PEDIATRIC PHARMACOTHERAPY A Monthly Newsletter for Health Care Professionals from the University of Virginia Children’s Hospital

Volume 11 Number 3 March 2005

Rece nt Actions by the Food and Drug Administration Marcia L. Buck, Pharm.D., FCCP

n the past year, the Food and Drug complicated urinary tract infections and I Administration (FDA) Center for Drug pyelonephritis. The drug is not recommended as Evaluation and Research (CDER) has made a first -line therapy in this age range. In clinical number of significant changes in the labeling of trials, there was an increased risk of adverse pres cription drugs for children as part of the eff ects in the patients receiving ciprofloxacin Pediatric Exclusivity Program. 1 A number of compared to those given placebo, including agents received pediatric indications. In several adverse effects related to joints and surrounding other cases, preliminary studies failed to tissues. The most frequent adverse effects in demonstrate safety and efficacy in children, but children were gastrointestinal (15% compared to provided useful informati on on dosing, 9% of controls) and mus culoskeletal (9.3% pharmacokinetics, or adverse effects that might compared to 6% of controls). aid prescribers in determining the appropriateness of these agents in children. In Clofarabine addition to these changes, there have been During the past year, only one agent received several important FDA Safety Alerts involving simultaneous pediatric and adult approval with medications commonly used in children. 2-4 an original New Drug Application. Clofarabine (Clolar ®; Genzyme) is indicated for the treatment Labeling Changes Under the Pediatric of r elapsed or refractory acute lymphoblastic Exclusivity Act leukemia after at least two prior regimens. This agent is currently approved for use in patients 1 Anagrelide to 21 years of age. The product labeling for anagrelide (Agrylin ®; Shire) was changed in December 2004 to include Desloratadine information on the pharmacokinetics, dosing, and The product information for desloratadine adverse effects in child ren 6 to 17 years of age. (Clarinex ®; Schering) was amended i n September Anagrelide is used in the treatment of 2004 to include an indication for patients 2 years thrombocytopenia due to myeloproliferative of age and greater with perennial allergic rhinitis disorders. and chronic idiopathic urticaria. Information on dosing, pharmacokinetics, and adverse effects Benazepril has been included in the product labeling. Labeling for benazepril (Lotensin ®; Novartis), an angiotensin converting enzyme inhibitor, was Dorzolamide changed in March 2004 to incl ude an indication The labeling of dorzolamide (Trusopt ®; Merck) for children 6 to 16 years of age. Benazepril is was modified in April 2004 to include efficacy not recommended for children under 6 years of and safety data in children. Dorzolamide reduces age (because of lack of sufficient data) or in intraocular pressure by decreasing production of patients with renal dysfunction. Pharmacokinetic aqueous humor in patients with glaucoma or studies have shown a significantly higher ocular hy pertension. cle arance rate in children than in adults, with an elimination half -life 1/3 of adult values. Fenoldopam Instructions for the preparation of an oral The use of fenoldopam (Corlopam ®; Hospira) suspension have also been included. was approved for the short -term reduction of elevated blood pressure in hospitalized pediatric Ciprofloxacin patients greater than one month of age or Ciprofloxacin (Cipro ®; Bayer), a quinolone weighing greater than 2 kg. Dosing, antibiotic, has been appro ved for use in children pharmacokinet ic, and adverse effect information 1 to 17 years of age for the treatment of is now available in the product labeling. Glyburide/metformin Methylphenidate In a clinical trial, the combination of glyburide The labeling of once -daily methylphenidate and metformin (Glucovance ®; BMS) was not (Concerta ®; Alza) has been expanded to include a found to be statistically superior to either agent new strength and in formation on the dosing, given alone for p ediatric patients with type 2 pharmacokinetics, and adverse effects in children diabetes mellitus. 13 to 17 years of age. A higher maximum dose for adolescents has also been incorporated. Irinotecan New information has been added to the product Because the data submitted to the FDA were labeling for irinotecan. Clinical trials did not deemed inadequate to determine whether chroni c establish the effectiveness of irinotecan use of stimulants suppresses growth, the labeling (Camptosar ®; Pfizer) in children. A phase 2 trial of this product has been amended to highlight the which enrolled 21 children with previously need for monitoring growth during treatment. untreated rhabdomyosarcoma was halted because Patients who are not growing or gaining weight of a 23.6% incidence of progressive disease and should have their treatment interrupted. In 14% incidence of early deaths. Adverse effect addition, cautio n should be used when data from a phase 2 trial of irinotecan in 170 prescribing methylphenidate for patients with children with refractory solid tumors was similar hypothyroidism, hypertension, or cardiovascular to that previously reported in adults, with conditions that might be worsened by drug - neutropenia in 31.8% of patients and diarrhea in related elevations in blood pressure or heart rate. 20.6% of patients. In another study, dehydration occurred in 28.6% of the patients. Several Nelfinavir experienced severe hypokalemia and A protease inhibitor for the tre atment of patients hyponatremia. Serious infections were reported with HIV -1 infection, nelfinavir (Viracept ®; in 23.8% of patients. Pfizer), has been approved for use in children 2 to 13 years of age. New dosing information has Lansoprazole been added to the labeling for this population. In In June 2004, lansoprazole (Prevacid ®; Tap) addition, the results of pharmacokinetic st udies labeling was amended to include an indication in patients from birth to 13 years of age have for patients 12 to 17 years of age. This drug, a been added, with attention to the problem of proton pump inhibitor used to decrease gastri c highly variable drug exposure in children. acid production, was previously approved for patients 1 to 11 years of age and adults. Nizatidine The labeling of nizatidine (Axid ®; Reliant Leflunomide Pharma), a histamine (H 2) blocker, was changed The safety and efficacy of leflunomide (Arava ®; in May 2004 t o include an indication for patients Aventis) has not been fully evaluated in children 12 years of age and older. Dosing, with juvenile rheumatoid arthritis (JRA), but pharmacokinetic, and safety data were added. prelimina ry information was added to the product labeling in March 2004. In a double -blind study Paricalcitol of 94 children with JRA, 68% of those given The safety and efficacy of paricalcitol (Zemplar ®; leflunomide demonstrated clinical improvement, Abbott) was studied in a 12 -week trial in 29 compared to 89% of patients on standard children with end -stage renal disease. Nine of therapies. In a study of 74 childre n with JRA, the 15 patients (60%) given paricalcitol had adverse effects were similar to those reported in significant decreases from baseline parathyroid adults. Fourteen patients experienced elevated hormone levels compared to 3 of 14 patients liver function tests, with 5 patients having values (21%) in the placebo group. greater than three -fold the upper limit of normal. Remifentanil Losartan Remifentanil (Ultiva ®; Abbott) labeling was The angiotensin receptor blocker losartan amended in Mar ch 2004 to include information (Cozaar ®; Merck) now has labeling for use in on its use for maintenance of anesthesia in hypertensive patients between 6 and 16 years of infants. Because of the highly variable clearance age. Information on dosing, pharmacokinetics, rate observed during clinical trials in neonates, a and adverse effects has been included, as well as recommendation for careful dose titration has information on the preparation of an been included. extemporaneous oral suspension. Lorsartan is currently not recommended for patients less than Sodium ferric gluconate complex 6 years of age or in patients with renal Labeling for sodium ferric gluconate complex dysfunction. (Ferrlecit ®; Watson) was amended in August 2004 to include patients 6 to 15 years of age. or the emergence of suicidality. On October Information on dosing, pharmacokinetics, and 15 th , the warning was expanded to all adverse effects in this age group has been added. antidepressants and a request was made to add a boxed warning to alert health care professionals Sumat riptan of the increased risk in children and adolescents. Five clinical trials of sumatriptan (Imitrex Nasal A proposed FDA Medication Guide on this topic Spray ®; Glaxo) have failed to show significant is available at www.fda.gov/cder/drug/ benefit when compared to placebo in pediatric antidepressants /SSRI/MedicationGuide.htm patients with migraines. Information from these trials, including the adverse effects observed in Atomoxetine childr en, was added to the product labeling. At On December 17, 2004, the FDA notified health this time, the use of sumatriptan in patients less care pr ofessionals of a new warning for than 18 years of age is not recommended. atomoxetine (Strattera ®; Lilly). The labeling for this agent was amended to include information Tolterodine on potential hepatic injury following two recent Pharmacokinetic data in patients 11 to 15 years case reports. of age was added to the product information for tolterodin e (Detrol LA ®; Pfizer). This drug is an Atypical antipsychotics anticholinergic used for patients with an In March 2004, the FDA requested tha t all overactive bladder. manufacturers of atypical antipsychotics revise their product labeling to address the risk of Venlafaxine hyperglycemia and diabetes with these agents. The antidepressant venlafaxine (Effexor ® and The following agents have undergone label Effexor XR ®; Wyeth) was studied in adolescents revision: aripiprazole (Abilify ®; BMS), clozapine with depression, but did not show significant (Clozaril ®; Novar tis), olanzapine (Zyprexa ®; benefit compared to placebo. During placebo - Lilly), risperidone (Risperdal ®; Janssen), controlled trials, decreased appetite and a quetiapine (Seroqel ®; AstraZeneca), and reduced growth velocity were observed. ziprasidone (Geodon ®; Pfizer). Elevations in blood pressure and serum cholesterol were reported in children at rates Controlled release amphetamine (Adderall XR ®) similar to those observed in adults. On February 9, 2005, the FDA issued a public health advisory to notify health care Zol mitriptan professionals that Health Canada had suspended As with sumatriptan, studies with zolmitripan the sale of Adderall XR ®. This action was based (Zomig ®; AstraZeneca) in adolescents with on post -marketing reports of sudden death in migraines have not established safety and pediatric patients. The FDA is currently efficacy when compared to placebo. The adverse evaluating these reports. A patient information effects observed were similar to those in adults. sheet describing this alert, as well as additional information for prescribers, is available at Safety Alerts for Pediatric Patients www.fda.gov/cder/drug/infopage/adderall/default .htm Anagrelide The labeling of anagrelide (Agrylin ®; Shire) was Infliximab revised in December 2004 to include a The FDA alerted health ca re professionals in contraindication for use in patients with severe August 2004 of a revision in the warnings for hepatic impairment and the need to reduce the infliximab (Remicade ®; Centocor), a monoclonal dose in patients with moderate hepatic antibody to tumor necrosis factor. The warning imp airment. These patients should be carefully calls attention to the risk for leukopenia, monitored for adverse cardiovascular effects. neutropenia, and pancytopenia with this drug, as we ll as reports of systemic vasculitis with central Antidepressants nervous system manifestations. In October, an On May 5, 2004, after more than a year of additional alert was distributed regarding the review, the FDA requested a warning be added to increased risk of lymphoma in treated patients; the labeling of bupropion (Wellbutrin ®), and in December, further revisions in the product citalopram (Celex a®), escitalopram (Lexapro ®), labeling were m ade to incorporate reports of fluoxetine (Prozac ®), fluvoxamine (Luvox ®), hepatotoxicity with infliximab use. paroxetine (Paxil ®), mirtazapine (Remeron ®), nefazodone (Serzone ®), and venlafaxine Non -steroidal anti -inflammatory drugs (Effexor ® and Effexor XR ®) to encourage close Beginning with the voluntary withdrawal of observation of patients for worsening depression rofecoxib (Vioxx ®; Merck) on September 30, 2004, there has been considerable attention to the www.fda.gov/cder/drug/infopage/elidel/default.ht risk of advers e cardiovascular events with non - m and www.fda.gov/cder /drug/infopage/ steroidal anti -inflammatory drugs (NSAIDS). protopic/default.htm The FDA is currently analyzing data from a large number of NSAID trials. The Public Health Summary Advisory issued on December 23 rd is available Over two dozen drugs have undergone labeling from the FDA CDER website at changes to incorporate pediatric information www.fda.gov/cder/drug/advisory/nsaids.htm since January 2004. While many of these changes have been to include pediatric dosing Oseltamivir information, there have also bee n some important On June 24, 2004, oseltamivir (Tamiflu ®; Roche) new safety warnings. For additional information, labeling was revised to address the lack of safety the FDA CDER and MedWatch websites contain and efficacy data in infants. The manufacturer information on these changes and links to new does not recommend this agent in infants because product labeling. 1 of the potential for penetration across an immature blood -brain barrier. References 1. Pediatric Exclusivity Labeling Changes. Available at: Promethazine www.fda.gov/cder/pediatric/labelchange.htm (accessed 2/19/05) In January 2005, a black box warning with a 2. Baker DE. Current FDA -related drug information. Hosp contraindication to use in patients less than 2 Pharm 2005;40:170 -83. years of age was added to t he labeling for 3. 2004 Safety Alerts for Drugs, Biologics, Medical Device s, promethazine (Phenergan ®; Wyeth and generic). and Dietary Supplements. Available at www.fda.gov/medwatch/SAFETY/2004/safety04.htm . The new labeling will call attention to the risk for (accessed 2/17/05) respiratory depression in this age range, even 4. 2005 Safety Alerts for Drugs, Biologics, Medical Devices, with standard dosing. It replaces earlier labeling and Dietary Supple ments. Available at which stated that the use of promethazine in www.fda.gov/medwatch/SAFETY/2005/safety05.htm . (accessed 2/17/05) these patients was not recommended. Formulary Update Saquinavir The following actions were taken by the Last month, health care professionals were Pharmacy and Therapeutics Committee at the ir alerted to a potential drug interaction between meeting on 2/25/05: saquinavir (Invirase ® and Fortovase ®; Roche) and 1. Ziconotide (Prialt ®) was added both to the rifampin. Use of this combination has resulted in Inpatient and Outpatient Formularies for hepatotoxicit y. intrathecal administration to patients with severe chronic pain (restricted to the Pain Service). Somatropin 2. Paclitaxel protein -bound particle inje ctable The use of somatropin (Nutropin Depot ®; suspension (Abraxane ®) was added both Genentech) is now contraindicated in patients Formularies for patients with refractory with Prader -Willi syndrome, according to metastatic breast cancer and documented labeling changes made in October 2004. hypersensitivity to paclitaxel. Fatalities have been reported with the use of this 3. The restriction on modafinil (Provigil ®) was agent in Prader -Willi p atients with the following amended to include use by the Neurology and risk factors: severe obesity, upper airway Pa lliative Care Service for specific indications. obstruction or sleep apnea, or respiratory 4. Cortisone tablets and triamcinolone acetonide infection. Males also appear to be at greater risk. spray were removed from the Formulary. 5. A protocol for the use of intravenous Topical Macrolide Immunosuppressants enoxaparin for patients undergoing percutaneous On February 14, 2005, the FDA issued alerts for coronary intervention was app roved. pime crolimus cream (Elidel ®; Novartis) and tacrolimus ointment (Protopic ®; Fujisawa). In Contributing Editor:Marcia L. Buck, Pharm.D. post -marketing reports, these agents have been Editorial Board: Kristi N. Hofer, Pharm.D. linked to lymphoma and skin cancer in children Michelle W. McCarthy, Pharm.D. and adults. Although a causal relationship has If you have comments or suggestions for future not been established, the FD A urges clinicians to issues, please contact us at Box 800674, UVA carefully weigh the risks and benefits of Health System, C harlottesville, VA 22908 or treatment. Prescribers are reminded that these by e -mail to [email protected] . This agents are not first -line therapies for atopic newsletter is also available at dermatitis and should not be used in children less www.healthsystem.vir ginia.edu/internet/pediatr than 2 years of age. FDA alerts and patient ics/pharma -news/home.cfm information sheets are available at