February 2012 FAQs
February 2012 FAQs
Do Stimulant Medications for Attention Deficit/Hyperactivity Disorder Cause an Increase in Cardiovascular Sudden Death?
Do Stimulant Medications for Attention Deficit/Hyperactivity Disorder Cause an Increase in Cardiovascular Sudden Death?
As the prevalence of attention deficit/hyperactivity disorder (ADHD) increases, so does the number of children prescribed medications to treat the condition. Some of the medications used to treat ADHD may result in an increase in both heart rate and blood pressure. Although the clinical significance of these increases is unknown, there has been growing concern regarding cardiovascular safety and the risk of sudden cardiac death associated with these agents, primarily stimulants, in the pediatric population.1,2 This article will review recent data on the cardiac risks associated with ADHD stimulant medications.
Attention Deficit/Hyperactivity Disorder
In 2003, ADHD was diagnosed in 7.8% of children age 4 to 17 years.3 The most recent report indicates this number has now climbed to 9.5% for children in the same age range-a 21.8% increase.4 With an expected annual increase of about 5.5%, an estimated quarter of a million children each year will be added to the number of children 4 to 17 years of age diagnosed with ADHD. While the cause of ADHD is unknown, there have been links drawn between both genetic and environmental factors.5,6Criteria for diagnosis of the disease are outlined in the Table.
Table. American Psychiatric Association DSM-IV TR criteria for diagnosis of attention deficit/hyperactivity disorder in children. 7
Symptoms of inattention
Symptoms of hyperactivity-impulsivity
Fails or is careless with detailed tasks Fidgets or squirms in seat Difficulty sustaining attention in activities Leaves seat when sitting is expected Does not listen when spoken to directly Runs or climbs in situations where it is inappropriate Does not follow through or fails to finish assigned tasks Difficulty with quiet activities Difficulty organizing tasks and activities "On the go" or acts as if "driven by a motor" Avoids, dislikes, or is reluctant for tasks that require sustained mental efforts Talks excessively Loses items necessary for tasks Blurts out answers before question is complete Easily distracted by extraneous stimuli Difficulty awaiting turn Forgetful in daily activities Interrupts or intrudes on others To be diagnosed with ADHD patient must have 6 or more of the criteria listed in any one column for > 6 months; symptoms must be present prior to age 7, are present and causing impairment in 2 or more setting (e.g., school, work, or home), and do not occur during known psychiatric disorder.
Treatment for ADHD includes behavioral-based therapy and medications.8 Behavioral therapy should start with the child's caregiver. First, caregivers should be educated about the disease and establish an incentive system to reinforce good behavior. Effective use of time outs, management of public displays of poor behavior, daily written behavior assessments from school, and learning to anticipate future negative behavior are all part of nonpharmacologic management of ADHD. These methods are most effective for children who are mildly to moderately affected by the condition.
If behavior cannot be controlled with these interventions, stimulant medications such as methylphenidate or amphetamine and nonstimulant medications such as atomoxetine have been approved by the Food and Drug Administration (FDA) for the treatment of ADHD.8 Stimulant medications work by inhibiting dopamine and norepinephrine reuptake as well as inhibiting monoamine oxidase.5,6 While many similarities exist between the stimulant medications, they modulate the various neurotransmitter pathways to slightly different degrees. This allows for several different stimulant medications to be tried even if the patient failed or was intolerant to previous stimulant medications. The stimulants have varying durations of action. Short-acting amphetamines and methylphenidate can have a duration of activity anywhere from 2 to 6 hours, while long-acting amphetamines and methylphenidate can exert an effect between 8 and 12 hours. Due to the variable duration of action of these medications, issues such as afternoon inattentiveness or insomnia at bedtime can be addressed by changing the formulation being used for treatment. If inattention is noticed in the afternoon, a long-acting formulation may benefit the patient; if insomnia is noticed, an intermediate or short-acting formulation may be used. Atomoxetine is classified as a nonstimulant (although it is frequently grouped with stimulants) and is approved for the treatment of ADHD. This medication works by inhibiting presynaptic norepinephrine transport.9 While all these medications are effective in most patients with ADHD, they have come under recent scrutiny because of the possible risk of sudden cardiac death.
Cardiovascular Adverse Effects
Sudden death has been implicated as a side effect of ADHD medications. In 2006, the FDA reviewed 34 reported cases of sudden deaths associated with stimulant medications, with a calculated rate between 0.2 and 0.5 per 100,000 for the stimulants (including atomoxetine) studied.8 These calculated rates were less than those in the general pediatric population (1.3 to 8.5 per 100,000). Although an earlier FDA advisory committee had recommended a boxed warning for stimulants and the risk of sudden death, the Pediatric Advisory Committee did not support this change.1,8
Concerns about the cardiovascular safety of stimulant medications were raised again following a 2009 study by Gould and colleagues.10 This was a matched case-controlled study highlighting the difference in sudden cardiac death between those taking stimulant ADHD medications and those who died suddenly due to nonmedical causes (e.g., motor vehicle accidents). The study was funded in part by the National Institutes of Health and the FDA. Five hundred sixty-four children and adolescents (cases) were included in the analysis with each one being matched to a control. The stimulant-treated ADHD group had 10 cases of sudden death as compared to 2 in the control group (odds ratio [OR] 7.4, 95% confidence interval [CI] 1.4-74.9; p=0.02) based on the primary analysis. The risk with stimulants remained significant after a sensitivity analysis adjusting for concomitant tricyclic antidepressant use (OR 6.4, 95% CI 1.1-67.0; p=0.03). However, no increased risk was seen when use of methylphenidate or any stimulant was confirmed by toxicological or medical examiner reports. Following this study, the FDA stated that data were still inconclusive about the risk of sudden death from stimulants, citing several study limitations.11 Subsequently, a large cohort study-Attention Deficit Hyperactivity Disorder Medication and Risk of Serious Cardiovascular Disease in Children and Youth-was conducted, sponsored by the FDA and the Agency for Healthcare Research and Quality (AHRQ). A similar study was also conducted in adults.
The Attention Deficit Hyperactivity Disorder Medication and Risk of Serious Cardiovascular Disease in Children and Youth cohort study
In 2011, Cooper and colleagues conducted a retrospective cohort study to evaluate the risk of serious cardiovascular events with medications used in the treatment of ADHD.12 Over 2 million person-years of data were analyzed by use of computerized health records dating from 1986 to 2005 from 4 major insurance companies (including Medicaid). The primary endpoint was the rate of serious cardiovascular events (sudden cardiac death, myocardial infarction, or stroke) among ADHD medication users and nonusers. Patients included in the trial were those who had used a medication for treatment of ADHD (methylphenidate, dextroamphetamine, amphetamine salts, atomoxetine, or pemoline) and were between the ages of 2 and 24 years at time of qualification. Patients with congenital heart disease were included in the study; however, those hospitalized in the previous year for myocardial infarction or stroke were excluded. Each patient case was then matched with 2 controls with no stimulant exposure (nonusers). The primary endpoint was a cardiovascular event (sudden cardiac death, myocardial infarction, or stroke).
A total of 1,200,438 children and young adults were included in the cohort, with a total of 2,579,104 person-years of follow-up. 12 This study showed there was no difference in the risk of serious cardiovascular events for nonusers, current users, and former users of stimulant medications. In the primary analysis, current users of ADHD medications yielded an adjusted hazard ratio of 0.75 (95% CI 0.31-1.85) when compared to nonusers and 1.03 (95% CI 0.57-1.89) when compared to former users. No differences were seen when each of the cardiovascular events were analyzed separately. Alternative analyses of the data were completed to compare other variables. The comparisons of new users (no ADHD medications in the year prior to the qualifying date) to nonusers or restricting the analyses to children 2 to 17 years, to patients with underlying cardiac disease, or to those without evidence of psychiatric disorders all yielded nonsignificant results. The authors concluded that even if ADHD medications caused an increase in the absolute magnitude of cardiovascular events, the increase would be so small it would be clinically insignificant.
The Attention Deficit Hyperactivity Disorder Medication and Risk of Serious Cardiovascular Disease in Young and Middle-aged Adults
A similar cohort study in adults was conducted by Habel and colleagues and the results reported in 2011.13 Electronic medical records from 4 large insurance providers were reviewed and adults aged 25 to 64 years with evidence of use of methylphenidate, amphetamine, or atomoxetine were identified. Each case (user) was matched to 2 nonusers as a control group. Use of stimulants was classified as current, indeterminate (first 89 days after end of current use), former (beginning 90 days after end of current use and ending at 364 days after last current use), remote (>364 days since last days supply), or nonuse (no current or past use with 365 days of study entry). The primary endpoint was a cardiovascular event (sudden cardiac death, myocardial infarction, or stroke). A total of 443,198 patients were enrolled in the trial, for a total of 806,182 person-years of follow-up. Similar to the study in children and youths, no difference was seen in cardiovascular risk between users and nonusers after adjustment for matching variables (relative risk [RR] 0.97, 95% CI 0.84-1.12). Additional adjustments for cardiovascular risk scores revealed a "modestly lower" risk for users versus nonusers (RR 0.83, 95% CI 0.72-0.96). Adjusted results for the individual components (myocardial infarction, sudden cardiac death, and myocardial infarction) between users and indeterminate, former, and remote users were similar, with no significant increase in risk seen.
As the number of patients diagnosed with ADHD increases it is important to ensure that medications used to treat the condition do not come with unwanted or serious side effects. The most recent data from Cooper et al analyzed over 2 million patient-years and found no difference in serious cardiovascular events between users and nonusers, contradicting previous data suggesting an increased risk. Similar results were reported by Habel and colleagues for adults taking stimulant medications for treatment of ADHD.
At this time the routine use of electrocardiograms for cardiac monitoring prior to initiating treatment with ADHD medications in otherwise healthy individuals is not recommended by the American Heart Association or the American Academy of Pediatrics.14,15 This recommendation is upheld by the current knowledge available about the cardiac risks associated with ADHD medications. However, children with cardiac abnormalities or defects who are at increased risk for cardiac sudden death should still be monitored closely. The FDA makes 2 recommendations to healthcare providers regarding stimulant use for treatment of ADHD:16
- "Stimulant products and atomoxetine should generally not be used in patients with serious heart problems, or for whom an increase in blood pressure or heart rate would be problematic."
- "Patients treated with ADHD medications should be periodically monitored for changes in heart rate or blood pressure."
Based on the available and current data, medications for ADHD are effective and safe for use in the healthy pediatric and adult populations and should not be restricted due to the concerns of cardiac events.
1. Nissen SE. ADHD drugs and cardiovascular risk. N Engl J Med. 2006;354(14):1445-1448.
2. U.S. Food and Drug Administration. Proceedings of the Pediatric Advisory Committee meeting. March 22,2006. http://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4210B-Index.htm . Accessed January 19, 2012.
3. Centers for Disease Control and Prevention (CDC). Mental health in the United States. prevalence of diagnosis and medication treatment for attention-deficit/hyperactivity disorder–United States, 2003. MMWR Morb Mortal Wkly Rep. 2005;54(34):842-847.
4. Centers for Disease Control and Prevention (CDC). Increasing prevalence of parent-reported attention-deficit/hyperactivity disorder among children-United States, 2003 and 2007. MMWR Morb Mortal Wkly Rep. 2010;59(44):1439-1443.
5. Dopheide JA, Pliszka SR. Attention-deficit-hyperactivity disorder: An update. Pharmacotherapy. 2009;29(6):656-679.
6. Dopheide J, Pliszka S. Childhood disorders In: DiPiro JT, Talbert RL, Yee CG, Matzke GR, Wells BG, Posey LM, ed. Pharmacotherapy: A Pathophysiologic Approach. 8th ed. New York, NY: McGraw-Hill Medical; 2011:1087-1099.
7. American Psychiatric Association. The Diagnostic and Statistical Manual of Mental Disorder. 4th edition, textrevision (DSM-IV-TR). Arlington, VA: American Psychiatric Association Press; 2000.
8. Pliszka S, AACAP Work Group on Quality Issues. Practice parameter for the assessment and treatment of children and adolescents with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2007;46(7):894-921.
9. Strattera [package insert]. Indianapolis, IN: Eli Lilly and Company; 2002.
10. Gould MS, Walsh BT, Munfakh JL, et al. Sudden death and use of stimulant medications in youths. Am J Psychiatry. 2009;166(9):992-1001.
11. U.S. Food and Drug Administration. Communication about an ongoing safety review of stimulant medications used in children with attention-deficit/hyperactivity disorder (ADHD). http: //www.fda.gov/drugs/DrugSafety/PostmarketDrugSafety InformationforPatientsandProviders/ DrugSafetyInformationforHeathcareProfessionals/ ucm165858.htm Accessed January 19, 2012.
12. Cooper WO, Habel LA, Sox CM, et al. ADHD drugs and serious cardiovascular events in children and young adults. N Engl J Med. 2011;365(20):1896-1904.
13. Habel LA, Cooper WO, Sox CM, et al. ADHD medications and risk of serious cardiovascular events in young and middle-aged adults. JAMA. 2011;306(24):2673-2683.
14. Perrin JM, Friedman RA, Knilans TK, Black Box Working Group, Section on Cardiology and Cardiac Surgery. Cardiovascular monitoring and stimulant drugs for attention-deficit/hyperactivity disorder. Pediatrics. 2008;122(2):451-453.
15. Vetter VL, Elia J, Erickson C, et al. Cardiovascular monitoring of children and adolescents with heart disease receiving medications for attention deficit/hyperactivity disorder [corrected]: A scientific statement from the American Heart Association Council on Cardiovascular Disease in the Young Congenital Cardiac Defects Committee and the Council on Cardiovascular Nursing. Circulation. 2008;117(18):2407-2423.
16. U.S. Food and Drug Administration. FDA drug safety communication: Safety review update of medications used to treat attention-deficit/hyperactivity disorder (ADHD) in children and young adults. http://www.fda.gov/Drugs/DrugSafety/ucm279858.htm. Accessed December 21, 2011.
Written by: Patrick Flemming, PGY1 Pharmacy Practice Resident
What are the new recommendations for management of acute uncomplicated cystitis and pyelonephritis in women?
What are the new recommendations for management of acute uncomplicated cystitis and pyelonephritis in women?
Epidemiology, risk factors, and common pathogens of acute cystitis
Acute uncomplicated cystitis, also known as uncomplicated urinary tract infection (UTI), is a common condition that affects a large number of otherwise healthy women.1 Throughout the course of a year, an estimated 10% of women will experience at least one episode, and as many as 60% will report at least one episode during their lifetime. Peak incidence occurs in college age women and recurrence of infection within 6 months to 1 year is common.
In premenopausal women, major risk factors associated with the development of acute uncomplicated cystitis include frequency of sexual intercourse and the use of spermicide.1 Genetic factors may also play a role. These differ from the risk factors in postmenopausal women, which include previous history of UTI, diabetes, and nonsecretor status.
The majority of acute uncomplicated cystitis infections are caused by Escherichia coli (75% – 95%).2 Other Enterobacteriaceae species also cause infection, but far less frequently, and infection due to other species is rare.
Diagnosis of acute uncomplicated cystitis
Clinical presentation of UTI consistently includes increased frequency of urination, dysuria, and urgency.1 Vaginal discharge, pain, or hematuria may also be present, and in older women, incontinence is common. Microbiologic diagnosis requires a pathogen count ≥ 103 colony forming units (CFU)/mL from a properly collected urine sample. However, samples from a proportion of infected women will not reach this threshold. As a result, empiric therapy should be initiated based on the presence of characteristic UTI symptoms.
Uncomplicated cystitis may in some instances progress to pyelonephritis.1 Many of the risk factors associated with UTI are also applicable to pyelonephritis, the strongest of which is sexual intercourse. While the mechanism of progression from cystitis to pyelonephritis is not fully elucidated, it is known to rely on the pathogen's transport from the bladder to the kidney. Once inside the kidney, the pathogen attaches itself to renal cells, and a host inflammatory reaction is induced. The species of pathogens that cause pyelonephritis typically mirror those that cause uncomplicated cystitis. However, the pyelonephritogenic pathogens also have virulence factors that aid them in their ascent through the urinary tract.
Diagnosis of uncomplicated pyelonephritis
The severity of symptoms at clinical presentation is variable.1 Women typically experience costoverterbral angle pain and tenderness, and fever and lower urinary tract symptoms may also be present. Severe cases may involve high fever, nausea and vomiting, intense pain, as well as systemic symptoms such as sepsis and bacteremia. Such severe symptoms may indicate the presence of obstructive, rather than uncomplicated, pyelonephritis.
Unlike uncomplicated cystitis in which treatment can be initiated upon the presence of clinical symptoms alone, the initiation of empiric therapy for uncomplicated pyelonephritis should not be initiated before a urine specimen is properly collected.1 Microbiologic diagnosis is contingent upon a pathogen count ≥ 104 CFU/mL, and initial empiric antibiotic treatment should be tailored to pathogen type and susceptibility.
International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women
In 1999, the Infectious Diseases Society of America (IDSA) published clinical practice guidelines for the treatment of patients with acute uncomplicated cystitis and pyelonephritis in non-pregnant, premenopausal women without urologic abnormalities or comorbidities.2 In the years that followed, antimicrobial resistance of pathogens that cause UTIs continued to increase and concerns developed regarding the ecological impact of antibiotic use. Furthermore, new clinical evidence has been gathered on the use of different agents and the utilization of alternate durations of therapy.
Important considerations of the guideline update
According to the authors of the update, data from 4 large in vitro surveillance studies indicate that antimicrobial resistance patterns exhibit high geographic variability.2 Therefore, the most suitable treatment may vary depending on region. The authors also point out that despite this variability, the resistance to some agents is uniformly high. For instance, the resistance rate of ampicillin was > 20% for all evaluated regions. The resistance to trimethoprim was also high in many areas regardless of whether or not it was in combination with sulfamethoxazole. In addition, although the resistance to quinolones is still relatively low, it is trending upward. Fortunately, the resistance rates to nitrofurantoin and fosfomycin remain low in all evaluated regions, and the new update reflects this in its categorization of these agents as appropriate for empiric therapy in most regions.
Other concerns regarding resistance include individual risk factors that may predispose a patient to infection with a resistant organism as well as determination of the threshold of resistance prevalence at which the risks associated with the use of an agent outweigh its potential benefit. 2 With regard to the former, the authors state that risk of resistance to trimethoprim-sulfamethoxazole may be increased with use of this medication during the preceding 3 to 6 months or by traveling to areas of endemic resistance during the preceding 3 to 6 months. Unfortunately, there is a relative dearth of evidence on other antimicrobials in relation to this topic, so no specific individual risk factors were identified other than traveling to areas of endemic resistance.
The majority of data on risk:benefit resistance thresholds is also focused on trimethoprim-sulfamethoxazole and suggests that a resistance prevalence of > 20% warrants the use of an alternative agent.2 Because data is lacking for other antimicrobials, decisions will depend on the individual practitioner. Due to the risk of rapid disease progression in cases of pyelonephritis, thresholds are set lower. As such, a threshold of 10% is given for the use of fluoroquinolones in the treatment of pyelonephritis.
Collateral damage refers to the ecologic adverse effects associated with antibiotic use, specifically, the selection of or infection with drug-resistant organisms.2 The authors cite 2 reasons as to why collateral damage is so concerning with regard to treatment of uncomplicated cystitis. The first is that the risk of disease progression is minimal, and in addition, a significant proportion of infections spontaneously resolve. Therefore, as the authors point out, differences in the clinical effectiveness of an agent with 80% efficacy versus another with 95% efficacy may be more minimal than expected. Secondly, the high incidence of uncomplicated cystitis warrants the frequent use of antibiotics, and over time, the small increments of collateral damage may in whole significantly impact the prevalence of resistant organisms. In fact, the use of broad spectrum agents including some cephalosporins and the fluoroquinolones have already been associated with increased prevalence of such organisms.
The panel of authors reviewed clinical literature published from 1998 to 2008.2 Searches were conducted on Pubmed using the following terms: cystitis or pyelonephritis, with the MESH terms: "acute uncomplicated UTI", "women", and specific antibiotic names or classes. All evaluated data came from randomized or open-label clinical trials of women with acute uncomplicated cystitis or pyelonephritis where at least one follow-up visit was conducted. Studies with patient populations that included > 10% men were excluded from review. Evaluated outcomes were early (0 to 7 days after last dose) and late (30 to 45 days after last dose) clinical cure, early microbiological cure, and adverse effects. In total, 295 articles were retrieved and 28 of these met the inclusion and exclusion criteria.
Evidence was evaluated based on the IDSA Handbook on Clinical Practice Guideline Development and rated according to the following scale (note: this scale differs from that utilized for the 1999 guidelines):2
Strength of recommendation A Good evidence to support a recommendation for or against use B Moderate evidence to support a recommendation for or against use C Poor evidence to support a recommendation Quality of evidence I Evidence from ≥ 1 properly randomized, controlled trial II Evidence from ≥ 1 well-designed clinical trial, without randomization; from cohort or case-controlled analytic studies (preferably from > 1 center); from multiple time-series; or from dramatic results from uncontrolled experiments III Evidence from opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees
Tables 1 and 2 contain the new recommendations.
Table 1. Guideline recommendations for treatment of acute uncomplicated cystitis. 2
Recommendation Rationale Appropriate choices for therapy Nitrofurantoin monohydrate/macrocrystals 100 mg twice daily for 5 days (A-I) Minimal resistance and propensity for collateral damage, comparable efficacy to 3 days of trimethoprim-sulfamethoxazole Trimethoprim-sulfamethoxazole 160/800 mg twice daily for 3 days if local resistance rates for acute uncomplicated cystitis pathogens < 20% or infecting strain is known to be susceptiple (A-I); 20% threshold is based on expert opinion (B-III)
Trimethoprim 100 mg twice daily for 3 days is preferred in some countries and regions and is considered equivalent to the recommended trimethoprim-sulfamethoxazole regimen (A-III)
Efficacy in many clinical trials Fosfomycin trometamol 3 g in a single dose (A-I) *appears to be inferior to standard short-course regimens in terms of efficacy Minimal resistance and propensity for collateral damage Alternative choices for therapy Fluoroquinolones (ofloxacin, ciprofloxacin, levofloxacin) are highly efficacious (A-I), but should be reserved for other uses and should be considered alternatives for acute cystitis treatment (A-III) High propensity for collateral damage ß-lactams (amoxicillin-clavulanate, cefdinir, cefaclor, cefpodoxime-proxetil) in 3 to 7 day regimens are appropriate when the other recommended agents cannot be used (B-I) Cephalexin may be appropriate in certain settings (B-III) Generally less efficacious with more adverse effects than other recommended agents (B-I) Agents that should NOT be used for empiric therapy Amoxicillin or ampicillin should not be used for empirical treatment (A-III) Poor efficacy and high resistance
* Fosfomycin for urinary tract infections. Med Lett Drugs Ther. 1997;39(1005):66-68.
With regard to the "appropriate choices for therapy" described above, the guideline authors suggest that therapeutic decisions within this category take into account patient allergies, compliance, local resistance patterns, cost, and availability.2
Table 2. Guideline recommendations for treatment of acute pyelonephritis. 2
Recommendation Urine culture and susceptibility test should always be performed, initial empiric therapy should be appropriately tailored (A-III) Appropriate choices for therapy in women not requiring hospitalization Oral ciprofloxacin 500 mg twice daily for 7 days +/- one-time initial 400 mg dose of IV ciprofloxacin when local fluoroquinolone resistance is < 10% (A-I) One-time dose of 1 g IV ceftriaxone or consolidated 24-hour dose of an aminoglycoside may be used in place of initial IV fluoroquinolone dose (B-III); if local fluoroquinolone resistance is > 10%, use of initial IV ceftriaxone or aminoglycoside is preferred over IV fluoroquinolone (B-III) Extended release oral ciprofloxacin 1000 mg once daily for 7 days or oral levofloxacin 750 mg once daily for 5 days when local fluoroquinolone resistance is < 10% (B-II) If local fluoroquinolone resistance is > 10%, an initial dose of IV ceftriaxone or aminoglycoside is recommended (B-III) Oral trimethoprim-sulfamethoxazole 160/800 mg twice daily for 14 days if pathogen is known to be susceptible (A-I) When susceptibility is unknown, an initial dose of IV ceftriaxone (B-II) or aminoglycoside (B-III) is recommended Less effective agents Oral ß-lactams are less effective than above agents (B-III), use of an initial dose of IV ceftriaxone (B-II) or aminoglycoside (B-III) is recommended, recommended duration remains 10 – 14 days Treatment in women requiring hospitalization Recommended IV regimens(decision should be based on pathogen susceptibility): fluoroquinolone OR aminoglycoside +/- ampicillin OR extended-spectrum cephalosporin or extended-spectrum penicillin +/- aminoglycoside OR carbapenem
The update to the International Clinical Practice Guideines for the Treatment of Acute Uncomplicated Cystitis and Pyelonephritis in Women provides revised recommendations to the original 1999 guidelines.2 Important considerations in the development of these revisions included increased antimicrobial resistance and the collateral damage stemming from antibiotic use. Major changes from the 1999 guidelines include the new classification of fluoroquinolones as an "alternative" therapy for the treatment of acute cystitis and the recommendation that nitrofurantion and fosfomycin be considered appropriate agents for treatment of this condition. In addition, more specific information regarding fluoroquinolone use in pyelonephritis is now included and recommendations are made for appropriate use of one-time intravenous antimicrobials for treatment of this indication.
Looking forward, future concerns will include gaining a better understanding of collateral damage, the effect of antibiotic use on development of resistance, and refinement of therapy in terms of agent selection and duration.
- Nicolle LE. Uncomplicated urinary tract infection in adults including uncomplicated pyelonephritis. Urol Clin North Am. 2008;35(1):1-12.
- Gupta K, Hooton TM, Naber KG, et al; for Infectious Diseases Society of America, European Society for Microbiology and Infectious Diseases. International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: A 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases. Clin Infect Dis. 2011;52(5):e103-120.
Written by: Brad Williams, PharmD Candidate, Class of 2012
What is the efficacy of atypical antipsychotics for off-label uses?
What is the efficacy of atypical antipsychotics for off-label uses?
In the United States, there are currently 10 available atypical antipsychotics – aripiprazole, asenapine, clozapine, iloperidone, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, and ziprasidone. Generally, the initial Food and Drug Administration (FDA)-approved indication for use of the atypical antipsychotics is treatment of schizophrenia.1 However, over the years, certain existing agents have received FDA approval for treatment of other psychiatric conditions including bipolar disorder and autism spectrum disorders, as well as augmentation therapy for major depression. Off-label administration of antipsychotics has been increasing.2 From 1995 to 2008, antipsychotic use for indications without FDA approval increased from 4.4 million visits to 9.0 million visits. The vast majority of this growth in off-label use is with atypical, not typical, antipsychotics. In fact, atypical use has expanded far beyond simply substitution of conventional typical antipsychotic therapy.
If the atypical antipsychotics were innocuous (i.e., had a favorable or negligible side effect profile), the increased off-label use of these agents would not be as concerning. However, the atypical antipsychotics have been associated with weight gain, type 2 diabetes mellitus, hyperlipidemia, QTc interval prolongation, and even an increased risk of death.3,4 Another concern is that these agents are being prescribed more frequently in both children and the elderly – 2 patient populations in which the adverse event profile of the atypical antipsychotics has a more serious impact.
Recently, the Agency for Healthcare Research and Quality (AHRQ) completed an updated comparative effectiveness review of the off-label use of atypical antipsychotics.1 The last such review in 2006 examined the scientific evidence on the safety, efficacy, and effectiveness of all atypical antipsychotics with the exception of clozapine (excluded due to its association with bone marrow suppression and requirement of frequent blood monitoring). The 2006 review evaluated 84 studies and found the most common off-label uses of atypicals to be treatment of depression, obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), personality disorders, Tourette's syndrome, autism, and dementia-related agitation. The report concluded "that with few exceptions, there was insufficient high-strength evidence to reach conclusions about the efficacy of any off-label uses" of the atypical antipsychotics. In addition, the authors of the report stated that strong evidence existed regarding significant safety concerns with the atypical antipsychotics including weight gain, sedation, and increased mortality, particularly among the elderly.
Since the publication of the 2006 report, new atypical antipsychotics have been approved and more studies on additional off-label uses have been completed (i.e., eating disorders, insomnia, attention-deficit hyperactivity disorder (ADHD), anxiety, substance abuse).1 Due to these changes, AHRQ decided that an update to the 2006 report was appropriate. Table 1 summarizes the efficacy findings in the 2011 AHRQ comparative effectiveness review that included data from 162 trials with efficacy outcomes.
Table 1. Efficacy summary of atypical antipsychotic off-label use.1
Efficacy data Off-label use Strength of evidence 2011 conclusions Major depressive disorder – augmentation of SSRI/SNRI therapy Moderate – risperidone, aripiprazole, quetiapine Low – olanzapine, ziprasidone Aripiprazole, quetiapine, and risperidone have efficacy as augmentation therapy. Olanzapine and ziprasidone may also have efficacy. Major depressive disorder – monotherapy Moderate Olanzapine does not have efficacy as monotherapy. Quetiapine has efficacy as monotherapy. OCD – augmentation of SSRI therapy Moderate – risperidone Low – olanzapine Risperidone has efficacy as adjunct therapy to SSRI in treatment of refractory patients. Olanzapine may also have efficacy. Quetiapine is more efficacious than ziprasidone and clomipramine as augmentation. OCD – augmentation of citalopram Low – quetiapine Very low – risperidone Quetiapine and risperidone may be efficacious as augmentation to citalopram. PTSD Moderate – risperidone Low – olanzapine Very low – quetiapine Risperidone is efficacious in reducing combat-related PTSD symptoms when used as an adjunct to primary medication. Personality disorders – borderline Low – aripiprazole Very low – quetiapine, olanzapine Olanzapine had mixed results in 7 trials. Aripiprazole was found efficacious in 2 trials and quetiapine in 1 trial. Ziprasidone was not efficacious in a single trial. Personality disorders – schizotypal Low Risperidone had mixed results in 2 small trials. Tourette's syndrome Low Risperidone is at least as efficacious as pimozide or clonidine. Anxiety Moderate Quetiapine has efficacy for generalized anxiety disorder. ADHD – no co-occurring disorders Low Risperidone may be efficacious. ADHD – mentally retarded children Low Risperidone may be superior to methylphenidate. ADHD – bipolar children Low Aripiprazole is inefficacious. Dementia High Aripiprazole, olanzapine, and risperidone have efficacy for behavioral symptoms of dementia. Eating disorders Moderate – olanzapine Low – quetiapine Olanzapine and quetiapine have no efficacy in increasing body mass in eating disorder patients. Insomnia Very low Quetiapine may be inefficacious for insomnia. Substance abuse – alcohol Moderate – aripiprazole Low – quetiapine Aripiprazole is inefficacious and quetiapine may be inefficacious in alcohol abuse. Substance abuse – cocaine Low Olanzapine is inefficacious in treating cocaine abuse/dependence. Risperidone may also be inefficacious. Substance abuse – methamphetamine Low Aripiprazole is inefficacious. Substance abuse – methadone clients Low Risperidone is an inefficacious adjunct to methadone maintenance
ADHD = attention-deficit hyperactivity disorder; OCD = obsessive-compulsive disorder; PTSD = post-traumatic stress disorder; SNRI = serotonin-norepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor.
With regard to safety, the authors of the report evaluated risks primarily in elderly and non-elderly (18 to 64 years) adult patient populations. 1 In elderly patients, adverse events of therapy included an increased risk of death, stroke, extrapyramidal symptoms, and urinary tract symptoms. In non-elderly adults, adverse events included weight gain (seen more with olanzapine), fatigue, sedation, akathisia (particularly with aripiprazole), and extrapyramidal symptoms.
In summary, although atypical antipsychotics are prescribed for a large number of off-label uses, there is moderate to high evidence of efficacy for only a few non-approved indications. The majority of the clinical evidence is for risperidone, olanzapine, and quetiapine for the off-label uses of dementia, depression, and OCD. For the most recently approved atypical antipsychotics (i.e., asenapine, iloperidone, and paliperidone), no clinical trials involving off-label use were found. In addition, few head-to-head trials among the atypical antipsychotics for off-label uses are available and data from placebo-controlled trials suggest that clinical efficacy may differ between drugs within the class.
1. Off-label use of atypical antipsychotics: an update. Executive summary. Agency for Healthcare Research and Quality Web site. http://www.effectivehealthcare.ahrq.gov/ehc/products/150/786/CER43_Off-LabelAntipsychotics_execsumm_20110928.pdf . Accessed January 18, 2012.
2. Alexander GC, Gallagher SA, Mascola A, Moloney RM, Stafford RS. Increasing off-label use of antipsychotic medications in the United States, 1995-2008. Pharmacoepidemiol Drug Saf. 2011;20(2):177-184.
3. Ucok A, Gaebel W. Side effects of atypical antipsychotics: a brief overview. World Psychiatry. 2008;7(1):58-62.
4. Schneider LS, Dagerman KS, Insel P. Risk of death with atypical antipsychotic drug treatment for dementia. JAMA. 2005;294(15):1934-1943.