FDA, industry work on dosing guidelines for kids

To standardize off-label, compounding formulas

It's a busy time for pediatric pharmacy. Pushed by the Clinton administration, pharmacy associations, drug makers, and the Food and Drug Administration are working on how best to establish testing and approval methods for infant and children's prescription drugs.

There are new guidelines for pediatric HIV treatment, and new antibiotic guidelines for treating otitis media in children. Some contaminants are showing up in pediatric parenteral nutrition (PN) solutions, and pharmacists are being asked to educate consumers on the threat of misdosing over-the-counter acetaminophen.

Here's a rundown of the salient points on each of these developments.


When it comes to treating kids, especially infants, off-label use, experimental formulations, and the lack of uniform compounding is the rule. The Pediatric Pharmacy Advocacy Group estimates that of all the drugs on the market, at least 60% do not carry indications for use in patients 12 and under. And this pertains to a variety of antibiotics, intravenous otitis media treatments, asthma, hypertension, and cardiac care drugs, as well as topical infection agents, among others.

And while the FDA overhaul bill (now law as the FDA Modernization & Accountability Act of 1997) includes incentives for pediatric testing - giving drug makers six months of market exclusivity in exchange for agreeing to any future mandatory product testing - manufacturers have predictably bemoaned the time and money needed for such testing in a market offering less financial return. At the same time, everyone involved is dealing with the ethical questions of possible drug trials conducted on infants and children.

But in a situation ripe for ineffective dosing and treatment, or even adverse reactions, the Clinton administration's more recent high profile push for mandatory testing and indications have set things in motion. Two new ideas have emerged for drugs already on the market.

1. The establishment of a prescription cutoff method, based on a patient condition and the drug needed for treatment. In other words, how many prescriptions would be needed annually for a specific drug would be the determining factor, with anything less than the agreed-upon number allowing that drug prescription to be filled. This cutoff would apply to specific drugs like those used to treat cystic fibrosis, for example, and not to drugs like antibiotics used to treat a variety of conditions. But right now, there is no consensus on what that cutoff number should be for any drug and condition.

2. Establishing a case-by-case analysis of what drugs should be tested.

Another proposal would simply call for pediatric testing if it can be established that the lack of specific indications poses a significant health threat. Meanwhile, the FDA is considering whether an "orange book" of uniform techniques and formulations can be compiled to standardize the off-label and compounding now being done for pediatric use.

Are children appropriate subjects?

But looming above the entire issue are questions on the appropriateness of using infants or children in clinical trials, at what phase of a trial, and with what types of drugs. Progress is expected on these issues at a three-day conference in Washington, DC, May 11-13, held by the American Academy of Pharmaceutical Scientists and the FDA.

A case in point on the lack of pediatric test-ing is the protease inhibitor class of HIV drugs, where none has been specifically approved for patients under two years old. Still, virologists convened by the National Pediatric and Family HIV Resource Center and the federal Health Resources and Services Administration have drafted treatment guidelines for pediatric AIDS patients that mirror recent National Institutes of Health guidelines for adult care.

Primarily, the guidelines also recommend aggressive, early treatment using a triple com-bination regimen of one protease inhibitor and two nucleoside reverse transcriptase inhibitors (NRTIs), despite the preference of many clinicians to begin pediatric treatment with two NRTIs alone. That tendency speaks to the lack of specific pharmacokinetic data on protease inhibitor dosing for infants, but the guidelines still push for the triple combination approach and do offer specific drug and dosage combinations.

And, also like adult patients, viral load monitoring is the recommended standard for tracking treatment success, while treat- ment should begin in patients under 12 months immediately upon diagnosis, regardless of initial viral load counts. The draft also includes indications on when to change a treatment regime based on treatment failure, toxicity, or intolerance - specific to pediatric patients - in times of growth failure or ongoing neurodevelopmental deterioration.

Virologists also note that the drug Retrovir (zidovudine), at this time, appears better tolerated in children than in adult patients.

[The Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection can be obtained through the National AIDS Clearinghouse at (800) 458-5231, or on-line at Web site: cdcnac.org. The information is also available from the HIV/AIDS Treatment Information Service at (800) 448-0440. Web site: hivatis.org.]


Questions concerning dosing levels also are behind the American Pharmaceutical Associa-tion's (APhA) educational effort aimed at parents giving over-the-counter acetaminophen - particularly the widely used and popular children's and infants' Tylenol - to their kids.

Tylenol maker McNeil Consumer Products (Fort Washington, PA) began the program after the FDA's OTC Drug Advisory Committee recommended labeling changes last Fall calling for more detailed dosing for children under two, along with stronger warnings against overdosing. (The American Association of Poison Control Centers estimates that in 1996 more than 30,000 kids six and under were given the wrong dosage of the drug.)

The APhA says most parents don't realize that McNeil's infant Tylenol carries a nearly four times stronger formula concentration than its children's Tylenol and believe few parents know that overdoses can cause liver damage in their children or can even be fatal. Dubbed the Be SAFE program, McNeil is sending out about 100,000 sets of posters, flyers, and tip cards to pharmacies, day care centers, and doctor's offices.

The APHA agreed to oversee the wording and focus of the materials and has agreed to urge its members to embrace the program. The materials basically urge parents to simply read and follow the label, ask a pharmacist or doctor to clear up any confusion, and keep a log of the doses and frequency given that can be reviewed by a professional.

[If you haven't received materials on the program and would like to, call (800) 472-3923 for a free set.]


With a variety of antimicrobials available to treat acute otitis media, pharmacists at Kaiser Permanente in Rockville, MD, reviewed 333 patient charts trying to determine which commonly used drugs offered the best treatment and/or cost-effective outcomes. The review covered only first-case patients up to 7 years old during a four-month period. Five commonly used treatments were reviewed (percentages represent frequency of use of that drug at Kaiser): amoxicillin (56%); amoxicillin-clavulanate potassium (7%); cefaclor (5%); erythromycin-sulfisoxazole (15%); and trimethoprim-sulfamethoxazole (17%).

The bottom line of this study was that trimethoprim-sulfamethoxazole was among the most effective in terms of treatment, rivaled only by cefaclor, and the best in terms of cost-effectiveness. The drug, however, was prescribed much less than amoxicillin but was second highest overall among the five drugs reviewed.

To reach this conclusion, eight categories of outcomes were established, ranging from successful to extended treatments, along with cases of otitis media with effusion, serous otitis media, and persistent otitis media, all while charting the drugs being prescribed, or in some cases changed. Symptomatic failure, extended treatment, and adverse reactions all were considered treatment failures.

Of the 79 cases deemed a treatment failure, 89% of patients received a different drug. In cases where a second drug was added, trimethoprim-sulfamethoxazole was again found to be the most effective. Cefaclor also fared well when added as part of a second regime.

Also noteworthy from the study was that erythromycin-sulfisoxazole was the most expensive and least-effective drug, while amoxicillin-clavulanate potassium was deemed the least cost-effective of the five. Based on the study, Kaiser pharmacists recommended trimethoprim-sulfamethoxazole and amoxicillin remain the primary first lines of therapy for acute otitis media.

[For more information, please contact Deborah Greiner, PharmD, clinical pharmacy program administrator at Kaiser, (301) 816-2424.]


Another good example of a drug recently labeled for pediatric use is Timentin, an effective antibiotic combination that treats a wide range of bacterial infections, says Michael Reed, PharmD, professor of pediatrics at the Case Western Reserve University School of Medicine and Rainbow Babies and Children's Hospital in Cleveland.

More than 700 children with various infections, including respiratory, bone and joint, skin, urinary, and gynecologic, were studied. The drug was found to be well-tolerated and was approved by the FDA for use in children over three months old.

Timentin, composed in part of the beta-lactam antibiotic ticarcillin, is designed to overcome a mechanism by which several important bacterial pathogens become resistant to therapy. Adverse reactions, similar to any penicillin, include skin rash, headache, and gastrointestinal disturbances. The drug is not indicated for treatment of septicemia or infections caused by Haemophilus influenza type B.

Timentin is administered by intravenous infusion. For pediatric patients less than 60 kg, the drug is dosed at 50mg/kg/dose based on the ticarcillin component. For mild to moderate infections, 200 mg/kg/day should be given in divided doses every six hours; for severe infections, 300 mg/kg/day in divided doses are given every four hours. In children over 60 kg, 3.1 grams should be given every six hours for mild to moderate infections, and 3.1 grams every four hours for severe infections.


Pharmacists at the University of Tennessee in Memphis are recommending that zinc and chromium levels be closely monitored in pediatric patients, following a study showing that trace element contamination found in PN solutions resulted in levels above recommended allowances. Specifically, researchers found zinc levels two times higher than recommended daily doses and chromium levels three times higher. Serum and urine testing were done to determine the levels, and patients on PN solutions for more than three months were tested.

Up to 20 types of PN solutions were included in the review, supplied by nine different manufacturers. PN solutions reviewed ranged from dextrose, cysteine hydrochloride, potassium chloride, sodium phosphate, calcium gluconate, magnesium sulfate and selenium, among others. Researchers noted that the amount and type of zinc and/or chromium contamination varied depending on the product, lot, and manufacturer of a given PN solution, and added that expiration dates did not make a difference in the levels found.

The simple presence of chromium in much of the raw materials that make up many PN solutions largely accounts for its presence, the study reports, and makes it that much harder to avoid. But zinc contamination can be avoided more easily, as zinc is used in the manufacturing of rubber stoppers and is part of the raw materials used to make glass. Therefore, zinc can be "leached" from rubber and glass into a PN solution over time. To cut down on zinc contamination, the authors recommend that PN solution containers be stored upright and in as large a container as possible, to avoid concentrated contact between the solution, the stoppers, and container walls. They also suggest that newer products be used as much as possible.

[For more details, contact Emily Hak, PharmD, BCNSP, University of Tennessee department of clinical pharmacy, (901) 448-6041.]