Off-label use of drugs in children.

The passage of the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act has collectively resulted in an improvement in rational prescribing for children, including more than 500 labeling changes. However, off-label drug use remains an important public health issue for infants, children, and adolescents, because an overwhelming number of drugs still have no information in the labeling for use in pediatrics. The purpose of off-label use is to benefit the individual patient. Practitioners use their professional judgment to determine these uses. As such, the term "off-label" does not imply an improper, illegal, contraindicated, or investigational use. Therapeutic decision-making must always rely on the best available evidence and the importance of the benefit for the individual patient.

Changes to Prescription Drug Pediatric Labeling: Awareness by Practicing Pediatricians.

The US Congress and the US Food and Drug Administration encouraged studies in children so that the labeling information about pediatric use could be updated for pharmaceutical products. Pediatricians receive this updated labeling information through many different sources. A pilot survey was conducted to determine what source pediatricians use to learn about this updated information and whether and when they learned of specific changes. It appears that most pediatricians did not know that there had been recent changes in pediatric drug labels, although changes to drugs that were used more commonly in practice were more likely to be known.

Effect of dialysis on all trans retinoic acid levels in a child with acute promyelocytic leukemia and renal failure.

All trans retinoic acid (ATRA) combined with chemotherapy has become the mainstay of treatment for patients with acute promyelocytic leukemia (APL). Renal dysfunction (RD) is commonly seen in patients with APL. We describe a patient with APL and multi-organ failure, who was on chronic veno-venous hemofiltration followed by hemodialysis (HD) and later peritoneal dialysis (PD), who received ATRA. ATRA levels were assessed as the body clearance of ATRA in children on HD and/or PD was unknown. Neither HD nor PD significantly affected ATRA levels, suggesting that dose modifications of ATRA may not be necessary for children with these forms of renal replacement therapy.

Vancomycin elimination in human infants with intrauterine growth retardation.

BACKGROUND: Intrauterine growth retardation (IUGR) results in substantial decrease in nephron number and renal and hepatic organ mass in experimental animals and newborn infants. Because the liver and the kidneys are the major organs for drug biotransformation and elimination, any decrease in their size and function may lead to impaired metabolism and elimination of drugs in newborns with IUGR. Our objective was to test the hypothesis that IUGR results in prolonged renal elimination of vancomycin in newborns. METHODS: Small for gestational age (SGA) infants (n = 20) were matched with appropriate for gestational age (AGA) infants (n = 123). Steady state peak and trough serum concentrations were used to calculate vancomycin clearance (Cl), volume of distribution (Vd) and half-life (t(1/2)) for each subject. Pharmacokinetic profiles were compared between groups. RESULTS: Overall, Cl, Vd and t(1/2) of vancomycin were the same between groups. However, stratification showed decreased Cl in those SGA versus AGA newborns 3-4 weeks old and in those newborns with a postconceptional age of 27-29 weeks. There was no difference in Vd, normalized for weight, between SGA and AGA babies. The half-life of vancomycin was similar across most groups but was prolonged in SGA newborns aged 3-4 weeks. CONCLUSIONS: Vancomycin Cl differs between SGA and AGA newborns. This difference is greatest early in life and normalizes between groups after the fourth week of life or after 29 weeks postconceptionally. Normalized Vd is similar between SGA and AGA newborns. The elimination of vancomycin is comparable between SGA and AGA infants, except before the fifth week of life, when SGA newborns may eliminate the drug more slowly. Specific vancomycin dose recommendations for SGA versus AGA neonates may therefore be justified during the first month of life.

Lidocaine 4% cream compared with lidocaine 2.5% and prilocaine 2.5% or dorsal penile block for circumcision.

This study evaluated the efficacy and safety of lidocaine 4% cream (LMX4), compared with lidocaine 2.5% and prilocaine 2.5% (EMLA) or dorsal penile block (DPNB) for analgesia during circumcision. Healthy, term males (n = 54), younger than 1 week old undergoing circumcision were randomly assigned to open-label pretreatment with LMX4, EMLA, or DPNB. Heart rate (HR; beats per minute [bpm]), respiratory rate (RR; breaths/minute), and arterial oxygen saturation as measured by pulse oximetry (Sp O2; %) were monitored at baseline, and during drug application, circumcision, and recovery. Mean differences were compared using the general linear model. At the end of drug application, mean HR for infants receiving LMX4 (146 bpm; standard error of mean [SEM], 8.0 bpm) was lower than that for DPNB (176 bpm; SEM, 8.3 bpm; p < 0.05). No significant difference in mean HR was observed between treatments during circumcision. Mean RR was higher during circumcision for EMLA compared with LMX4 (p < 0.05) and DPNB (p < 0.05). At lysis, mean RR was significantly lower in DPNB than LMX4 and EMLA. The number of Sp O2 samples was too small for comparison. Three infants (one receiving LMX4 and two receiving EMLA) experienced local reactions (p = 0.54). No adverse effects were observed with DPNB. No difference in analgesic efficacy was observed between treatments according to HR. Differences in RR may reflect a varying level of analgesia. The safety profile was similar for all treatments. LMX4 is an effective analgesic for newborn circumcision.

Adverse drug reactions and avalanches: life at the edge of chaos.

Although many reports have described the incidence of adverse drug reactions, none have explained their variable severity or why they happen. Because human physiology shares many of the features of other complex adaptive systems, reactions to drug therapy were examined mathematically for specific patterns to show (1) that the severity of adverse drug reactions follows a distribution seen in other complex adaptive systems, called a power law distribution, and (2) that preventable reactions occurred for reasons fundamentally different from those that underlie the nonpreventable reactions. Two reports detailing adverse drug reaction incidence and severity were evaluated: a meta-analysis of prospective adverse drug reaction studies and a prospective cohort study. Incidence of drug reaction was plotted as a function of severity and fit to an equation. The incidences of overall and nonpreventable drug reaction, plotted as a function of severity, followed a similar power law distribution regardless of sample size or the nature of the population or drugs studied. An exception to this was the preventable reactions, which were described by a different type of equation. Response to pharmacotherapy exhibits many properties of systems with self-organized criticality. An exception to this is the preventable reactions, which seem to be fundamentally different from the nonpreventable ones. These observations suggest that the presence and the distribution of severity of reaction to pharmacotherapy is a consequence of our adaptation as biological systems, and although adverse reactions can be made less frequent, a certain percentage will not be preventable.

Pharmacokinetics of Rofecoxib in Children With Sickle Cell Hemoglobinopathy.

Rofecoxib is a selective cyclooxygenase-2 (COX-2) inhibitor approved for the treatment of pain and arthritis in adults. It is available as a suspension, but there are no published pediatric pharmacokinetic data. This study characterized the disposition of rofecoxib in children with sickle cell hemoglobinopathy in a single-oral-dose, intensive pharmacokinetic study. Eight subjects aged 3 to 14 years (mean 8.9 years, 5 boys and 3 girls) received a single oral dose of rofecoxib (1 mg/kg, maximum 50 mg) as a suspension. Blood samples were collected over 72 hours following drug administration and plasma was assayed for rofecoxib using high-performance liquid chromatography (HPLC). Pharmacokinetic parameters (peak concentration [Cmax], time to reach peak concentration [tmax], area under the curve [AUC], oral clearance [Cl/F], elimination half-life [t½]) were calculated using standard noncompartmental methods. The mean dose was 35.6 mg (range 15-50 mg). Cmax averaged 582 ± 129 ng/mL, with a median tmax of 4.0 hours. Secondary peaks were observed in two subjects. Two subjects were discharged at 12 hours, preventing characterization of elimination. In the remaining six subjects, Cl/F averaged 1.34 ± 0.32 mL/min/kg, with a t½ of 14.8 ± 4.5 hours. No significant adverse events were observed. The disposition of rofecoxib in children appears to be similar to that in adults, with comparable values for Cmax, tmax, t½, and Cl/F.

Pharmacokinetics of rofecoxib in children with sickle cell hemoglobinopathy.

Rofecoxib is a selective cyclooxygenase-2 (COX-2) inhibitor approved for the treatment of pain and arthritis in adults. It is available as a suspension, but there are no published pediatric pharmacokinetic data. This study characterized the disposition of rofecoxib in children with sickle cell hemoglobinopathy in a single-oral-dose, intensive pharmacokinetic study. Eight subjects aged 3 to 14 years (mean 8.9 years, 5 boys and 3 girls) received a single oral dose of rofecoxib (1 mg/kg, maximum 50 mg) as a suspension. Blood samples were collected over 72 hours following drug administration and plasma was assayed for rofecoxib using high-performance liquid chromatography (HPLC). Pharmacokinetic parameters (peak concentration [Cmax], time to reach peak concentration [tmax], area under the curve [AUC], oral clearance [Cl/F], elimination half-life [t1/2]) were calculated using standard noncompartmental methods. The mean dose was 35.6 mg (range 15-50 mg). Cmax averaged 582 +/- 129 ng/mL, with a median tmax of 4.0 hours. Secondary peaks were observed in two subjects. Two subjects were discharged at 12 hours, preventing characterization of elimination. In the remaining six subjects, Cl/F averaged 1.34 +/- 0.32 mL/min/kg, with a t1/2 of 14.8 +/- 4.5 hours. No significant adverse events were observed. The disposition of rofecoxib in children appears to be similar to that in adults, with comparable values for Cmax, tmax, t1/2, and Cl/F.

Characterization of the role of physicochemical factors on the hydrolysis of dipyrone.

Dipyrone is a prodrug which is used mainly for its analgesic and antipyretic effects. After oral intake, dipyrone is rapidly hydrolyzed to its main metabolite, 4-methylaminoantipyrine (4-MAA), from which many other metabolites are produced by enzymatic reactions. Even though it is well known that dipyrone is a prodrug and hydrolyzed non-enzymatically, in most of the studies of dipyrone the prodrug form is tested using in vitro methodologies, which do not represent or predict the actual in vivo activity of dipyrone. In this study, we characterize the hydrolysis kinetics of dipyrone as functions of concentration, temperature, and pH using a HPLC assay. Concentration is an important factor in the hydrolysis of dipyrone. Low concentrations of dipyrone are hydrolyzed more rapidly than are solutions of higher concentrations. At a concentration of 0.1M, which is 140 times, the concentration of the marketed pharmaceutical form, dipyrone is only minimally (10%) hydrolyzed to 4-MAA at 5h. Temperature, as expected, affects the hydrolysis reaction dramatically. We tested three temperatures (4, 21, and 37 degrees C) and found that at body temperature the hydrolysis is significantly faster than at room or at refrigerator temperatures. Compared with more alkaline solutions, the hydrolysis rate of dipyrone increases dramatically in acidic solutions. At low pH (2.5) and at a 0.01 mM concentration, the hydrolysis of dipyrone is completed within almost 30 min, which is the highest rate we observed. Experiments which involve in vitro and/or local application of dipyrone should consider these physicochemical factors and interpret the results accordingly.

Antifungals in systemic neonatal candidiasis.

Fungal infections are common in the newborn period, especially among premature neonates, and are responsible for considerable morbidity and mortality. Currently, three classes of antifungals are commonly used in the treatment of systemic fungal infections in neonates: the polyene macrolides (e.g. amphotericin B [deoxycholate and lipid preparations]); the azoles (e.g. fluconazole); and the fluorinated pyrimidines (e.g. flucytosine). The echinocandins (e.g. caspofungin and micafungin) are a newer class of antifungals which shows promise in this population.The available kinetic data on amphotericin B deoxycholate in neonates are derived from very small studies and exhibit considerable variability. There are no kinetic data available for the use of lipid preparations in this population and, again, much has been inferred from adult studies. The information available for flucytosine is also limited but appears similar to what is observed in adults. Fluconazole has the most neonatal pharmacokinetic data, which show slightly less variability than the other antifungals. Genomic factors which affect the metabolism of amphotericin B and fluconazole may explain some of the observed variability. Most of the data for the efficacy of antifungal drugs in neonates are derived from retrospective studies and case reports. The data for amphotericin B deoxycholate and flucytosine are limited. There are more data for the liposomal and lipid complex preparations of amphotericin B and for fluconazole in this population. These support the use of these drugs in neonates, but because of their largely noncomparative nature they can not define the optimal dosage or duration of therapy. Amphotericin B deoxycholate is primarily nephrotoxic. It also induces electrolyte abnormalities and is to a lesser degree cardiotoxic. This toxicity in neonates appears similar to published data in older children and adults. While the lipid preparations of amphotericin B owe their existence to a presumed decrease in toxicity, the observed toxicity in neonates appears to be equal to that seen with the deoxycholate, although it should be noted that the lipid preparations are usually given at much higher dosages. Fluconazole toxicity appears to be milder and less frequent in this population than is seen with amphotericin B. In the final analysis, we do not have sufficient data to define the pharmacokinetic profiles, optimal dose or duration of therapy, or toxicity for any of these compounds in neonates. Further studies are necessary if the optimisation of antifungal therapy in this population is to continue.