Atypical Antipsychotics |
According to an affidavit by Jerry F. Wells, Pharmacy Program Manager for the Florida Medicaid Program: "Determining whether a drug is eligible for reimbursement and prescribed for a purpose that is covered by Medicaid is governed by 42 U.S.C. 1396r-8, Chapter 465 F.S., and the Florida Medicaid Prescribed Drug Services Provider Handbook." Per the Florida Medicaid Prescribed Drug Services Coverage, Limitations, and Reimbursement Handbook to be reimbursed by Medicaid, a drug must be medically necessary and prescribed for medically accepted indications and dosages found in the (A) drug labeling ("labeling" means all labels and other written, printed, or graphic matter upon any article or any of its containers or wrappers, or accompanying such article), the (B) American Hospital Formulary Service Drug Information, the (C) United States Pharmacopeia-Drug Information or the (D) DRUGDEX Information System Legend A. Drug Labeling - Ages Not Approved (from FDA website) B. Supported by citation in the American Hospital Formulary Service Drug Information? C. Supported by citation in the United States Pharmacopeia-Drug Information? D. Supported by citation in the DRUGDEX Information System? (The lowdown on DRUGDEX) E. Number of Prescriptions/Refills, under 16 years of age, year 2005, paid for by Florida Medicaid - based on records provided by Florida's Agency for Health Care Administration. F. Cost to Florida Medicaid on the drug only. This does not include the cost of the office visit billed to Medicaid REFERENCES
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Summary: Abilify and Geodon are not eligible for reimbursement for any use in the pediatric population. Although Risperdal, Seroquel and Zyprexa are not approved for children by the FDA and are not generally eligible for reimbursement by Medicaid for pediatric uses, some supporting citations for specific uses were found in Drugdex as summarized below. Abilify is not FDA approved for pediatric use. There are no supporting citations in the specified drug compendia. Geodon is not FDA approved for pediatric use. There are no supporting citations in the specified drug compendia. Risperdal is FDA approved for irritability associated with autistic disorder ages 5 and above. Supporting citations were found in Drugdex favoring efficacy for Tourette syndrome, conduct disorder, oppositional defiant disorder and disruptive behavior disorder. Supporting citations were found in Drugdex with inconclusive evidence for schizophrenia, pervasive developmental disorder and bipolar disorder. A supporting citation was found in the American Hospital Formulary Service Drug Information for decreasing disruptive behavioral problems with Autistic Disorder in children 15-17 of age with the caveat that it is not curative and has not been shown to improve the core symptoms of autism such as language deficits and social withdrawal. Seroquel is not FDA approved for pediatric use. Supporting citations were found in Drugdex favoring efficacy for psychotic disorders, Tourette's disorder, schizoaffective disorder and bipolar disorder with psychotic features. Zyprexa is not FDA approved for pediatric use.Supporting citations were found in Drugdex with inconclusive evidence for bipolar disorder, developmental disabilities or psychotic disorders and schizophrenia. Olanzapine was effective in reducing hyperactivity, aggression, and hallucinations in only 3 of 12 pediatric patients (aged 5 to 17 years) with developmental disabilities or psychotic disorders. Footnotes: * - The safety and effectiveness of RISPERDAL® in pediatric patients with schizophrenia or bipolar mania have not been established. The efficacy and safety of RISPERDAL® in the treatment of irritability associated with autistic disorder were established in two 8-week, placebo-controlled trials in 156 children and adolescent patients, aged 5 to 16 years. Additional safety information was also assessed in a long-term study in patients with autistic disorder, or in short- and longterm studies in more than 1200 pediatric patients with other psychiatric disorders who were of similar age and weight, and who received similar dosages of RISPERDAL® as patients who were treated for irritability associated with autistic disorder. The safety and effectiveness of RISPERDAL® in pediatric patients with autistic disorder less than 5 years of age have not been established. 1. Autistic Disorders. Risperidone has been used for the management of severe behavioral problems associated with autistic disorders. Results of an open-label study and a separate, randomized, double-blind, placebo-controlled study indicate that risperidone is an effective treatment for decreasing some of the more disruptive behavioral problems (e.g. aggression, anger/uncooperativeness, hyperactivity, self-injurious behavior, tantrums) in children and adolescents 15-17 of age) with autistic disorder. Although not curative, pharmacologic agents, such as risperidone, generally are used to facilitate the child's adjustment and engagement in intensive, targeted educational interventions. Risperidone has not been shown to improve the core symptoms of autism (e.g. language deficits, social withdrawal) and some clinicians state the drug should be reserved for treatment of moderate to sever behavioral problems associated with autistic disorders. In addition, the possible risks of clinically important weight gain, tardive dyskinesia, withdrawal dyskinesia, and other extrapyramidal reactions associated with the drug should be considered. 2. Risperidone was beneficial in children and adolescents with pervasive developmental disorder. Starting doses of 0.25 milligrams (mg) twice daily and increased in 0.25 mg/day increments every 5 to 7 days have been used (Fisman & Steele, 1996). Optimal doses ranged from 0.75 to 6 mg daily (Perry et al, 1997; Fisman & Steele, 1996). 3. Efficacy: Pediatric, Evidence favors efficacy. Risperidone was safe and effective as a short- and long-term therapy for the reduction of severe behavior problems in children with mild or moderate intellectual disabilities. In a 6-week, randomized, double- blind, placebo controlled study, patients (ages 5 to 12 years) with below average intelligence (IQ, 36 to 84) and a diagnosis of conduct disorder, oppositional defiant disorder, or disruptive behavior disorder not otherwise specified received placebo (n=63) or risperidone (n=55) 0.02 to 0.06 milligrams (mg)/kilogram/day (mean dose, 1.16 mg/day). Efficacy of risperidone was assessed according to the change in score from baseline to endpoint on the conduct problem sub-scale of the Nisonger Child Behavior Rating Form. Patients treated with risperidone showed a significantly larger reduction in mean conduct problem sub-scale scores from baseline to endpoint as compared with placebo (-15.2 vs -6.2, respectively; p less than 0.001). Risperidone- treated patients also showed significantly better improvements than did placebo-treated patients on all other sub-scales of the Nisonger Child Behavior Rating Form. Risperidone was generally well tolerated and most adverse effects were mild to moderate, including somnolence (51%) and headache (29%). As a long-term, open-label extension, 107 patients from this controlled study received risperidone (initial, 0.01 mg/kg/day, titrated up to maximum of 0.06 mg/kg/day; mean dose 1.51 mg/day) for 48 weeks. Throughout the 48- week extension, symptom improvement was maintained in patients treated with risperidone during the controlled trial and significant symptom improvement was observed in patients who had received placebo during the controlled trial. Risperidone was generally well tolerated throughout the extension phase of the trial. Adverse events included headache (32.7%), somnolence (32.7%), rhinitis (28%), increased appetite (9.3%), weight gain (20.6%; mean increase from baseline, 5.5 kilograms), and transient, mild elevations in prolactin levels (mean maximum level, 27.6 nanograms/milliliter (ng/mL) in boys; 23.9 ng/mL in girls). Additional studies are needed to investigate the safety and efficacy of risperidone therapy beyond 1 year for the treatment of severe, disruptive behavior in pediatric patients (Findling et al, 2004; Aman et al, 2002). 4. Efficacy: Pediatric, Evidence is inconclusive. In a case series including 11 children and adolescents aged 5 to 16 years with difficult to manage mood disorders (suggestive of bipolar disorder) and aggressive behavior, 8 had therapeutic responses to risperidone 0.75 to 2.5 milligrams (mg) daily. The patients and symptoms were clinically very diverse and most were taking concurrent medications, such as mood stabilizers. No standardized psychometric instruments were used for assessment, so improvement was purely subjective. Seven patients were considered to have marked improvement and one patient was considered moderately improved. Side effects reported included sedation, weight gain and anxiety (Schreier, 1998). 5. Efficacy: Pediatric, Evidence favors efficacy. Tourette syndrome patients demonstrated a reduction in aggression in 78.5% of 28 patients and a decrease in the frequency and severity of tics in 61.7% of 28 patients. The average daily dose of risperidone was 2 milligrams daily. The tics and aggressive behavior were evaluated at baseline and 2 weeks to 4 months later (average 2 months) (Sandor & Stephens, 2000). 6. Efficacy: Pediatric, Evidence is inconclusive. Risperidone improved functionality on the Children's Global Assessment Scale in 13 out of 14 cases in an open trial of children and adolescents (ages 9 to 17 years) treated for pervasive developmental disorders. Starting doses of 0.25 milligrams (mg) twice daily were increased in 0.25 mg/day increments every 5 to 7 days to optimal doses ranging from 0.75 to 1.5 mg daily in divided doses. Improvements occurred in attention, lessening of obsessional behaviors, decrease in agitation and anxiety and improvement in social awareness (Fisman & Steele, 1996). 7. Efficacy: Pediatric, Evidence is inconclusive. Behavioral symptoms improved in a series of 6 children (ages 7 to 15) with pervasive developmental disorder. After a mean duration of treatment for 5 months (range 1-8 months) at a mean optimal dose of 2.7 milligrams (mg) daily (range 1 to 6 mg daily) in an open label trial, patient rating scores decreased, which reflected improvements in aggression, temper tantrums, and mood instability. Three patients were followed for more than 2 years, of whom one discontinued risperidone due to increased liver enzymes; one patient was switched to another new agent, and the third patient continued risperidone with good response (Perry et al, 1997) 8. Efficacy: Pediatric, Evidence is inconclusive. The results of a small study suggest that risperidone may be effective in the treatment of schizophrenia in adolescent patients. In a prospective, open-label trial, eleven patients (mean age, 17.27 years) with first-episode, early-onset schizophrenia received risperidone (initial, 0.5 milligrams (mg)/day, titrated based on clinical response and adverse effects; mean dose, 3.14 mg/day) for 6 weeks. At 6 weeks, the Positive and Negative Syndrome Scale (PANSS) total score and positive symptoms score were significantly reduced from baseline (p less than 0.01 and p less than 0.0001, respectively), however, a significant reduction was not observed for the negative symptoms score on the PANSS (p=ns). Total scores for the Brief Psychotic Rating Scale were significantly reduced from baseline to week 6 (p less than 0.01). From baseline to endpoint, Clinical Global Impression-Severity (CGI-S) scores decreased by 31.6% (p less than 0.001) and CGI-Improvement scores decreased by 45.5% (p less than 0.0001). The most common adverse events observed were weight gain (72%), somnolence (72%), depression (63%), orthostatic hypertension (45%), emotional indifference (45%), akathisia (36%). Because three patients in this study improved significantly at a dose of only 1 mg/day, the authors suggest that lower initial doses of risperidone should be utilized in adolescents, as compared with adults, in order to minimize the risk of extrapyramidal side effects. Larger, controlled studies are needed to further define the safety and efficacy of risperidone for the treatment of schizophrenia in pediatric patients (Zalsman et al, 2003). 9. Efficacy: Pediatric, Evidence is inconclusive. A 15-year old boy, with a diagnosis of simple deteriorative disorder (DSM-IV criteria or simple schizophrenia), showed significant improvement following risperidone therapy. He was started on 2 mg daily and this dosage was increased to 3 mg per day the following week. He did not report any significant side effects and showed clinical improvement. The author advocates the further study of the efficacy of risperidone in the treatment of simple schizophrenia (Hirose, 2000). 10. In a small trial (n=10) of adolescents (mean age of 13.6 years) with selected psychotic disorders, quetiapine administered in a dosage range of 50 to 800 milligrams daily led to satisfactory clinical results and similar pharmacokinetic and side effect profiles to that of adults (McConville et al, 2000). 11. Efficacy: Pediatric, Evidence favors efficacy. Quetiapine therapy was effective in the reduction of motor and phonic tics in pediatric patients with Tourette's disorder. In a prospective, open-label study (n=12) patients 8 to 16 years of age (11 boys, 1 girl) with Tourette's disorder received 8 weeks of quetiapine therapy at an initial dose of 25 milligrams (mg) daily, titrated to maximum doses of 75 mg/day (under 12 years) or 100 mg/day (12 years and older). The mean dose of quetiapine was 72.9 mg/day with a range of 50 to 100 mg/day. The mean total tic score of the Yale Global Tic Severity Scale was significantly reduced from baseline to 4 weeks (61.17 vs 30.67, respectively; p less than 0.01) and from baseline to 8 weeks (61.17 vs 24.17, respectively; p less than 0.001). All twelve patients demonstrated a 30% to 100% improvement in tic severity (mean change, 61.91; 95% CI=50.03- 73.79 for week 8). Mild, transient sedation was reported in three patients; however, extrapyramidal adverse effects and statistically significant weight gain were not observed. Larger, randomized, controlled studies are needed to confirm the safety and efficacy of quetiapine for the treatment of Tourette's disorder in children (Mukaddes & Abali, 2003). 12. Efficacy: Pediatric, Evidence favors efficacy. A small study (n=10) of adolescents ranging in age from 12.3 through 15.9 years concluded quetiapine was well tolerated and effective in the treatment of schizoaffective disorder or bipolar disorder with psychotic features. Quetiapine therapy in the open-label, rising-dose trial was initiated at 25 milligrams (mg) twice daily and reached 400 mg twice daily by day 20. The trial concluded on day 23. Quetiapine improved both positive and negative symptoms significantly (p less than 0.05) when baseline and endpoint symptoms were compared and there were no unexpected side effects (McConville et al, 2000). In an extension of this trial, all ten patients continued open-label treatment with quetiapine (initial, 800 mg/day titrated over two weeks to optimal dose; mean dose, 600 mg/day) for up to 88 weeks. Significant improvements in mean scores from baseline to endpoint were seen at all time points through week 64 for the Brief Psychiatric Rating Scale (BPRS) and Clinical Global Improvement (CGI) Severity of Illness scale (p less than 0.05). Improvements in mean scores on the Scale for Assessment of Negative Symptoms (SANS) were significant through week 52 (p less than 0.05). Quetiapine was well tolerated and adverse events were mild to moderate, with somnolence (60%), headache (50%), and pharyngitis (40%) being reported most frequently. Extrapyramidal symptoms were not observed during the trial, however, 30% of patients reported increases in mean weight and body mass index as a "mild" adverse event. Larger, controlled studies are needed to further establish long-term clinical efficacy and safety in this patient population (McConville et al, 2003). 13. Efficacy: Pediatric, Evidence is inconclusive. Olanzapine monotherapy effectively treated symptoms of psychosis, depression, and mania in a group of 23 youths diagnosed with pediatric bipolar disorder (BPD). In this open-label, 8-week study, 23 youths, 5 to 14 years old, discontinued their current BPD treatments and were started on olanzapine 2.5 milligrams (mg) per day. Olanzapine was increased by 2.5 mg/day every 3 days to a maximum dose of 20 mg/day (mean dose at endpoint was 9.6 +/- 4.3 mg per day). Lorazepam (up to 4 mg/day) and benztropine (up to 2 mg/day) were allowed as needed for rescue medication and for extrapyramidal symptoms respectively. Patients taking guanfacine or clonidine for attention deficit hyperactivity disorder (ADHD) were allowed to continue their medications, but could not adjust the dose during the study. Psychiatric symptoms were assessed at baseline and once weekly using the Young Mania Rating Scale (YMRS), the Clinical Global Impressions Severity Scale (CGI-S), the Brief Psychiatric Rating Scale (BPRS), and the Children's Depression Rating Scale (CDRS). Extrapyramidal symptoms were assessed on the same schedule using the Simpson-Argus Scale, the Barnes Akathisia Scale, and the Abnormal Involuntary Movement Scale (AIMS). Significant improvement from baseline to endpoint was noted on YMRS (62%, p less than 0.001), CGI-S (38%, p less than 0.001), and BPRS (62%, p less than 0.001). The most frequently reported adverse effects were increased appetite (n=14), somnolence (n=10), abdominal pain (n=7) and weight gain (n=7). There was no significant difference in extrapyramidal symptoms during the study, although 2 patients had treatment-emergent akathisia. There were small statistically significant decreases in hematocrit, hemoglobin, and mean cell volume and statistically significant increases in alanine transferase (ALT) and prolactin levels. One patient dropped out of the study after 6 weeks due to worsening of depressive symptoms (Frazier et al, 2001). 14. Efficacy: Pediatric, Evidence is inconclusive. A retrospective chart review demonstrated that olanzapine therapy (2.5 to 15 milligrams per day (mg/d)) was effective in reducing hyperactivity, aggression, and hallucinations in only 3 of 12 pediatric patients (aged 5 to 17 years) with developmental disabilities or psychotic disorders. Teachers or parents determined efficacy reporting improvement or worsening of symptoms. Ten of the 12 studied had previously failed other psychotropic medications. Seven patients were mentally retarded. Eight of the 12 children discontinued olanzapine after a mean duration of 50 days due to adverse effects (6), lack of positive effects (5), and exacerbated target symptoms or a combination of these issues (2). The most frequent side effects were an increased appetite and sedation. Slurred speech, tremulousness, drooling, and suicidal ideation were also reported (Demb & Roychoudhury, 2000). In another short-term study, 2 of 4 children discontinued olanzapine due to weight gain despite a positive response to therapy, while adult responders continued therapy without incident, suggesting that different age groups may exhibit diverse responses to olanzapine treatment (Potenza & McDougle, 2001). b) In a 12-week open-label pilot study of eight children, adolescents, and adults with pervasive developmental disorders, six patients treated with olanzapine were rated as much improved or very much improved on the Clinical Global Impression Scale. Patients ranged in age from 5 to 42 years and met DSM-IV criteria for pervasive developmental disorder (autistic disorder, N=5; not otherwise specified, N=3). Mean olanzapine doses were 8 milligrams per day. Significant changes from baseline were observed on the Vineland Maladaptive Behavior Scale, Rivto-Freeman Real-life Rating Scale, Self-Injurious Behavior Questionnaire, and portions of the Clinician-Rated Visual Analog Scale (all p less than 0.001). One patient dropped out at week 9 due to lack of efficacy, six patients experienced weight gain, and three patients reported sedation (Potenza et al, 1999). 15. Efficacy: Pediatric, Evidence is inconclusive. Olanzapine seemed to be effective in the treatment of children with drug-resistant schizophrenia. In an open-label study, nine patients, 11 to 14 years of age (mean age, 12.5 years), with childhood-onset schizophrenia refractory to previous treatment with at least two typical antipsychotics received olanzapine (initial, 2.5 milligrams (mg)/day, titrated to doses of 10, 15, or 20 mg per day; mean dose, 15.56 mg/day) for 12 weeks following a 2-week washout period. Significant reductions were observed at week 12 as compared with baseline in the mean scores for the Brief Psychotic Rating Scale (decreased from, 54.89 vs 37.3; p=0.03) and the Clinical Global Impression scale (decreased from 6.09 to 4.7; p less than 0.005). The Positive and Negative Syndrome Scale (PANSS) total mean score was reduced from 123.56 at baseline as compared with 96.7 at week 12 (p=0.026). In addition, the positive and negative syndrome scores showed significant reductions at week 12 as compared with baseline (p=0.048 and p=0.05, respectively). The most common adverse effects included somnolence (77%) and weight gain (100%; mean weight gain, 6.1 kilograms). No extrapyramidal side effects, dystonias, elevated hepatic transaminase levels, blood abnormalities, electrocardiogram or electroencephalogram abnormalities were observed. Larger,controlled studies are needed to further establish the safety and efficacy of olanzapine for the treatment of childhood-onset schizophrenia (Mozes et al, 2003). |