the child for whom the drug is approved. Key Words: Children, Food and Drug Administration (FDA), pediatric, topical ophthalmic drugs, treatment Coulter RA. Pediatric use of topical ophthalmic drugs Optometry 2004;75: VOLUME 75lNUMBER 7lJULY 2004 A s recently as five years ago, clinicians treating eye disease in children were forced to prescribe ophthalmic drugs "off-label"; that is, few drugs had undergone the appropriate randomized controlled study demonstrating safety and efficacy for that particular use. Short of meeting these Food and Drug Admhktration (FDA) requirements, the manufacturer could not provide labeling information within the "Indications and Usage" and "Dosage and Administration" sections regarding pediatric use.' Observant clinicians, checking the package insert or consulting with the company's sales representative for information on pediatric use, were more likely to discover word- ing stating, "Safety and effectiveness in children have not been e~tablished."~~~ The number of ophthalmic drugs with labeling for instructions on therapeutic use in children has recently increased rapidly. This article provides clinicians with a summary of the antibiotic, anti-allergy, and antiviral drugs now approved for use in young children (see'bble). Important aspects of appropriate pediatric use are discussed, including important differences in pediatric physiology and pharmacology for topical ophthalmic drugs. The article also explains what forces are responsible for these changes, and why clinicians can expect the emergence of new information on pediatric use. What has driven the inclusion of pediatric use instructions by the manufacturer? An incentive program developed by the FDA in collaboration with the pharmaceutical industry in the late 1990s has been credited with stimulating research on therapeutic use of medications in children. As stated by Robert Ward, M.D., Chair of the American Academy of Pediatrics' Committee on Drugs: "This is the biggest change in both the attitude and the conduct of studies of medicine in the past 40 years. It required that kind of financial reward for the companies to invest the money in doing the studies. And it brings enormous benefit to children in all areas of therapeutic^."^ 41 9

2 Table. Ocular medication approved for pediatric use - - Brand name Generic name Manufacturer Indications Allergy Medications Acular 0.05% Ketorolac tromethamine Allergan Alamast 0.1 % Pemirolast potassium Santen Alocril 2% Nedocromil sodium Allergan Emadine 0.05% Emedastine difumarate Alcon Optivar 0.05% Azelastine hydrochloride MedPointe Zaditor 0.025% Ketotifen fumarate Novartis Patanol 0.1 % Olopatadine hydrochloride Alcon Opticrom Sodium cromoglycate Allergan Alomide 0.1 % Lodoxamide tromethamine ophthalmic solution Alcon Vernal keratoconjunctivitis, vernal conjunctivitis, and vernal keratitis Crolom 4% Cromolyn ophthalmic solution cromoglycic acid; sodium cromoglycate Antibiotics Many Vernal keratoconjunctivitis, vernal conjunctivitis, and vernal keratitis Polytrim Trimethoprim sulfate-polymyxin B Allergan Bacterial conjunctivitis, sulfate ophthalmic solution blepharitis, blepharoconjunctivitis, bacterial conjunctivitis Many AK-Sulf; 10% Sulfacetamide, 15% solution and ointment1 Many1 Blepkl 0; Cetamide, lsopto Cetamide; Ocu-sulf-10; Sodium Sulamyd Bacterial conjunctivitis Many E-Mycin; llotycin Erythromycin ophthalmic ointment2 Many2 Ocular infections Tobrex Tobramycin ophthalmic solution and ointment Alcon Ocular infections Ciloxan Ophthalmic solution 0.3% Ciprofloxacin ophthalmic solution Alcon Ocular infections Ocuflox 0.3% Ofloxacin ophthalmic solution Allergan Bacterial infections of the eye, such as conjunctivitis and corneal ulcers 42 0 VOLUME 75lNUMBER 7lJULY 2004

3 Pharmacologic effects Pediatric use Dosage Inhibits prostaglandin synthesis Approved for children r 3 years old 1 gtt q.i.d. Mast-cell stabilizer Approved for children r 3 years old 1 to 2 gtt bid. to q.i.d. Mast-cell stabilizer Approved for children r 3 years old 1 gtt b.i.d. Relatively selective H1 antihistamine Approved for children r 3 years old 1 gtt up to q.i.d. Relatively selective HI antihistamine Approved for children r 3 years old 1 gtt b.i.d. Relatively selective HI antihistamine Approved for children z 3 years old 1 gtt b.i.d. and mast-cell stabilizer Relatively selective HI antihistamine Approved for children r 3 years old 1 gtt b.i.d. and mast-cell stabilizer Mast-cell stabilizer Approved for children r 4 years old 1 to 1 gtt q4h to q6h Mast-cell stabilizer Approved for children a 2 years old 1 to 2 gtt q.i.d. Mast-cell stabilizer Approved for children r 4 years old 1 to 2 gtt q.i.d. to q4h I Inhibition of enzyme dihydrofolate reductase Approved for children a 2 years old Mild-to-moderate infections, 1 to 2 gtt blocking production of tetrahydrofolic acid; q3h(upt06dosedday)x7toloda/s bactericidal by increasing permeability of Severe infections, 1 to 2 gtt cell membrane ql h until improvement observed, then reduced to 1 to 2 gtt q3h Competitive antagonists to Approved for use in infants r 2 months 1 gtt q 2 to 3 h during day and para-aminobenzoic acid (PABA) less frequently at night; ointment q.i.d. and before bedtime lnhibits RNA-dependent protein synthesis Approved for use in infants s 2 months 112-inch ribbon to affected eye q.i.d. Aminoglycosides interrupt bacterial Approved for use in infants r 2 months Mild-to-moderate disease, 1 to 2 gtt q4h; ribosome synthesis, causing cell death severe disease, 2 gtt q4h. then reduce frequency with improvement Fluoroquinolones inhibit DNA synthesis Approved for children r 1 year 1 gtt q2h, while awake, for 2 days, then 1 gtt q4h, while awake, for 5 more days Fluoroquinolones inhibit DNA synthesis Approved for children a 1 year Conjunctivitis: 1 gtt q2h to q4h during waking hours x 2 days, then 1 drop gtt for up to 5 days; Bacterial corneal ulcers: 1 drop every 30 minutes during waking hours and 1 drop 4 to 6 hours after bedtime x 2 days, then 1 gtt qh for up to 7 days, then 1 gtt q.i.d. until treatment complete VOLUME 75lNUMBER 7lJULY

4 Table. (continued) Brand name Generic name Manufacturer Indications Allergy Medications Ciloxan ointment (Ciprofloxacin HCI ophthalmic ointment); 0.3% as Alcon Conjunctivitis base sterile ophthalmic ointment Zymar 0.3% Gatifloxacin ophthalmic solution Allergan Conjunctivitis Vigamox 0.5% Moxifloxacin; 0.5% ophthalmic solution Alcon Conjunctivitis Quixin 0.5% Levofloxacin ophthalmic solution Santen Conjunctivitis Anti-inf lammatorv Fluorometholone 0.1 % Fluorometholone Falcon Inflammatory conditions of the conjunctiva, cornea, and anterior segment, where risk of bacterial infection exists Combination Tobradex 0.3% Tobramycin; 0.1 % dexamethasone ointment Alcon Steroid-responsive ocular inflammation with risk of bacterial infection Antiviral Viroptic, generics available 1 % Trifluorothymidine King, others Keratitis and conjunctivitis caused by Herpes simplex RNA, Ribonucleic acid and DNA, deoxyribonucleic acid. Information for cromolyn ophthalmic solution and sulfacetamide ointment provided by Medline Plus, a service of the U.S. National Libray of Medicine and the National Institutes of Health under 'Sulfonamides' (Ophthalmic). Information on erythromycin ointment from Thomson Micromedex ( All information obtained from prescribing information provided by manufacturers, except for cromolyn ophthalmic solution, erythromycin, and sulfacetamide ointment: Alcon Laboratories South Freeway, Ft. Worth. Texas Allergan. Inc., P.O. Box 19534, Iwine. California Falcon Pharmaceuticals, Forth Worth. Texas King PharmaceuticalsTM, Inc., 501 Fifth Street, Bristol, Tennessee MedPointe Pharmaceutical, 265 Davidson Avenue, Suite 300, Somerset. New Jersey Novartis Ophthalmics, John's Creek Parkway, Duluth, Georgia Santen Incorporated, 555 Gateway Drive, Napa, California Pediatric prescribing nightmares were not infrequent in the twentieth century. In 1937, S.E. Massengill produced an oral solution of the antibiotic sulfanilamide, an effective but unpalatable medication in tablet form. The fruity flavor created was dissolved in diethylene glycol, a poisonous substance similar to antifreeze. More than 100 individuals, mostly children, died and the chemist who developed the solution committed ~uicide.~ In the late 1950s and early 1960s, the antibiotic chlo- 422 ramphenicol was used to treat infections in newborns in doses safe for older infants and children. Later, investigation determined the drug had caused gray baby syndrome. Gray syndrome occurs because babies and young chidren do not have the necessary enzymes that allow the liver to metabolize this drug appropriately. The chloramphenicol accumulates in the baby's blood stream, causing abdominal distention, vomiting, ashen color, hypothermia, progressive pallid cyanosis, VOLUME 75lNUMBER 7lJULY 2004

5 Pharmacologic effects Pediatric use Dosage Bactericidal results from interference with the Approved for children 2 2 years old enzyme DNA-gyrase, which is needed for the synthesis of bacterial DNA Fluoroquinolone with 8-methoxy group inhibits Approved for children > 1 year both DNA-gyrase and topoisomerase IV Apply a 1.2-inch ribbon t.i.d. on the first two days, then apply %-inch ribbon b.i.d. for the next 5 days Days 1 and 2: instill 1 gtt q2h up to 8 times daily; Days 3 through 7: instill 1 gtt up to q.i.d. Fluoroquinolone with 8-methoxy group inhibits Approved for children 2 1 year Instill 1 drop in the affected eye both DNA-gyrase and topoisomerase IV t.i.d. x 7 days Inhibits both DNA-gyrase and topoisomerase IV Approved for children 2 1 year Days 1 and 2: instill 1 gtt q2h while awake, up to 8 times daily; Days 3 through 7: instill 1 to 2 gtt q4h up to a.i.d. Corticosteroids inhibit inflammatory response Approved for children 2 2 years old by inhibiting edema, fibrin deposition, capillary dilation, leukocyte migration, fibroblast proliferation 1 gtt b.i.d. to q.i.d.; initially may increase to q4h x 24 to 48 hours Aminoglycosides interrupt bacterial ribosome Approved for children 2 2 years old synthesis; steroids decrease inflammatory response 1 to 2 gtt q4h (initial dose may increase to 1 to 2 gtt q2h), decrease gradually Inhibits thymidylate synthetase Approved for children 2 6 years old Keratitis: q2h up to 9 times a day Conjunctivits: prophylactic against corneal infection q.i.d irregular respiration, and circulatory collapse, followed by death. Children treated with chloramphenicol had higher death rates than those who were not treated at all. Studies later found that infant metabolism differed from older children and adults. Reduced ability in the glucoronidation of chloramphenicol and decreased glomerular filtration rate caused an accumulation of the drug. This accumulation accounted for the fatal complications following chloramphenicol use.6 VOLUME 75lNUMBER 7lJULY 2004 History of FDA oversight of pediatric use Pediatric use of all drugs was largely unstudied in the remaining portion of the twentieth century. As of 2003, less than one quarter of all drugs approved by the Food and Drug Administration listed an indication for pediatric use. The remaining three quarters were never tested for ~hildren.~ Recommended doses, if provided, were extrapolated from adult tests. Though little scientific study was available, 42 3

6 nearly all drugs marketed in the United States were being used in patients less than 18 years of age. The lack of research supporting pediatric use was the result of the perceived limited increase in marketability connected to pediatric usage in comparison to the huge cost of clinical pediatric trials. Other challenges unique to the pediatric population made clinical testing particularly problematic. The pediatric population included age groups that are physiologically and metabolically distinct: newborns, infants, pre-school children, school-age children, and adolescents. In the time required for a multi-year clinical trial, a subject could pass through two or more age groups, making statistical analysis more difficult. Clinical trials, for ethical reasons, are done on subjects who are ill when they enroll. Many parents are understandably reluctant to enroll a "sick" child to the additional demands and uncertainty of an experiment. Technical procedures such as drawing blood or getting a urine sample can be difficult with children. In addition, developing a pediatric form of the drug has special delivery issues. A 3-year-old, for example, cannot swallow a capsule. Instead, he or she needs a liquid or chewable form that will differ from the adult capsule or tablet. Other requirements arise, including special storage considerations or the need to concoct a composition that tastes good.8 With few pediatric use instructions available, clinicians relied on individual case reports, case series, and small-scale studies to determine pediatric therapy The reality frequently meant that "When parents give children a medication, they're often engaging in a mini clinical trial of their own."14 The FDA long recognized the limitations of the approval system, which had begun with the 1938 Food, Drug and Cosmetic Act, and stipulated that drugs be proved safe for the use intended by the manufacturer.15 The 1962 Harris Kefauver Amendment required additional proof of effectiveness and initiated the sequence of pre-marketing trials, which continues through today. Populations with additional risk, such as the elderly, pregnant women, and children, were usually excluded from the clinical trials presented the FDA. Consequently, these groups were not included in the approved uses of the drug. Pediatric health care providers had no choice but to use most drugs off-label. Though legal, this usage reinforced the absence of pediatric-specific dosing, administration, or adverse effects on label packaging and product information. In 1963, Harry Shirkey coined the term "therapeutic orphans" to highlight the truth that very few drugs were ever studied in ~hildren.~ Reform began in 1992, in an FDA ruling entitled "specific requirements on content and format of labeling for human prescription drugs: Revision of 'Pediatric use' Subsection in the Labeling." The policies promoted the inclusion of information from clinical trials, published studies, and case reports in children that stress the importance of pharmacokinetic and pharmacodynamic studies. This was an attempt to provide some information on dosing, as well as a monitoring mechanism. With support from the National Institutes of Health, a system of pediatric pharmacology research units (PPRUs) was developed in 1993 to conduct studies in children.16 By 2002, the PPRUs succeeded in undertaking 1,000 studies, including more than 750 clinical trials.17 In 1994, industry research identified the top ten drugs prescribed to children without pediatric labeling. The magnitude of the problem was obvious, as these drugs were prescribed more than 5 million times in a single year to children in age groups for which the drugs were not adequately labeled.15 One study found that, on average, a child received 8.5 prescriptions by age 5 years.6 In 1994, a new ruling mandated labeling information on pediatric use for all new drug applications likely to be used in the pediatric population. The ruling also required manufacturers to examine their existing products and determine if there was enough pediatric use to warrant labeling specifying dose, administration, and adverse effects in children. A pediatric subcommittee of the FDA staff was formed to watch over implementation. For those products not used in children, manufacturers could apply for waivers. Controversy resulted, as manufacturers contended that the necessary research required to procure pediatric approval could significantly increase medication cost and could block the introduction of new drugs for the adult market. FDA response The FDA responded with a "carrot-and-stick" approach to encourage pediatric studies.17 The VOLUME 75lNUMBER 7lJULY 2004

7 "carrot" was the Modernization Act (FDAMA) of This act used an incentive of patent exclusivity to encourage manufacturers to participate. The FDA began by specifying which drugs needed pediatric labeling to avoid severe misuse. More than 300 prescription drugs commonly used in the pediatric population were identified for labeling ~hanges.l~-~~ Identified drugs became known as the "Pediatric Priority List" and were updated annually to reflect changes, as new drugs were introduced and drugs that had added Pediatric Use labeling were removed. The population of individuals affected was broad; for regulatory purposes the term pediatric describes children between ages 2 and 18 years old.21 In return for volunteering to participate in the FDAMA, the FDA would award an additional 6 months of exclusivity rights to the manufacturer. In addition to requesting information for new drugs, the FDA could also request that manufacturers voluntarily provide pediatric labeling information for products already being marketed.22 The "stick" of the FDA's approach was the controversial enforcement component. This component, the Pediatric Rule, stated that testing of pediatric use should not only be requested but also required, if the drug was likely to be used with children. The intent of the Pediatric Rule was to improve the treatment children received, because doctors would have more complete information on how the drugs affected children and what ageappropriate doses are needed. Exclusions for the requirement for pediatric study were available if the FDA found the product unsafe or ineffective in pediatric patients, if pediatric studies were impractical, or if efforts toward pediatric formulation had not been su~cessful.~~ The pharmaceutical industry initially opposed the Pediatric Rule, but the patent extension incentives appeased their concerns. In fact, drug manufacturers enthusiastically sought to participate in the program in exchange for the extra patent protection. The FDA's original request for child-specific information on 170 drugs was exceeded by 211 requests to participate in the program. By December 2000, 27 drugs were granted 6- month patent extensions and 14 products had their labels modified to include aspects specific to pediatric usage.23 Enthusiasm was not universal, however. In December 2000, three groups-the Association of Physicians and Surgeons, Inc., the Competitive Enterprise Institute, and Consumer Alert-sued the FDA. Their suit argued that the FDA had overstepped its authority and that the Pediatric Rule was unnecessary, and would slow drug approval and delay medicines' availability to the p ~blic.~~!~~ These groups also expressed concern that the Pediatric Rule would create a precedent that could restrict offlabel usage in other instances.26 The FDA initially tried to avoid the lawsuit by suspending the rule, but many researchers and pediatricians protested. Richard Gorman, chairman of the American Academy of Pediatricsf Committee on Drugs, stated, "When a drug comes to market under the Pediatric Rule, children will be protected from the very first day."ls Dr. Gorman also noted that the groups who filed the lawsuit cannot "name one example where an adult drug has been delayed under FDAMA or the Pediatric Rule," and added that pediatric trials can provide critical data. For example, Neurontin, a drug used to control seizures, was found to require higher dosages in children younger than 5 years than had been predicted from adult studies, and Propofol, an anesthetic agent, was found unsafe for use in the long-term sedation of children. In response, the FDA reversed its decision to suspend the rule. The case progressed to the U.S. District Court for the District of Columbia. The resulting court decision overthrew the Pediatric Rule. Judge Henry H. Kennedy, Jr. stated that, though the Pediatric Rule was well intended, the FDA had overstepped its regulatory boundaries. The FDA could not require drug companies to study drugs for pediatric use, unless the drug was being marketed for pediatric ~ s e. The ~ ~ court, ~ ruling ~, stated ~ ~ that the FDA can only regulate drugs in that population to whom the industry is marketing, and other measures must be voluntary.27 This ruling is currently under appeal. Bipartisan interest remains focused on the issue of pediatric use. Senators Hillary Clinton (D-NY) and Edward Kennedy (D-MA) proposed legislation to replace the FDA's Pediatric Rule policy with a federal law to mandate drug testing for pediatric ~ s e Alternatively,. ~ ~ the Bush ~ ~ Administration ~ ~ ~ ~ advocated an incentive stance by supporting $7 million in funding for federally sponsored pediatric clinical trials in the 2002 budget, at an estimated value of $3 to $4 million per tria1.20,27 This amount was increased to $25 million in 2003 and is projected to increase to $50 million in The Best Pharmaceuticals for Children Act, which passed in January 2002, established the Office of VOLUME 75lNUMBER 7/JULY 2004

8 Pediatric Therapeutics to coordinate and facilitate all activities of the FDA that may have any effect on a pediatric pop~lation.~~ In addition to the political solutions presented for this problem, a culture shift has occurred. Health care providers can expect that labeling specifying pediatric use, clinical trials investigating unique aspects in children, and expanded attention to this area will continue. Pediatric issues in ophthalmic drug use Children are not just small adults. In addition to differences in body weight, there are the effects of growth dynamics, organ maturation, and changes in metabolism throughout infancy and childhood, and changes in body proportion. Other characteristics unique to the pediatric population include: the lack of commercially available dosage forms and concentrations appropriate for pediatric patients; the resulting need for routine calculation of individual dosages based on patient age, weight, body composition or body surface area, and clinical condition; the high frequency of errors in dosage calculations and associated serious medication errors; lack of published research on the pharmacokinetics and clinical use of new drugs; and the need for precise drug measurement and drug-delivery ~ystems.~l-~~ The pediatric population is extremely diverse, varying in weight from less than 500 grams to more than 100 kg, and in age from minutes to 18 years of age.30 Systemic effects, tolerance, kidney function, and metabolism are all different in children. In addition, rapid growth (a pre-term infant may quadruple in size during hospitalization) adds unique challengesz7 The eye of the newborn is roughly two thirds of its adult size at birth. It reaches adult size around ages 3 to 4 year^.^^,^^ In the eye, membranes are thin in neonates and infants, and systemic side effects in the very young are not uncommon. Though the dimensions of the pediatric eye are quite similar to the adult's, the lower body weight and immature metabolism of the infant and young child make systemic absorption a more worrisome issue. instillation When drops are instilled into an adult's eye, some of the liquid spills over onto the cheek. The supine posture of infants and young children potentially limits this spilling.37 Following drop instillation, 90% of the drug passes into the lacrimal Achieving therapeutic concentrations in the aqueous occurs more easily in children than in adults. The cornea of the neonate has 70% of the absorptive surface of the adult cornea, but the total intraocular volume is barely one third of the adult eye.38 Although the volume of the lacrimal fluid is smaller than that of an adult, tear flow might be greater, resulting in more-rapid dilution. This factor may be greater if the child is crying during in~tillation.~~ Instillation of drops in young children is sometimes difficult, at times requiring two people to achieve it. Punctal occlusion may not be possible, but wiping away excess drops is achievable and can be effective in minimizing the drug volume receiveds4o When the lids close tightly, relatively little of the drug passes down the nasolacrimal duct.41 Blepharospasm following instillation, then, may be advantageous in minimizing systemic absorpti~n.~~ Interest in pediatric spray instillation has grown through the last decade. Though the exact sequence of delivery remains to be studied, it is believed that smaller droplet size, and probably a smaller total amount, reaches the eye surface with spray instillation. Theoretically, the smaller volume of drug reaching the eye could result in a reduced tear flow reaction. The resulting concentration might (or might not) be more dilute in the lacrimal tear fluid than that which resulted from eye drop in~tillation.~"~~ Distribution Following the lacrimal system, the drops pass to the vascular mucous membrane of the nasopharyngeal area, where systemic absorption is greater than subcutaneous injection or slow intravenous injection.40 Alternatively, the drops may pass from the nasolacrimal system to the gastrointestinal tract, where some will be inactivated by gastric enzymes. As the drops pass to the systemic circulation, they are far less diluted than in the adult's circulation due to the smaller circulating blood volume. In five small children treated for glaucoma with tim- 0101, the blood levels of the drug were studied. The range was 3.5 to 34 nglrnl, contrasting greatly with adult blood levels of 2.45 nglml or less.48 VOLUME 75lNUMBER 7lJULY 2004

9 In the bloodstream, this relatively large dose is metabolized at a slower rate. The result is that one drop will achieve a higher plasma level and will last for a longer period of time. Adjusting dosages for very young children To offset the potential for systemic toxicity in children, several proposals have been generated. Some have argued that reducing eyedrop size might decrease systemic toxicity risk. Adult tear film typically is made up of 7 to 10 pl. After the instillation of an eyedrop, the tear film briefly increases to 30 pl, until a blink occurs, lowering the volume back to the 10-pL range. The overflow spills out onto the cheek or is pumped into the nasolacrimal sy~tem.~~,~~ Pharmacokinetic studies have shown that a 20-pL drop achieves the maximum tear film concentration, though the average size of a conventional ophthalmic eyedrop is more than double the amount, at 50 to 70 pl.51,52 Decreasing the volume of the eyedrop would have little if any effect on ocular absorption, but potentially could have a significant effect on systemic ab~orption.~~ In a study of effects-related drop size of phenylephrine, researchers compared an 8 pl of 10% phenylephrine to a 32yL drop of 2.5% phenylephrine. Systemic absorption was equal for both drops, but maximal dilation was almost 50% greater for the smaller drop with the higher con- ~entration.~~ The clinical effectiveness of smaller drops was first revealed by Lynch et a1.,55 who found that neonates dilated with 8 pl in one eye and 30 pl of 2.5% phenylephrine in the opposite eye achieved an equivalent dilation in each eye, but the systemic concentration (corresponding to the 30 pl drop) was more than twice that of the 8 pl.55 Another study of the effects of reduced drop size in the dilation of premature infants found no statistical difference in the pupil dilation achieved using a 5-pL drop of 0.5% cyclopentolate and a 5-pL drop of 2.5% in one eye, as compared to using a 26-pL drop of 0.5% cyclopentolate and a 26-pL drop of 2.5% phenylephrine in the opposite eye.56 Reducing drop size cannot be achieved by just changing the size and opening of the tip of the dropper. Formulations vary in their surface tension that results in different size drops when the volume of fluid is the same. Investigation now focuses on altering surface tension by changing the inactive ingredients. VOLUME 75lNUMBER 7lJULY 2004 A rule of thumb for adjusting eyedrop dosage Calculating dosages for pediatric patients can be a tricky business. Body weight, surface area, development, metabolism, other medications taken, and physiologic function can all affect the dosage.36 For the youngest pediatric patients, an approximate titration may be to use half the adult dose for children from birth to age 2 years and two thirds the dose for children 2 to 3 years old.40c57 Ophthalmic drugs approved for pediatric use Progression in the area of eye disorders has been significant. By 2000, four drugs were in pediatric clinical trials or awaiting FDA approval for use in children. Analysts of current trends have suggested the future will see many more drugs of a diverse character, increasing pediatric use in the number and frequency of drug usage, and more demands placed on the screening and regulatory system associated with pediatric therapy.58 At this time, the ocular medications that have been approved for pediatric use include a variety of drugs used to treat inflammation, allergy, vernal disease, and bacterial and viral infection (see 'bble). Of note, the age of a child for which the drug is approved differs from drug to drug, and the clinician should give specific attention to this detail, referring to the Pediatric Use labeling. Though the pediatric glaucoma population is relatively small, the FDA's 6- month patent extension program has enticed all pharmaceutical companies to investigate their glaucoma drugs for pediatric use. Some of these studies were scheduled for completion in Another benefit of this trend is that information about side effects, as experienced by the pediatric population, will become increasingly available. Side effects reported in the past were almost always those experienced by adults, not pediatric patients. As stated, due to physiologic differences, children may experience side effects not reported by adults, or may experience side effects at different dosages. The ocular drugs listed have only recently obtained pediatric use approval. Prior to obtaining this approval, side effects were hard to track, as pediatric use was virtually always "off-label," and reporting of side effects was inconsistently done. At this time, limited information is available regarding the occurrence of side effects in children distinct from adults. Clinicians should be aware of the increasing number of topical ophthalmic drugs that are approved 42 7

10 for pediatric use. Social, regulatory, and economic factors suggest that this trend will continue. Clinicians who obtain new or updated information from pharmaceutical companies should remember to inquire specifically about pediatric use. Pediatric Use Information can be used to further enhance vision care of infants and young children. 1. Cote CJ. Adverse drug reactions and the package insert. Acta Paediatr 1999;88: Nahata MC. (May 1997) Licensing of medicines for children in the USA. Paediatric and Perinatal Drug Therapy Last accessed April 3, Metry DW, Hebert AA. Topical therapies and medications in the pediatric patient. Pediatr Clin North Am 2000; 47(4): Shelton DL. (June 12, 2000). Pace picks up in pediatric studies. Amednews.com. arnnewslpick-00/hlsa0612. hid. Last accessed April 3, Modem regulatory environment shaped by pediatric pharmacology. Cited from Brown University Child and Adolescent Psychopharmacology Update 2002;4(5):1, 2-3. Medscape. 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