FDA OVERSIGHT OF PEDIATRIC DRUG LABELING

The efficacy and safety of more than half of commonly prescribed ophthalmic medications have not been well studied in pediatric patients.(1) There is a particular paucity of information on pediatric use safety profiles for anti-inflammatory agents and glaucoma medications. Lack of pediatric labeling does not mean drugs are necessarily harmful, ineffective, or contraindicated in children, but simply that the clinical trials that satisfy the Food and Drug Administration (FDA) requirements for labeling have not been conducted in children. Lacking this information, doctors may be reluctant to prescribe certain medications for their pediatric patients, or they may prescribe medications based on information from limited clinical observations rather than from comprehensive multi-centered clinical trials conducted in the pediatric population. To circumvent at least some of the problems associated with pediatric drug labeling, the FDA passed a ruling in 1995 to recognize methods of establishing substantive evidence to support pediatric labeling claims other than from adequate and well-controlled studies in the pediatric population.(2) For example, products may be labeled for pediatric use based on adequate and well-controlled studies in adults, together with other information supporting pediatric use including pharmacokinetic and pharmacodynamic data. Just as with adult drug testing, there are problems associated with testing drugs in the pediatric population, which include obtaining informed consent for tests not of direct benefit to the child, and the use of placebo controls in a vulnerable population.

To further provide practitioners with adequate information to encourage the safe and effective prescribing of medications for children, the U.S. Congress enacted the Food and Drug Administration Modernization Act of 1997.(3) This law encouraged pediatric drug trials by awarding manufacturers an additional 6 months of exclusivity marketing rights for those drugs under patent protection. The Best Pharmaceuticals for Children Act signed into law in 2002 provided financial incentives for companies to conduct trials for those drugs used in children but no longer covered by patent protection.(4) The Pediatric Rule of 1998 allowed the FDA to require pediatric testing for new drugs that are therapeutically important for children, or will be used in a substantial number of pediatric patients.(5) This ruling should have resulted in a rapid increase of topical ophthalmic drugs with sufficient pediatric safety labeling information. However, the Pediatric Rule was challenged in court and in 2002, the courts barred the FDA from enforcing it.(6) Health care providers can expect the battle between drug manufacturers and children protection agencies to continue, possibly leading to an expansion of pediatric clinical trials.

DRUG LABELING DEFINITIONS

Some widely used drugs include disclaimers stating that safety and effectiveness in pediatric patients have not been established. Not established means there is insufficient evidence to support a specific pediatric indication or pediatric use. If the evidence is lacking for any pediatric age group, the "Pediatric use" subsection of the drug's labeling will state "Safety and effectiveness in pediatric patients have not been established.”(2) Similarly, if evidence is lacking for a particular pediatric subgroup, the label will read "Safety and effectiveness in pediatric patients below the age of (years/months/weeks) have not been established.” Thus, if pediatric safety is not established it may or may not mean that the drug is safe for use. On the other hand, a drug listed as “not recommended” means there are animal studies and/or anecdotal cases of adverse drug side effects or hazards to the pediatric population. The pediatric safety labeling may also change over time because demonstrated clinical use did not result in adverse outcomes or it may change based on anecdotal reported cases of efficacy, safety or adverse reactions. Drug manufacturers may also submit data for pediatric use of drugs subsequent to obtaining FDA approval for use in adults. “Off-label” prescribing is an unapproved use of an approved drug. When pediatric use information is not available, “off-label” prescribing may be considered acceptable when there is not a suitable alternative and use of a drug is based on current knowledge of clinical drug usage, the scientific literature, and current prescribing practices.(7)

Drug sources use a variety of terms in reference to drug safety for the pediatric population. The different terms used are: children, child, infant, newborn, and neonate. Medline defines pediatrics as ages from birth through 18 years and uses the following breakdown for “pediatrics”: newborn (birth to 1 month), infant (1 to 23 months), preschool (2 to 5 years), child (6 to 12 years) and adolescent (13 to 18 years).(8) FDA's definition for the pediatric population differs slightly. It defines pediatrics as ages birth to 16 years. Specifically, in 1994, the agency offered the following admittedly arbitrary age categories for the pediatric population: neonates (birth to 1 month), infants (1 month to 2 years), children (2 to 12 years) and adolescent (12 to 16 years).(2)

DRUG INFORMATION SOURCES

Drug information sources include print resources as well as many Web-based resources. Commercial sources give drug information provided by the manufacturers. Professional sources come from professional pharmacy organizations. Both commercial and professional sources are now available electronically, as online databases, CD-ROM versions and as Internet Web sites. Pricing varies from costly to free.(10)

One of the most popular commercial sources of drug information is the Physicians’ Desk Reference (PDR), an annual compilation of package inserts provided by participating drug manufacturers.(9) The package insert contains basic information about the drug and is approved by the FDA. The package insert is not necessarily complete or unbiased. Information in the PDR is arranged by company name and lists many, but not necessarily all, products marketed in the United States since drug companies are charged for inclusion in the PDR.(10) Thus, all drug companies do not participate, and those that do may only include information about their most profitable medications. Recently, the PDR has expanded and now contains information about off-label use of medications, which for certain drugs has become the standard of care for children due to inadequate pediatric labeling. The PDR for Ophthalmology, but not the general PDR, contains useful information on the pediatric safety of topical ophthalmic drugs. The mobilePDR is available to carry on a handheld device, and includes drug labeling updates within 24-48 hours of announcement. PDR.net provides monthly updates and has a drug interaction checker.

In contrast to the PDR, Drug Facts and Comparisons and Ophthalmic Drug Facts have a comprehensive compilation of FDA materials, which include literature reports and journal articles.(11,12) In addition, “off-label” uses of drugs are mentioned in these publications. Drug Facts and Comparisons is commonly used by pharmacists and monthly updates are available.(10) Both these references contain concise and useful information on drug safety in children for most of the topical ophthalmic drugs. Drug Facts and Comparisons is available on CD-Rom and can be downloaded onto handheld personal data assistants for subscribers.

The chief benefit of drug information from professional societies lies in their critical and authoritative evaluation. The American Hospital Formulary Service (AHFS) Drug Information is produced by the American Society of Hospital Pharmacists.(13) It is a collection of unbiased and evaluated monographs. Investigational uses of approved drugs are included. This source contains pediatric safety information for the majority of the topical ophthalmic drugs. AHFS is available on-line for a fee at ahfsdruginformation.com. Two other professional sources are the United States Pharmacopeia Dispensing Information (USP DI) and the Handbook of Nonprescription Drugs. The former lists prescription and nonprescription drugs approved by the FDA and the dates they were approved.(14) The latter includes charts comparing different products, and addresses the uses and possible adverse side effects of nonprescription drugs.(15)

Several free resources containing pediatric labeling are:
www.drugs.com
www.search.medscape.com
www.rxlist.com
www.FDA.gov

These websites provided limited pediatric usage information for some medications. Given that pediatric safety labeling is expected to improve over time, a useful website that lists the clinical trials database is www.centerwatch.com. You can also register to receive email alerts on new FDA approved medications.

Pediatric safety labeling information included in this course was referenced primarily from print sources, with some from internet websites.

PEDIATRIC ISSUES IN TOPICAL THERAPEUTICS

Caution is required in the application of topical ocular medications, especially in infants. Topically applied medications may be absorbed from conjunctival capillaries and the nasolacrimal duct system into the systemic circulation.(16,17,18) The eye membranes of neonates and infants under the age of 2 years are especially thin, combined with the relatively lower body weight and immature metabolism, make systemic absorption a much greater risk in infants than adults.(19) Without punctual occlusion, as much as 90% of an eye drop may be absorbed by the nasal mucosa.(20,21) The result is that the drug will achieve a higher plasma level and will last for a longer period of time. Caution should be exercised in children with susceptible nervous systems, such as Down Syndrome, spastic paralysis, or brain damage, and possibly in those with light pigmentation, since there have been reports of idiosyncratic adverse side effects.(16)

Instillation

Figure 1: Punctal occlusion

There are some techniques to minimize systemic drug absorption. Be careful to instill a single drop at a time. When possible, perform punctal occlusion. Gentle pressure with fingers should be exerted over the lacrimal sac for one to two minutes after instillation to help prevent the drug from being absorbed by the nasal mucosa.(16) Punctal occlusion can slow systemic absorption and lower toxicity by up to 40%.(22,23) When punctal occlusion is not possible, encourage eyelid closure. When the lids are closed tightly, relatively less drug is absorbed through the nasolacrimal duct.(18) For an uncooperative patient, instill drops on the inner canthus of the closed eye while the patient is supine. When the eye opens, some of the medication will enter the eye, and the excess medication on the periorbital area is wiped away with a tissue. Alternatively, medication can be administered by spray instillation to the closed or open eyelid. One spray is considered equivalent to one drop.(16) Any excess overflow should be immediately blotted away.

Adjusting dosages

When prescribing drugs without specific pediatric labeling, it has been suggested that an approximate topical dosage is one-half the adult dose from birth to age 2 years; two-thirds the adult dose at age 2 to 3 years; and the adult dose after 3 years of age.(24) This dosing regimen may make sense given that the eye of the newborn is two-thirds the adult size, and reaches adult size at age 3 to 4 years.(25) Perhaps a smaller eyedrop size may help to decrease systemic toxicity. Pharmacokinetic studies show that a 20-uL drop achieves an optimal tear film concentration of drug, though a typical ophthalmic eyedrop is 50 to 70-uL.(21,26)

Ointments

Ointments have advantages, especially in infants and toddlers, for whom the transient visual disturbances are less incapacitating.(21) Ointments are more comfortable upon instillation, result in less absorption into the lacrimal drainage system, and allow for longer contact time with the eye, resulting in higher concentrations of the drug while minimizing systemic absorption. Thus, ointments can be used less frequently than eye drops.(27) Ointments are particularly useful for treating children who may "cry out" topically applied solutions. When an infant or child cries, the dilution and washing effects of the tears reduce the amount of drug absorbed as well as that ultimately available for therapeutic use.

ANTIBIOTICS

Two broad uses for antibiotics are to treat active infections and as prophylaxis. Active ocular infections requiring topical drugs include conjunctivitis, blepharitis, keratitis, and nasolacrimal duct occlusion with purulent discharge. Topical antibiotics are shown to decrease the severity and time period of symptoms.(28,29) In children, the most common ocular infection is acute conjunctivitis, with a peak incidence between 12 and 36 months of age.(30). Most childhood bacterial infections are caused by Streptococcus pneumoniae or Haemophilus influenzae. Polymyxin B/trimethoprim (Polytrim) is widely prescribed for treating bacterial conjunctivitis, and is approved for use in patients 2 months or older. The only drawback to this drug is its relatively greater frequency of instillation, one drop every three waking hours, instead of the typical one drop four times daily for 5-7 days. When an ointment is preferred for bacterial infections, polymyxin B/bacitracin (Polysporin) is commonly prescribed. Polymyxin B/trimethoprim combined with neomycin (Neosporin) is available as a solution and an ointment, but is not prescribed often due to its association with allergic reactions.(31)

 

Erythromycin 0.5% ointment continues to be used for mild bacterial conjunctivitis, although continued use is associated with staphylococcal resistance. Erythromycin is also used for neonatal prophylaxis. Other antimicrobials acceptable for prophylaxis of ophthalmia neonatorum are 1% silver nitrate solution, 1% tetracycline, and povidone-iodine 2.5%.(32) Since most Pseudomonas species are resistant to sulfas, sulfa drugs are no longer the topical of choice. The aminoglycosides (tobramycin, gentamicin, neomycin, and amikacin) are broad-spectrum agents, but can be toxic to corneal epithelium with long-term use. Streptococcus and Chlamydia are resistant to aminoglycosides. Fluoroquinolones, ciprofloxacin (Ciloxan) and ofloxacin (Ocuflox) are preferable to less expensive agents because they are effective against Pseudomonas as well as Haemophilus. Fourth generation fluroquinolones, moxifloxacin (Vigamox) and gatifloxacin (Zymar), are effective against S. aureus and Chlamydia. Both are approved for use in children as young as 1 year of age.

A review of available pediatric labeling for antibiotics shows adequate prescribing information for 80% (12 out of 15) of the commonly prescribed topical drugs.(Table 1)

Table 1: Antibiotics

OCULAR ALLERGY MEDICATIONS

Topical allergy medications are indicated for the treatment of seasonal allergic conjunctivitis, and vernal conjunctivitis. Children experience symptoms and decreased quality of life from allergic conjunctivitis at a rate similar to adults.(33) Anti-allergy medications are available as antihistamines, mast-cell stabilizers, vasoconstrictors, anti-inflammatory agents, and steroids. These medications are available as prescription only and over-the-counter. Children tend to rubs their eyes when they experience itch. Thus, hand washing as an adjunct therapy to topical medications is particularly important in children with allergies. Also keep in mind the drying effect of oral antihistamines, adding to children’s propensity to rub their eyes. Most of the topical allergy medications are approved for children 3 years of age and older. The only one exception is lodoxamide tromethamine (Alomide), which is approved for age 2 years. Agents approved for age 4 years and older include azelastine (Optivar), and the cromolyns (Crolom and Opticrom). Loteprednol etabonate (Alrex) is approved for age 12 years and older.

Vasoconstrictors are available over the counter and are approved for use in children older than age 6 years. Accidental oral ingestion can lead to central nervous system depression, coma, and marked hypothermia. The ocular side effects of vasoconstrictors include burning, stinging, and mydriasis, especially in those of lighter irides. Two such products are naphzoline 0.025%-pheniramine 0.3% (Naphcon-A) and naphazoline 0.05%-antazoline 0.5% (Vasocon-A).

Dual agents, with mast-cell stabilizers and antihistamines are well-tolerated in children and have a twice daily dosing only.(34) Olopatadine hydrochloride (Patanol), epinastine (Elestat), azelastine (Optivar), and ketotifen fumarate (Zaditor) are four such drugs. All are approved for age 3 years and older, except for Optivar, approved for age 4 years and older. The next generation olopatadine is given once daily and is awaiting FDA approval.

Second generation antihistamines such as emedastine difumarate (Emadine) are also frequently used, though a notable side effect is somnolence. While the adverse effect of somnolence is much less likely with the second compared to first generation antihistamines, none of them are completely free of central nervous system effects, such as impaired concentration, dizziness, headache, and insomnia.(35) These side effects should be included in the differential diagnoses of like symptoms elicited in the course of examining a pediatric patient.

A review of the most common topical anti-allergy ophthalmic medications shows 100% (10 out of 10) drugs have pediatric labeling information.(Table 2)

Table 2: Anti-Allergy Medications

ANTI-INFLAMMATORY MEDICATIONS

Corticosteroids are used to treat ocular inflammation and severe allergic reactions. Side effects from corticosteroid use include elevation of intraocular pressure and posterior subcapsular cataracts. There is some evidence suggesting children have a greater ocular hypertensive response to steroids than adults.(36,37) Such dose-dependent differences are of significance in situations, such as treatment of uveitis, when the course may be prolonged.

There are several mild steroids approved for pediatric use in patients age 2 years and older. They are the fluorometholones, FML, eFlone, Flarex, and Fluor-Op. Safety in pediatric patients has not been established for any of the maximum strength steroids, such as the presdnisolones (Inflamase Forte, Pred Forte, Pred Mild), loteprednol (Lotemax), and rimexolone (Vexol).

Table 3: Corticosteroids

Nonsteroidal anti-inflammatory drugs (NSAIDs) may play a role in the management of corneal abrasions, post foreign body removal, strabismus surgery, and allergic conjunctivitis. Ketorolac (Acular LS) is a preservative-free non-steroidal anti-inflammatory topical ophthalmic agent safe and effective in the treatment of seasonal allergic conjunctivitis in children age 3 years and older.(38) Nepafenac (Nevanac) is approved for age 10 years and older. Diclofenac (Voltaren) and bromfenac (Xibrom) are nonsteroidal anti-inflammatory agents whose safety and efficacy profiles for use in children have not been established.

Table 4: Nonsteroidal Anti-Inflammatory Medications (NSAIDs)

A review of the most commonly prescribed anti-inflammatory medications show that 40% (6 out of 15) have pediatric safety information, specifically 27% (3 out of 11) of corticosteroids and 75% (3 out of 4) of NSAIDs.(Tables 3 and 4)

COMBINATION CORTICOSTEROID-ANTIBIOTICS

Combination corticosteroid-antibiotic medications are used in the treatment of corneal abrasions or burns, postsurgical management, and inflammatory conditions of the ocular surface or eyelids. A combination steroid-antibiotic provides prophylactic protection while decreasing inflammation. Frequently prescribed combination medications tobramycin/dexamethasone (Tobradex) as well as fluorometholone, sodium sulfacetamide (FML-S) are approved for use in patients age 2 years and older. and dexamthasone/neomycin/polymyxin B. Others combinations with pediatric use labeling are sulfacetamide/prednisolone combinations, Blephamide and Vasocidin, both approved for use in age 6 years and older.

A review of the most commonly prescribed corticosteroid-antibiotic combinations shows that 31% (4 out of 13) have pediatric use safety profiles.(Table 5)

Table 5: Combination Corticosteroid-Antibiotics

ANTIVIRAL MEDICATIONS

When Herpes Simplex Virus (HSV) and Herpes Zoster Virus (HZV) infections occur in children, the disease frequently result in severe ocular inflammation. This is in contrast to adenoviral infections, which usually result in less ocular effects in children than in adults.

The drug of choice for the treatment of HSV is trifluoridine (Viroptic), approved for use in patients age 6 years and older. Vidarabine (Vira-A), approved for age 2 years and older, is reserved for cases of hypersensitivity to trifluridine, but is no longer commercially available.

 

Table 6: Antiviral medications

GLAUCOMA MEDICATIONS

Medical treatment of pediatric glaucomas is usually adjunctive to surgical interventions. Topical medications are generally used temporarily until surgery can be performed, in later childhood onset glaucomas, and glaucoma secondary to ocular or systemic diseases. The glaucoma medications include cholinergic agonists (miotics), sympathomimetics, beta-adrenergic antagonists, carbonic anhydrase inhibitors, alpha-2-slective agonists, and prostaglandin analogs. All of the commonly prescribed topical glaucoma medications have a pediatric safety profile of either not established or not recommended in pediatric patients. However, some practitioners are more comfortable prescribing beta-adrenergic antagonists and the carbonic anhydrase inhibitor acetazolamide to infants based on its safe in lactation status established by the American Academy of Pediatrics.(39)

Side effects from glaucoma medications are of concern particularly in cases of prolonged treatment. It has been found that one drop of 0.5% timolol can reach cardiac beta-blockade levels in infants under 2 years of age.(40) Timolol can also exacerbate asthma, and thus is contraindicated in children with cardiac arrhythmias and bronchospasm.(41) Alpha-adrenergic agonists are contraindicated in children due to side effects of somnolence and fatigue. Sleep disturbances and sweating have been reported in children prescribed prostaglandin drugs.

Only one glaucoma medication, alphagan, has established safety in pediatric patients. Many of the other medications are not recommended for use in children.

Table 7: Glaucoma Medications

ANTIFUNGAL MEDICATION

There is only one commercially available topical antifungal, it is natamycin and its safety in pediatric patients has not been established.

Table 8: Antifungal Medication

DILATING AGENTS

Dilating agents are frequently used for refraction and retinal examination. Dilating agents are composed of sympathomimetics and parasympatholytics, with potentially significant side effects of hypertension, tachycardia, arrhythmias, headache, restlessness, seizures, psychosis, gastrointestinal disturbances, and respiratory depression. Premature infants are especially sensitive to side effects. Phenylephrine can cause hypertension and tachycardia and should be used with caution in children with hyperthyroidism or tachyarrhythmias.(42)

Cycloplegic agents are indicated for refraction in infants and young children, penalization therapy for amblyopia, postoperative cycloplegia, and uveitis management. Some patients are especially susceptible to toxic systemic side effects from use of atropine and cyclopentolate, including those with spastic paralysis or brain damage, lightly pigmented individuals, and Down syndrome. Cyclopentolate and atropine in concentrations greater than 0.5% are not recommended in small infants because of possible central nervous system disturbances. The combination of cyclopentolate 0.2% and phenylephrine 1% (Cyclomydril) provides adequate mydriasis while minimizing unwanted systemic effects, particularly for the examination of premature infants.(42) Atropine 1% solution has been shown to be a safe and effective treatment of moderate amblyopia in three to seven year olds.(43) The recommended dosage is once daily or weekends only in the sound eye.(44)

CONCLUSION

Clinicians should be aware of the increasing number of topical ophthalmic drugs that are approved for pediatric use. Changes in FDA requirements along with economic factors suggest that the trend is for more and more pharmaceutical companies to provide pediatric use labeling. This paper provides clinicians with a summary of the most commonly prescribed topical ophthalmic medications and indicates which drugs are currently FDA approved for young children. Clinicians should use the variety of resources available for up-to-date pediatric use information when treating their younger patients, and choose those with established pediatric safety profiles.

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