The Middle East & North Africa "Gender and Development E-Brief" NEWS & ARTICLES GENDER ACTIVISM Tunisians protest to demand legal protection of women's rights Lebanese protest against anal exams on suspected gays Lebanese advocates ABAAD partner with men for gender equality United Arab Emirates - First Women's Museum Libya - Women Win 33 Seats in National Assembly Elections GENDER BASED VIOLENCE Women Refugees Flee Conflict & Gender-Based Violence in Syria Devil in the detail: abortion drug [misoprostol] banned in Turkey Iran Obstructs Women's Access to Education, Moves Closer to Segregating University Classes and Bars Women's Entry to Certain Majors And … Aggressive Enforcement by Morality Police as for the Women's Dress Code in Iran Women in Gaza: how life has changed Several arrested as sexual harassment surges in Cairo GENDER & HUMAN RIGHTS Egypt's Mursi appoints Christian man and two women for his cabinet Women-Only Industrial Cities in Saudi Arabia Women in Prison - Drama - Social & Personal Issues in Lebanon Woman Triumphs over Disability - Inspiring Video Women's Land Rights - International Land Coalition RESOURCES & CALLS
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Faculty.gordonstate.eduCHILD AND ADOLESCENT PSYCHIATRY PSYCHIATRIC TIMES 25 The Adolescent Brain Is Different Criminal Responsibility and Adolescents . . the Court has already en- lescents rarely use an insanity de- about adolescent development that dorsed the proposition that less fense, in part because the incidence are important to keep in mind when ixteen-year-old John and 2 culpability should attach to a of psychosis is considerably lower in evaluating juvenile offenders for the friends go to a club where crime committed by a juvenile adolescents than in adults, and in part they get into a verbal argu- than to a comparable crime com- because youths who are so obviously For most youths, the onset of seri- ment with 3 members of a rival gang. mitted by an adult. The basis for mentally ill as to qualify for an insan- ous violence is an adolescent phe- After receiving a particularly gross this conclusion is too obvious to ity defense are often not waived to nomenon, with a peak age of onset insult, John pulls out a handgun and require extended explanation. adult court. While it is fairly clear at around 16.5 If a person has not fires 3 shots at one of the gang mem- Inexperience, less education, that adolescents overall are less acted violently before age 21, the bers. He misses, but one of his shots and less intelligence make the blameworthy than adults, it is often likelihood he or she will ever do so hits a 15-year-old girl in the head teenager less able to evaluate the unclear in a particular case how is quite low.
and kills her. John is tried in adult consequences of his or her con- much less blameworthy a particular Serious violent offending (de- criminal court and is convicted of duct while at the same time he or adolescent is. Psychiatrists may be fined as aggravated assault, robbery, she is much more apt to be moti- called on to consult in such cases to gang fights, or rape) is surprisingly Judges and attorneys who deal vated by mere emotion or peer assist in determining the adolescent's common in adolescence: the Sur- with such cases have many questions pressure than is an adult. The geon General's report on youth vio- that involve mental health issues. reasons why juveniles are not lence noted that 30% to 40% of boys How morally responsible is the ado- trusted with the privileges and Developmental considerations and 16% to 32% of girls had com- lescent defendant? How likely is he responsibilities of an adult also of adolescent aggression mitted a serious violent offense by to offend again? How amenable is he explain why their irresponsible to rehabilitation? How will handling conduct is not as morally repre- One metaphor sometimes used in For most youths, offending is lim- this case in a particular way affect hensible as that of an adult.2(p835) discussing adolescent aggression is ited to adolescence. About 80% of other juveniles? Punishment is often that compared with adults, adoles- adolescent violent offenders stop of- seen as having 4 potential purposes: In the years since that decision, a cents have their foot on the gas and fending when they reach adulthood, retribution, incapacitation, rehabili- good deal of research has put meat have inadequate brakes. The litera- tation, and deterrence. Mental health on the bones of Justice Stevens' ture reveals a number of key findings (Please see The Adolescent Brain, page 26) experts potentially have something characterization of adolescent be-to say that is relevant to each of these havior and on the neurobiology that Mental health issues in purposes—both at the level of the in- underlies it. In the 2005 case Roper v punishing adolescents dividual defendant and at the level of Simmons, the Supreme Court found developing social policy for handling that the execution of minors was offending adolescents (Table 1).
cruel and unusual punishment and Purpose of punishment Mental health issue thus unconstitutional, basing a re- Retribution Culpability duced culpability analysis on 3 as- This past June, the US Supreme pects of adolescence: immaturity Likelihood of recidivism Court decided the case Miller v Ala with impulsivity, vulnerability to ad- Amenability to treatment bama, in which the Court held 5 to 4 verse environmental factors, and the that youths younger than 18 years fact that an adolescent's character is Effect on thinking of potential offenders could not be given mandatory life not well formed.3(pp569-570) In 2010, us-without parole.1 This decision does ing much of the reasoning of Roper v leave open the possibility of a life Simmons, the Court found it uncon- Factors to consider in assessing sentence without parole for a youth, stitutional to sentence adolescents to adolescent culpability9 but only after a judge or jury deter- life without parole for crimes less mines that such a sentence is suitable than murder.4 In cases involving less • Appreciation of wrongfulness in that particular case.
serious charges, psychiatric assess- The Miller v Alabama decision is ments may be used in arguing that • Ability to conform to law the latest in a line of cases going a case should be tried in juvenile • Developmental course of aggression and impulsivity back 25 years in which the Supreme court—an outcome that usually re- Court has increasingly limited the sults in less severe penalties.
• Immaturity: IQ; psychosocial maturity, including time sense, susceptibility to situations in which minors may re- peer pressure, risk taking, ability to empathize ceive the most extreme punishments, Criminal responsibility of based largely on a theory of reduced • Environmental circumstances culpability. In Thompson v Okla Because children are typically con- • Peer group norms homa, the Supreme Court held that sidered insufficiently responsible, it was unconstitutional to impose the their cases are not heard in adult • Out-of-character action death penalty on defendants who court, while adults are legally pre- • Incomplete personality development were younger than 16 years when sumed fully responsible. Adoles-they committed their offenses.2 The cents lie somewhere in the middle of • Mental illness basic logic was laid out by Justice this continuum.
Stevens, who wrote for the majority A successful insanity defense ne- • Reactive attitudes toward the offense gates criminal responsibility. Ado- 1211PT206400ASH.indd 25 26 PSYCHIATRIC TIMES CHILD AND ADOLESCENT PSYCHIATRY CHILD AND ADOLESCENT PSYCHIATRY The Adolescent Brain inal behavior into adulthood have level offenses (vandalism and shop- adolescent crime tends to be more Continued from page 25
different developmental patterns: lifting), progresses to nonconfron- impulsive than adult crime.8 Adoles- those who persist in criminal activ- tational offenses (theft), and then to cent culpability is a complex con- and fewer than half of those who do ity tend to have a worsening of im- violent offenses (aggravated assault cept. A number of factors should be continue have an adult career of vio- pulsiveness and ability to suppress and rape).5 Delinquents do not begin assessed in evaluating the criminal lence that lasts longer than 2 years.6 their aggression, rather than the im- their antisocial activities by shooting responsibility of an adolescent of- There is little evidence to suggest provement that typically comes with fender (Table 2).9
that one can accurately predict who maturation.7 Finally, adolescent crime is differ- will go on to offend as an adult and Serious violence is typically the ent from adult crime. Adolescents Adolescent immaturity who will not. Some data suggest that end of a developmental progression typically offend in groups, while The area that has received the most delinquents who continue their crim- of offenses that begins with low- adults typically offend alone. Also, attention is adolescent immaturity ATIENT RUNNING UP
THE SOUND OF YOUR P
AGAINST SCHIZOPHRENIA SYMPTOMS.FANAPT MAY HELP.
• FANAPT signiﬁ cantly improved overall symptoms in 2 clinical trials, as measured by the Positive
and Negative Syndrome Scale (PANSS) (4-week trial) and the Brief Psychiatric Rating Scale (BPRS) (6-week trial)1 Tolerability
• Discontinuation rates due to adverse events were similar for FANAPT (5%) and placebo (5%)1*
The most common adverse reactions were dizziness, dry mouth, fatigue, nasal congestion, somnolence, tachycardia, orthostatic hypotension, and weight increase1 EPS†/Akathisia
• Incidence of EPS and akathisia was similar to placebo1*
FANAPT is an atypical antipsychotic agent indicated for the treatment of schizophrenia in adults. In choosing among treatments, prescribers should consider the ability of FANAPT to prolong the QT interval and the use of other drugs ﬁ rst. Prescribers should also consider the need to titrate FANAPT slowly to avoid orthostatic hypotension, which may lead to delayed effectiveness compared to some other drugs that do not require similar titration.
IMPORTANT SAFETY INFORMATION
WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of
death. Analysis of seventeen placebo-controlled trials (modal duration 10 weeks), largely in patients taking
atypical antipsychotic drugs, revealed a risk of death in the drug-treated patients of between 1.6 to 1.7 times
the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of
death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group.
Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart
failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to
atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent
to which the ﬁ ndings of increased mortality in observational studies may be attributed to the antipsychotic drug
as opposed to some characteristic(s) of the patients is not clear. FANAPT is not approved for the treatment of
patients with dementia-related psychosis.
Please see additional Important Safety Information and brief summary of Prescribing Information,
including Boxed WARNING, on adjacent pages.
(Please see XXXXXXXXX, page 26) 1211PT206400ASH.indd 26 CHILD AND ADOLESCENT PSYCHIATRY CHILD AND ADOLESCENT PSYCHIATRY PSYCHIATRIC TIMES 27 and impulsivity. Cauffman and self-regulation have been used to wards and lack the impulse control the hypothesis that the decrease in Steinberg10 found that lower levels of argue for mitigation of adolescent of mature adults.13-15 These findings impulsivity seen with aging into ear- psychosocial maturity correlated culpability.11,12 show that the limbic system, respon- ly adulthood is due to delayed matu- with more decisions to commit anti- Over the past decade, there has sible for emotions, matures before ration of the prefrontal cortex (the social acts. Moreover, psychosocial also been considerable research on the prefrontal cortex, which is re- brakes) and its ability to control im- maturity was a more significant pre- adolescent brain development. The sponsible for executive functioning. pulses emanating from the limbic dictor than age. Considerable re- findings are consistent with a bio- Furthermore, the tracts between the system (the gas). Such findings pro- search has further refined our views logical explanation for the behavior- prefrontal cortex and the limbic vide a biological substrate to the ar- of components of adolescent judg- al findings in adolescence and point system continue to be myelinated gument that adolescents are less ma- ment; such factors as risk-taking, to an evolving understanding of why reward-seeking, impulsivity, and adolescents overvalue immediate re- These findings are consistent with (Please see The Adolescent Brain, page 28) Metabolics
• Mean change in weight from baseline at end point for FANAPT patients was 2.1 kg across all
short-term and long-term trials1‡ • The majority of patients taking FANAPT 24 mg/day did not experience a shift from normal to high in fasting lipid measurements in a 4-week study1§ Undesirable alterations in lipids have been observed in patients treated with atypical Dosing ﬂ exibility
• Efﬁ cacy demonstrated at 6 mg twice daily, with dosing ﬂ exibility up to 12 mg twice daily1
START YOUR PATIENTS ON FANAPT — FOR FREE.
FANAPT vouchers are good for 34 days (68 tablets) of FANAPT. Vouchers are
available for download at www.FANAPT.com.
*Based on pooled data from 4 placebo-controlled, 4- or 6-week, ﬁ xed- or ﬂ exible-dose studies.
‡ Percentage of patients who experienced weight gain of ≥7% of body weight was 12% for FANAPT 10-16 mg/day and 18% for FANAPT 20-24 mg/day versus 4% for placebo.
§3.6% of patients taking FANAPT 24 mg/day experienced a shift from normal (<200 mg/dL) to high (≥240 mg/dL) in fasting total cholesterol versus 1.4% of patients taking placebo. 10.1% of patients taking FANAPT 24 mg/day experienced a shift from normal (<150 mg/dL) to high (≥200 mg/dL) in fasting triglycerides versus 8.3% of patients taking placebo.
IMPORTANT SAFETY INFORMATION
Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all atypical antipsychotic drugs have been shown to produce some metabolic changes, each drug in the class has its own speciﬁ c risk proﬁ le.
FANAPT® is a registered trademark of Vanda Pharmaceuticals Inc. and is used by Novartis Pharmaceuticals Corporation under license.
FANAPT® is licensed by Novartis Pharmaceuticals Corporation from Titan Pharmaceuticals, Inc.
Reference: 1. FANAPT [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp;
1211PT206400ASH.indd 27 28 PSYCHIATRIC TIMES CHILD AND ADOLESCENT PSYCHIATRY CHILD AND ADOLESCENT PSYCHIATRY The Adolescent Brain crime is planned and predatory, the Environmental circumstances creased culpability: "[Adolescents'] Continued from page 27
impulsivity argument may not ap- An adolescent typically has no own vulnerability and comparative ply. In some cases, historical data choice in such matters as what lack of control over their immediate ture than adults.
from collateral sources (such as re- neighborhood to live in; what school surroundings mean juveniles have a In a particular case, the strongest ports of persons who know the de- to attend; whom to live with; or greater claim than adults to be for- evidence for impulsivity usually fendant, previous mental health as- whether to continue to live in abu- given for failing to escape negative comes from the details of the crime sessments and treatment, and prior sive, neglectful, or dangerous cir- influences in their whole environ- itself. If the crime can be shown criminal activities) may provide cumstances. Also, he is not respon- ment."3 There is strong statistical to have occurred in the heat of the corroborative information regarding sible for the economic circumstances support linking adolescent crime moment, as in the example given the defendant's impulsi vity in other of his family. The Supreme Court has rates to conditions of socioeconomic above, impulsivity is clear. If the situations.
recognized this as a basis for de- IMPORTANT SAFETY INFORMATION
Hyperglycemia and Diabetes: Hyperglycemia, in some cases extreme
WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH
and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics Elderly patients with dementia-related psychosis treated with
including FANAPT. Patients with an established diagnosis of, or with antipsychotic drugs are at an increased risk of death. Analysis of
risk factors for, diabetes mel itus who are starting treatment with seventeen placebo-controlled trials (modal duration 10 weeks),
atypical antipsychotics should undergo fasting blood glucose testing largely in patients taking atypical antipsychotic drugs, revealed a risk
at the beginning of treatment and periodically during treatment. Any of death in the drug-treated patients of between 1.6 to 1.7 times the
patient treated with atypical antipsychotics should be monitored for risk of death in placebo-treated patients. Over the course of a typical
symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, 10-week controlled trial, the rate of death in drug-treated patients
and weakness. Patients who develop symptoms of hyperglycemia was about 4.5%, compared to a rate of about 2.6% in the placebo
during treatment with atypical antipsychotics should undergo fasting group. Although the causes of death were varied, most of the deaths
blood glucose testing. In some cases, hyperglycemia has resolved appeared to be either cardiovascular (e.g., heart failure, sudden
when the atypical antipsychotic was discontinued; however, some death) or infectious (e.g., pneumonia) in nature. Observational studies
patients required continuation of antidiabetic treatment despite suggest that, similar to atypical antipsychotic drugs, treatment with
discontinuation of the antipsychotic. conventional antipsychotic drugs may increase mortality. The extent
Dyslipidemia: Undesirable alterations in lipids have been observed
to which the ﬁndings of increased mortality in observational studies
in patients treated with atypical antipsychotics. may be attributed to the antipsychotic drug as opposed to some
characteristic(s) of the patients is not clear. FANAPT is not approved
Weight Gain: Weight gain has been observed with atypical
antipsychotic use. Clinical monitoring of weight is recommended. for the treatment of patients with dementia-related psychosis.
Seizures: As with other antipsychotics, FANAPT should be used cautiously
Contraindications: FANAPT is contraindicated in individuals with a known
in patients with a history of seizures or with conditions that potential y hypersensitivity reaction to the product.
lower seizure threshold, e.g., Alzheimer's dementia.
Cerebrovascular Adverse Events, Including Stroke: In placebo-control ed
Orthostatic Hypotension and Syncope: FANAPT can induce orthostatic
trials with risperidone, aripiprazole, and olanzapine in elderly patients with hypotension associated with dizziness, tachycardia, and syncope. dementia, there was a higher incidence of cerebrovascular adverse events Therefore FANAPT must be titrated as directed. FANAPT should be (cerebrovascular accidents and transient ischemic attacks) including used with caution in patients with known cardiovascular disease, fatalities compared to placebo-treated patients. FANAPT is not approved cerebrovascular disease, or conditions that predispose the patient to for treatment of patients with dementia-related psychosis.
hypotension. Monitoring of orthostatic vital signs should be considered QT Prolongation: FANAPT was associated with QTc prolongation of 9 msec
in patients who are vulnerable to hypotension.
at an iloperidone dose of 12 mg twice daily. The effect of FANAPT on Leukopenia, Neutropenia, and Agranulocytosis: In clinical trial and
the QT interval was augmented by the presence of CYP450 2D6 or 3A4 postmarketing experience with antipsychotic agents, events of leukopenia/ metabolic inhibition (e.g., paroxetine 20 mg once daily and ketoconazole neutropenia have been reported temporally. Agranulocytosis (including 200 mg twice daily, respectively). Under conditions of metabolic inhibition death) has also been reported. Patients with a preexisting low white blood for both 2D6 and 3A4, FANAPT 12 mg twice daily was associated with cel count or a history of drug-induced leukopenia/neutropenia should have a mean QTcF increase from baseline of about 19 msec. No cases of their complete blood count (CBC) monitored frequently during the ﬁrst few torsades de pointes or other severe cardiac arrhythmias were observed months of therapy and should discontinue FANAPT at the ﬁrst sign of a during the premarketing clinical program. FANAPT should be avoided in decline in WBC in the absence of other causative factors.
combination with other drugs that are known to prolong QTc. FANAPT should also be avoided in patients with congenital long QT syndrome Hyperprolactinemia: As with other drugs that antagonize dopamine
and in patients with history of cardiac arrhythmias, and in circumstances D2 receptors, FANAPT elevates prolactin levels. Galactorrhea, that may increase risk of torsades de pointes and/or sudden death in amenorrhea, gynecomastia, and impotence have been reported with association with use of drugs that prolong the QTc interval. Use caution and consider dose modiﬁcation. Patients being considered for FANAPT Body Temperature Regulation: Appropriate care is advised when prescribing
treatment who are at risk for signiﬁcant electrolyte disturbances should FANAPT for patients who will be experiencing conditions which may have baseline serum potassium and magnesium measurements with contribute to an elevation in core body temperature, e.g., exercising periodic monitoring. FANAPT should be discontinued in patients who strenuously, exposure to extreme heat, receiving concomitant medication are found to have persistent QTc measurements >500 msec.
with anticholinergic activity, or being subject to dehydration.
Neuroleptic Malignant Syndrome (NMS): NMS, a potential y fatal symptom
Dysphagia: Esophageal dysmotility and aspiration have been associated
complex, has been reported in association with administration of with antipsychotic drug use. Aspiration pneumonia is a common cause antipsychotic drugs. NMS can cause hyperpyrexia, muscle rigidity, altered of morbidity and mortality in elderly patients, in particular those with mental status, irregular pulse or blood pressure, tachycardia, diaphoresis, advanced Alzheimer's dementia. FANAPT and other antipsychotic drugs and cardiac dysarrhythmia. Additional signs may include elevated should be used cautiously in patients at risk for aspiration pneumonia.
creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal Suicide: The possibility of a suicide attempt is inherent in psychotic
failure. Management should include immediate discontinuation of the il ness, and close supervision of high-risk patients should accompany antipsychotic drugs and other drugs not essential to concurrent therapy, drug therapy. Prescriptions for FANAPT should be written for the smal est intensive symptomatic treatment and medical monitoring, and treatment quantity of tablets in order to reduce the risk of overdose.
of any concomitant serious medical problems. If antipsychotic treatment is required after recovery from NMS, reintroduction should be careful y Priapism: Three cases of priapism have been reported in the premarketing
considered and patient should be careful y monitored.
FANAPT program. Severe priapism may require surgical intervention.
Tardive Dyskinesia (TD): Risk of developing tardive dyskinesia, and the
Cognitive and Motor Impairment: FANAPT, like other antipsychotics, has the
likelihood that it wil become irreversible, may increase as the duration potential to impair judgment, thinking, or motor skil s. Patients should be of treatment and the total cumulative dose increases. However, the cautioned about operating hazardous machinery, including automobiles, syndrome can develop, although much less commonly, after relatively brief until they are reasonably certain that therapy with FANAPT does not affect treatment periods at low doses. Prescribing should be consistent with the them adversely.
need to minimize TD. If signs and symptoms appear, drug discontinuation Commonly observed adverse events: Commonly observed adverse reactions
should be considered. (incidence ≥5% and twofold greater than placebo) were: dizziness, dry Metabolic Changes: Atypical antipsychotic drugs have been associated
mouth, fatigue, nasal congestion, orthostatic hypotension, somnolence, with metabolic changes that may increase cardiovascular/cerebrovascular tachycardia, and weight increase.
risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all atypical antipsychotic drugs have been shown to produce some metabolic changes, each drug in the class has its own Pregnancy: FANAPT is Pregnancy Category C.
speciﬁc risk proﬁle. Hepatic Impairment: FANAPT is not recommended for patients with
Drug Interactions: Given the primary CNS effects of FANAPT, caution
should be used when it is taken in combination with other central y acting drugs and alcohol. FANAPT has the potential to enhance the effect of certain antihypertensive agents. Coadministration of FANAPT with potential CYP2D6 inhibitors (e.g., ﬂuoxetine, paroxetine) and potential CYP3A4 inhibitors (e.g., ketoconazole) should be done with caution. FANAPT dose should be reduced by one-half. Cautiously approach coadministration of drugs mainly eliminated via CYP3A4 with FANAPT. Please see brief summary of Prescribing Information, including Boxed WARNING, on adjacent pages.
1211PT206400ASH.indd 28 CHILD AND ADOLESCENT PSYCHIATRY CHILD AND ADOLESCENT PSYCHIATRY PSYCHIATRIC TIMES 29 Ascertaining the socioeconomic Peer group effects where it is necessary to appear tough whether peer group effects were background of a juvenile offender If you want to know how much trou to avoid being seen as weak and significant. In some cases, there can often be done from collateral ble an adolescent is getting into, ask therefore vulnerable to attack. Such may be characteristics in the defen sources. Assessing the effect of ad how much trouble his friends are environments decrease responsibil dant's history that suggest suscepti verse circumstances on an individual getting into. Most adolescent offend ity when the violence, while consid bility to peer pressure as well, such defendant is more complex, but there ing occurs in groups, and adolescents ered wrong by society, is considered as when an intellectually disabled is nevertheless considerable social are especially vulnerable to peer right in the subculture where a youth youth has a history of being easily science data on the effects of factors pressure. Gang membership is one lives.
talked into unwise actions by delin such as abuse, neglect, and family of the leading risk factors for pred The details of the crime, particu quent peers.
disruption that the expert may draw atory violence. Peer group ef fects larly if the crime involved multiple on to help justify his conclusions.
are amplified in street subcultures, perpetrators, provide evidence as to (Please see The Adolescent Brain, page 30) FANAPT® (iloperidone) tablets
prolong the QTc interval (e.g., pentamidine, levomethadyl acetate, Initial U.S. Approval: 2009
methadone). FANAPT should also be avoided in patients with congenital BRIEF SUMMARY: Please see package insert for full prescribing information.
long QT syndrome and in patients with a history of cardiac arrhythmias.
Certain circumstances may increase the risk of torsade de pointes and/or WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS
sudden death in association with the use of drugs that prolong the QTc WITH DEMENTIA-RELATED PSYCHOSIS
interval, including (1) bradycardia; (2) hypokalemia or hypomagnesemia; (3) concomitant use of other drugs that prolong the QTc interval; and Elderly patients with dementia-related psychosis treated with anti -
(4) presence of congenital prolongation of the QT interval; (5) recent acute psychotic drugs are at an increased risk of death. Analysis of seventeen
myocardial infarction; and/or (6) uncompensated heart failure.
placebo-controlled trials (modal duration 10 weeks), largely in patients
Caution is warranted when prescribing FANAPT with drugs that inhibit taking atypical antipsychotic drugs, revealed a risk of death in the drug-
FANAPT metabolism [see Drug Interactions (7.1)], and in patients with treated patients of between 1.6 to 1.7 times the risk of death in placebo-
reduced activity of CYP2D6 [see Clinical Pharmacology (12.3) in the full treated patients. Over the course of a typical 10-week controlled trial,
the rate of death in drug-treated patients was about 4.5%, compared to
a rate of about 2.6% in the placebo group. Although the causes of death
It is recommended that patients being considered for FANAPT treatment were varied, most of the deaths appeared to be either cardiovascular
who are at risk for significant electrolyte disturbances have baseline serum (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in
potassium and magnesium measurements with periodic monitoring.
Hypokalemia (and/or hypomagnesemia) may increase the risk of QT prolon- Observational studies suggest that, similar to atypical antipsychotic
gation and arrhythmia. FANAPT should be avoided in patients with histories drugs, treatment with conventional antipsychotic drugs may increase
of significant cardiovascular illness, e.g., QT prolongation, recent acute mortality. The extent to which the findings of increased mortality in
myocardial infarction, uncompensated heart failure, or cardiac arrhythmia.
observational studies may be attributed to the antipsychotic drug as
FANAPT should be discontinued in patients who are found to have persistent opposed to some characteristic(s) of the patients is not clear. FANAPT
QTc measurements >500 ms.
is not approved for the treatment of patients with Dementia-Related
If patients taking FANAPT experience symptoms that could indicate the Psychosis. [see Warnings and Precautions (5.1)]
occurrence of cardiac arrhythmias, e.g., dizziness, palpitations, or syncope, the prescriber should initiate further evaluation, including cardiac monitoring.
1 INDICATIONS AND USAGE
5.3 Neuroleptic Malignant Syndrome (NMS)
FANAPT® tablets are indicated for the treatment of adults with schizophrenia.
A potentially fatal symptom complex sometimes referred to as Neuroleptic Efficacy was established in two short-term (4- and 6-week) placebo- and Malignant Syndrome (NMS) has been reported in association with adminis- active-controlled studies of adult patients with schizophrenia [see Clinical tration of antipsychotic drugs. Clinical manifestations include hyperpyrexia, Studies (14) in the full prescribing information].
muscle rigidity, altered mental status (including catatonic signs) and evi- When deciding among the alternative treatments available for this condi- dence of autonomic instability (irregular pulse or blood pressure, tachy - tion, the prescriber should consider the finding that FANAPT is associated cardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include with prolongation of the QTc interval [see Warnings and Precautions (5.2)].
elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and Prolongation of the QTc interval is associated in some other drugs with the acute renal failure.
ability to cause torsade de pointes-type arrhythmia, a potentially fatal poly- The diagnostic evaluation of patients with this syndrome is complicated. In morphic ventricular tachycardia which can result in sudden death. In many arriving at a diagnosis, it is important to identify cases in which the clinical cases this would lead to the conclusion that other drugs should be tried presentation includes both serious medical illness (e.g., pneumonia, sys- first. Whether FANAPT will cause torsade de pointes or increase the rate of temic infection, etc.) and untreated or inadequately treated extrapyramidal sudden death is not yet known.
signs and symptoms (EPS). Other important considerations in the differen- Patients must be titrated to an effective dose of FANAPT. Thus, control of tial diagnosis include central anticholinergic toxicity, heat stroke, drug fever, symptoms may be delayed during the first 1 to 2 weeks of treatment com- and primary central nervous system (CNS) pathology.
pared to some other antipsychotic drugs that do not require a similar titration.
The management of this syndrome should include: (1) immediate discon- Prescribers should be mindful of this delay when selecting an anti psychotic tinuation of the antipsychotic drugs and other drugs not essential to drug for the treatment of schizophrenia [see Dosage and Administration concurrent therapy, (2) intensive symptomatic treatment and medical moni- (2.1) and Clinical Studies (14) in the full prescribing information].
toring, and (3) treatment of any concomitant serious medical problems for The effectiveness of FANAPT in long-term use, that is, for more than 6 weeks, which specific treatments are available. There is no general agreement has not been systematically evaluated in controlled trials. Therefore, the about specific pharmacological treatment regimens for NMS.
physician who elects to use FANAPT for extended periods should periodically If a patient requires antipsychotic drug treatment after recovery from NMS, re-evaluate the long-term usefulness of the drug for the individual patient the potential reintroduction of drug therapy should be carefully considered.
[see Dosage and Administration (2.3) in the full prescribing information].
The patient should be carefully monitored, since recurrences of NMS have 4 CONTRAINDICATIONS
FANAPT is contraindicated in individuals with a known hypersensitivity 5.4 Tardive Dyskinesia
reaction to the product. Reactions have included pruritus and urticaria.
Tardive dyskinesia is a syndrome consisting of potentially irreversible, 5 WARNINGS AND PRECAUTIONS
involuntary, dyskinetic movements, which may develop in patients treated 5.1 Increased Risks in Elderly Patients with Dementia-Related Psychosis
with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible Elderly patients with dementia-related psychosis treated with atypical
to rely on prevalence estimates to predict, at the inception of antipsychotic antipsychotic drugs are at an increased risk of death compared to
treatment, which patients are likely to develop the syndrome. Whether antipsy- placebo. FANAPT is not approved for the treatment of patients with
chotic drug products differ in their potential to cause tardive dyskinesia is dementia-related psychosis [see Boxed Warning].
Cerebrovascular Adverse Events, Including Stroke
The risk of developing tardive dyskinesia and the likelihood that it will In placebo-controlled trials with risperidone, aripiprazole, and olanzapine become irreversible are believed to increase as the duration of treatment in elderly patients with dementia, there was a higher incidence of cerebro - and the total cumulative dose of antipsychotic administered increases.
vascular adverse events (cerebrovascular accidents and transient ischemic However, the syndrome can develop, although much less commonly, after attacks) including fatalities compared to placebo-treated patients. FANAPT relatively brief treatment periods at low doses.
is not approved for the treatment of patients with dementia-related psychosis There is no known treatment for established cases of tardive dyskinesia, [see Boxed Warning].
although the syndrome may remit, partially or completely, if antipsychotic 5.2 QT Prolongation
treatment is withdrawn. Antipsychotic treatment itself, however, may sup- In an open-label QTc study in patients with schizophrenia or schizoaffective press (or partially suppress) the signs and symptoms of the syndrome and disorder (n=160), FANAPT was associated with QTc prolongation of 9 msec thereby may possibly mask the underlying process. The effect that sympto- at an iloperidone dose of 12 mg twice daily. The effect of FANAPT on the matic suppression has upon the long-term course of the syndrome is QT interval was augmented by the presence of CYP450 2D6 or 3A4 meta- bolic inhibition (paroxetine 20 mg once daily and ketoconazole 200 mg Given these considerations, FANAPT should be prescribed in a manner that twice daily, respectively). Under conditions of metabolic inhibition for both is most likely to minimize the occurrence of tardive dyskinesia. Chronic 2D6 and 3A4, FANAPT 12 mg twice daily was associated with a mean QTcF antipsychotic treatment should generally be reserved for patients who suf- increase from baseline of about 19 msec.
fer from a chronic illness that (1) is known to respond to antipsychotic No cases of torsade de pointes or other severe cardiac arrhythmias were drugs, and (2) for whom alternative, equally effective, but potentially less observed during the pre-marketing clinical program. harmful treatments are not available or appropriate. In patients who do The use of FANAPT should be avoided in combination with other drugs that require chronic treatment, the smallest dose and the shortest duration of are known to prolong QTc including Class 1A (e.g., quinidine, procainamide) treatment producing a satisfactory clinical response should be sought. The or Class III (e.g., amiodarone, sotalol) antiarrhythmic medications, anti - need for continued treatment should be reassessed periodically. psychotic medications (e.g., chlorpromazine, thioridazine), antibiotics (e.g., gatifloxacin, moxifloxacin), or any other class of medications known to 1211PT206400ASH.indd 29 30 PSYCHIATRIC TIMES CHILD AND ADOLESCENT PSYCHIATRY CHILD AND ADOLESCENT PSYCHIATRY The Adolescent Brain The fact that personality frequently nal aspects of antisocial personality, useful in sentencing an individual Continued from page 29
changes from adolescence to adult- such as exploitativeness and severe delinquent.17 In addition to the clini- hood has repeatedly been cited by deficits in empathy and guilt) is an cal interview, a variety of personality Unfinished character the Supreme Court as one of the rea- especially worrisome personality tests can be used to buttress conclu- sons why adolescents have lessened type when seen in adolescents. Nev- sions about the defendant's present We expect that a 15-year-old ado- ertheless, psychopathy diagnosed in lescent imprisoned for life will not Antisocial personality, by DSM adolescence is not highly predictive be the same person at age 45; the convention, cannot be diagnosed un- of adult psychopathy: the reported Mental illness same is not true for someone con- til age 18. Psychopathy (a non-DSM correlation of r = 0.31, while signifi- It is well established that among de- victed as an adult whose personality diagnosis, but one used in forensic cant, is not strong enough to account linquent youths, the rate of mental is likely to remain relatively stable. psychiatry to get at the more inter- for enough of the variance to be very disorders across the entire range of If signs and symptoms of tardive dyskinesia appear in a patient on FANAPT, Table 3. Change in Fasting Lipids (cont)
drug discontinuation should be considered. However, some patients may require treatment with FANAPT despite the presence of the syndrome.
5.5 Metabolic Changes
Atypical antipsychotic drugs have been associated with metabolic changes Proportion of Patients with Shifts
that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain [see Normal to High
Patient Counseling Information (17.3) in the full prescribing information].
(<200 mg/dL to ≥240 mg/dL)
While all atypical antipsychotic drugs have been shown to produce some metabolic changes, each drug in the class has its own specific risk profile. Normal to High
Hyperglycemia and Diabetes Mellitus
(<100 mg/dL to ≥160 mg/dL)
Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics including FANAPT. Assessment of the relationship Normal to Low
between atypical antipsychotic use and glucose abnormalities is compli- (≥40 mg/dL to <40 mg/dL)
cated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mel- Normal to High
litus in the general population. Given these confounders, the relationship (<150 mg/dL to ≥200 mg/dL)
between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies Pooled analyses of cholesterol and triglyceride data from clinical studies suggest an increased risk of treatment-emergent hyperglycemia-related including longer term trials are shown in Tables 4 and 5.
adverse events in patients treated with the atypical antipsychotics included Table 4: Change in Cholesterol
in these studies. Because FANAPT was not marketed at the time these stud- ies were performed, it is not known if FANAPT is associated with this Mean Change from Baseline (mg/dL)
Patients with an established diagnosis of diabetes mellitus who are started FANAPT 10-16 mg/day on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obes - FANAPT 20-24 mg/day ity, family history of diabetes) who are starting treatment with atypical Table 5: Change in Triglycerides
antipsychotics should undergo fasting blood glucose testing at the begin- ning of treatment and periodically during treatment. Any patient treated Mean Change from Baseline (mg/dL)
with atypical antipsychotics should be monitored for symptoms of hyper- 3-6 months
glycemia including polydipsia, polyuria, polyphagia, and weakness. Patients FANAPT 10-16 mg/day -8.9 (N=726) -17.7 (N=428) who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some FANAPT 20-24 mg/day cases, hyperglycemia has resolved when the atypical antipsychotic was dis- continued; however, some patients required continuation of antidiabetic treatment despite discontinuation of the suspect drug.
Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.
Data from a 4-week, fixed-dose study in adult subjects with schizophrenia, in which fasting blood samples were drawn, are presented in Table 1. Across all short- and long-term studies, the overall mean change from base- line at endpoint was 2.1 kg.
Table 1. Change in Fasting Glucose
Changes in body weight (kg) and the proportion of subjects with ≥7% gain in body weight from four placebo-controlled, 4- or 6-week, fixed- or flexible- 24 mg/day
dose studies in adult subjects are presented in Table 6.
Mean Change from Baseline (mg/dL)
Table 6. Change in Body Weight
Serum Glucose Change from Baseline
10-16 mg/day 20-24 mg/day
Proportion of Patients with Shifts
Serum Glucose Normal to High
(<100 mg/dL to ≥126 mg/dL) Change from Baseline
Pooled analyses of glucose data from clinical studies including longer term Weight Gain
trials are shown in Table 2.
≥7% increase from Baseline
Table 2: Change in Glucose
Mean Change from Baseline (mg/dL)
In short-term placebo-controlled trials (4- to 6-weeks), seizures occurred in 3-6 months
0.1% (1/1344) of patients treated with FANAPT compared to 0.3% (2/587) on placebo. As with other antipsychotics, FANAPT should be used cau- FANAPT 10-16 mg/day tiously in patients with a history of seizures or with conditions that poten- FANAPT 20-24 mg/day tially lower the seizure threshold, e.g., Alzheimer's dementia. Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older.
Undesirable alterations in lipids have been observed in patients treated with 5.7 Orthostatic Hypotension and Syncope
FANAPT can induce orthostatic hypotension associated with dizziness, Data from a placebo-controlled, 4-week, fixed-dose study, in which fasting tachycardia, and syncope. This reflects its alpha1-adrenergic antagonist blood samples were drawn, in adult subjects with schizophrenia are pre- properties. In double-blind placebo-controlled short-term studies, where sented in Table 3.
the dose was increased slowly, as recommended above, syncope was Table 3. Change in Fasting Lipids
reported in 0.4% (5/1344) of patients treated with FANAPT, compared with 0.2% (1/587) on placebo. Orthostatic hypotension was reported in 5% 24 mg/day
of patients given 20-24 mg/day, 3% of patients given 10-16 mg/day, and 1% of patients given placebo. More rapid titration would be expected to Mean Change from Baseline (mg/dL)
increase the rate of orthostatic hypotension and syncope.
Change from baseline
FANAPT should be used with caution in patients with known cardiovascular disease (e.g., heart failure, history of myocardial infarction, ischemia, or Change from baseline
conduction abnormalities), cerebrovascular disease, or conditions that pre- dispose the patient to hypotension (dehydration, hypovolemia, and treat- Change from baseline
ment with antihypertensive medications). Monitoring of orthostatic vital signs should be considered in patients who are vulnerable to hypotension.
Change from baseline
5.8 Leukopenia, Neutropenia and Agranulocytosis
In clinical trial and postmarketing experience, events of leukopenia/ neutropenia have been reported temporally related to antipsychotic agents. Agranulocytosis (including fatal cases) has also been reported.
1211PT206400ASH.indd 30 CHILD AND ADOLESCENT PSYCHIATRY CHILD AND ADOLESCENT PSYCHIATRY PSYCHIATRIC TIMES 31 diagnoses is high.18,19 Excluding con culpability through such pathways time," with its implication for full we will use, or have to find, a differ duct disorders, more than 60% of as further impairing judgment and adult punishment, to "they're just ent set of attitudes.
incarcerated juveniles report at least slowing consolidation of a healthy kids"—a response that elicits more Attorneys often ask experts to tes one disorder, about triple the rate in identity. When an evaluation reveals parental feelings of helping offend tify "about the adolescent brain" in the general population, and more a mental illness, the youth's amena ers not repeat their problematic be sentencing hearings. Why does such than 40% report more than one dis bility to treatment has implications havior. Reacting to adolescents as testimony have power? The data order. In most cases, delinquent be for rehabilitation.
though they are adults brings with it showing that adolescents are more havior is not thought to be "caused" the ready set of attitudes that we ap impulsive come from studies of be by mental illness, but a mental dis Attitudes toward adolescence ply to adult offenders. If we see ado havior, not imaging studies. But the order likely magnifies the effects of Attitudes toward juvenile of lescents as different from adults, but neuroimaging data indicate that the other factors relevant to reducing range from "do the crime, do the also as different from children, then (Please see The Adolescent Brain, page 32) Possible risk factors for leukopenia/neutropenia include preexisting low patients exposed to FANAPT at doses of 10 mg/day or greater, for the treat- white blood cell count (WBC) and history of drug induced leukopenia/ ment of schizophrenia. All of these patients who received FANAPT were neutropenia. Patients with a pre-existing low WBC or a history of drug participating in multiple-dose clinical trials. The conditions and duration of induced leukopenia/neutropenia should have their complete blood count treatment with FANAPT varied greatly and included (in overlapping cate- (CBC) monitored frequently during the first few months of therapy and gories), open-label and double-blind phases of studies, inpatients and should discontinue FANAPT at the first sign of a decline in WBC in the outpatients, fixed-dose and flexible-dose studies, and short-term and absence of other causative factors.
Patients with neutropenia should be carefully monitored for fever or other Adverse reactions during exposure were obtained by general inquiry and symptoms or signs of infection and treated promptly if such symptoms or recorded by clinical investigators using their own terminology. Conse- signs occur. Patients with severe neutropenia (absolute neutrophil count quently, to provide a meaningful estimate of the proportion of individuals <1000/mm3) should discontinue FANAPT and have their WBC fol owed until experiencing adverse reactions, reactions were grouped in standardized categories using MedDRA terminology.
The stated frequencies of adverse reactions represent the proportions of As with other drugs that antagonize dopamine D2 receptors, FANAPT ele- individuals who experienced a treatment-emergent adverse reaction of the vates prolactin levels.
type listed. A reaction was considered treatment emergent if it occurred Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced for the first time or worsened while receiving therapy following baseline pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadalsteroidogenesis in both female and male The information presented in these sections was derived from pooled data patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have from four placebo-controlled, 4- or 6-week, fixed- or flexible-dose studies been reported with prolactin-elevating compounds. Long-standing hyper- in patients who received FANAPT at daily doses within a range of 10 to prolactinemia when associated with hypogonadism may lead to decreased 24 mg (n=874).
bone density in both female and male patients.
Adverse Reactions Occurring at an Incidence of 2% or More among
Tissue culture experiments indicate that approximately one-third of human FANAPT-Treated Patients and More Frequent than Placebo
breast cancers are prolactin-dependent in vitro, a factor of potential impor- Table 7 enumerates the pooled incidences of treatment-emergent adverse tance if the prescription of these drugs is contemplated in a patient with pre- reactions that were spontaneously reported in four placebo-controlled, 4- or viously detected breast cancer. Mammary gland proliferative changes and 6-week, fixed- or flexible-dose studies, listing those reactions that occurred increases in serum prolactin were seen in mice and rats treated with in 2% or more of patients treated with FANAPT in any of the dose groups, FANAPT [see Nonclinical Toxicology (13.1) in the full prescribing informa- and for which the incidence in FANAPT-treated patients in any dose group tion]. Neither clinical studies nor epidemiologic studies conducted to date was greater than the incidence in patients treated with placebo.
have shown an association between chronic administration of this class of Table 7: Treatment-Emergent Adverse Reactions in Short-Term, Fixed- or
drugs and tumorigenesis in humans; the available evidence is considered Flexible-Dose, Placebo-Controlled Trials in Adult Patients*
too limited to be conclusive at this time.
Percentage of Patients Reporting Reaction
In a short-term placebo-controlled trial (4-weeks), the mean change from Placebo FANAPT FANAPT
baseline to endpoint in plasma prolactin levels for the FANAPT 24 mg/day- Body System or Organ Class 10-16 mg/day 20-24 mg/day
treated group was an increase of 2.6 ng/mL compared to a decrease of Dictionary-derived Term (N=587) (N=483) (N=391)
6.3 ng/mL in the placebo-group. In this trial, elevated plasma prolactin levels were observed in 26% of adults treated with FANAPT compared to 12% in Body as a Whole
the placebo group. In the short-term trials, FANAPT was associated with modest levels of prolactin elevation compared to greater prolactin elevations observed with some other antipsychotic agents. In pooled analysis from Musculoskeletal Stiffness 1 1 3 clinical studies including longer term trials, in 3210 adults treated with Weight Increased 1 1 9 iloperidone, gynecomastia was reported in 2 male subjects (0.1%) com- pared to 0% in placebo-treated patients, and galactorrhea was reported in Tachycardia 1 3 12 8 female subjects (0.2%) compared to 3 female subjects (0.5%) in placebo- treated patients.
Vision Blurred 2 3 1 5.10 Body Temperature Regulation
Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when pre- scribing FANAPT for patients who will be experiencing conditions which Abdominal Discomfort 1 1 3 may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication Nasopharyngitis 3 4 3 with anticholinergic activity, or being subject to dehydration.
Upper Respiratory Tract Infection 1 2 3 Nervous System Disorders
Esophageal dysmotility and aspiration have been associated with antipsy- Dizziness 7 10 20 chotic drug use. Aspiration pneumonia is a common cause of morbidity and Somnolence 5 9 15 mortality in elderly patients, in particular those with advanced Alzheimer's Extrapyramidal Disorder 4 5 4 dementia. FANAPT and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia [see Boxed Warning].
The possibility of a suicide attempt is inherent in psychotic illness, and Ejaculation Failure <1 2 2 close supervision of high-risk patients should accompany drug therapy.
Prescriptions for FANAPT should be written for the smallest quantity of Nasal Congestion 2 5 8 tablets consistent with good patient management in order to reduce the risk Dyspnea <1 2 2 of overdose.
Three cases of priapism were reported in the pre-marketing FANAPT pro- gram. Drugs with alpha-adrenergic blocking effects have been reported to Orthostatic Hypotension 1 3 5 induce priapism. FANAPT shares this pharmacologic activity. Severe pri- Hypotension <1 <1 3 apism may require surgical intervention. *Table includes adverse reactions that were reported in 2% or more of patients 5.14 Potential for Cognitive and Motor Impairment
in any of the FANAPT dose groups and which occurred at greater incidence FANAPT, like other antipsychotics, has the potential to impair judgment, than in the placebo group. Figures rounded to the nearest integer.
thinking or motor skills. In short-term, placebo-controlled trials, somno- Dose-Related Adverse Reactions in Clinical Trials
lence (including sedation) was reported in 11.9% (104/874) of adult Based on the pooled data from four placebo-controlled, 4- or 6-week, fixed- patients treated with FANAPT at doses of 10 mg/day or greater versus 5.3% or flexible-dose studies, adverse reactions that occurred with a greater than (31/587) treated with placebo. Patients should be cautioned about operat- 2% incidence in the patients treated with FANAPT, and for which the inci- ing hazardous machinery, including automobiles, until they are reasonably dence in patients treated with FANAPT 20-24 mg/day were twice than the certain that therapy with FANAPT does not affect them adversely.
incidence in patients treated with FANAPT 10-16 mg/day were: abdominal 6 ADVERSE REACTIONS
discomfort, dizziness, hypotension, musculoskeletal stiffness, tachycardia, 6.1 Clinical Studies Experience
and weight increased.
Because clinical trials are conducted under widely varying conditions, Common and Drug-Related Adverse Reactions in Clinical Trials
adverse reaction rates observed in the clinical trial of a drug cannot be Based on the pooled data from four placebo-controlled, 4- or 6-week, fixed- directly compared to rates in the clinical trials of another drug and may not or flexible-dose studies, the following adverse reactions occurred in ≥5% reflect the rates observed in clinical practice. The information below is incidence in the patients treated with FANAPT and at least twice the placebo derived from a clinical trial database for FANAPT consisting of 2070 rate for at least one dose: dizziness, dry mouth, fatigue, nasal congestion, 1211PT206400ASH.indd 31 32 PSYCHIATRIC TIMES CHILD AND ADOLESCENT PSYCHIATRY CHILD AND ADOLESCENT PSYCHIATRY The Adolescent Brain vidual cases; however, the courts Dr Ash is Associate Professor of Psychiatry 4. Graham v Florida, 560 US, 130 S.Ct. 2011, (2010).
Continued from page 31
are moving away from mandatory and Behavioral Sciences, Chief of Child and 5. Elliott DS. Serious violent offenders: onset, devel-
sentencing to individual determina opmental course, and termination: The American Adolescent Psychiatry, and Director of the Society of Criminology 1993 Presidential Address. adolescent brain is different, which tions, even for the most heinous Psychiatry and Law Service, Emory University, Criminology. 1994;32:1-22.
carries with it an implication that the crimes. These individual determi Atlanta. He reports no conflicts of interest 6. Office of the Surgeon General. Youth Violence:
reactive attitudes that we have to nations can frequently be assisted concerning the subject matter of this article. A Report of the Surgeon General. Rockville, MD: US ward adults should not apply.
by psychiatrists, because they have Public Health Service, Office of the Surgeon General; an everincreasing database of be havioral and neurobiological un 7. Monahan KC, Steinberg L, Cauffman E, Mulvey EP.
1. Miller v Alabama, 567 US (2012).
Assessments of partial culpability derstanding on which to base their Trajectories of antisocial behavior and psychosocial 2. Thompson v Oklahoma, 487 US 815 (1988).
of adolescents are difficult in indi 3. Roper v Simmons, 543 US 551; 2005.
maturity from adolescence to young adulthood. Dev somnolence, tachycardia, orthostatic hypotension, and weight increased.
Musculoskeletal and Connective Tissue Disorders: Frequent – myalgia, Dizziness, tachycardia, and weight increased were at least twice as common muscle spasms; Rare – torticollis on 20-24 mg/day as on 10-16 mg/day.
Nervous System Disorders: Infrequent – paresthesia, psychomotor hyper- Extrapyramidal Symptoms (EPS) in Clinical Trials
activity, restlessness, amnesia, nystagmus; Rare – restless legs syndrome Pooled data from the four placebo-controlled, 4- or 6-week, fixed- or flexible- Psychiatric Disorders: Frequent – restlessness, aggression, delusion; dose studies provided information regarding treatment-emergent EPS.
Infrequent – hostility, libido decreased, paranoia, anorgasmia, confusional Adverse event data collected from those trials showed the following rates of state, mania, catatonia, mood swings, panic attack, obsessive-compulsive EPS-related adverse events as shown in Table 8.
disorder, bulimia nervosa, delirium, polydipsia psychogenic, impulse- Table 8: Percentage of EPS Compared to Placebo
control disorder, major depression Placebo (%) FANAPT FANAPT
Renal and Urinary Disorders: Frequent – urinary incontinence; Infrequent – 10-16 mg/day (%) 20-24 mg/day (%)
dysuria, pollakiuria, enuresis, nephrolithiasis; Rare – urinary retention, renal Adverse Event Term (N=587) (N=483) (N=391)
All EPS events 11.6 13.5 15.1
Reproductive System and Breast Disorders: Frequent – erectile dysfunction; Infrequent – testicular pain, amenorrhea, breast pain; Rare – menstruation Akathisia 2.7 1.7 2.3 irregular, gynecomastia, menorrhagia, metrorrhagia, postmenopausal hem- Bradykinesia 0 0.6 0.5 Dyskinesia 1.5 1.7 1.0 Respiratory, Thoracic and Mediastinal Disorders: Infrequent – epistaxis, Dystonia 0.7 1.0 0.8 asthma, rhinorrhea, sinus congestion, nasal dryness; Rare – dry throat, Parkinsonism 0 0.2 0.3 sleep apnea syndrome, dyspnea exertional Tremor 1.9 2.5 3.1 6.2 Postmarketing Experience
Adverse Reactions Associated with Discontinuation of Treatment in
The following adverse reactions have been identified during postapproval use of Fanapt: retrograde ejaculation. Because these reactions were Based on the pooled data from four placebo-controlled, 4- or 6-week, reported voluntarily from a population of uncertain size, it is not possible to fixed- or flexible-dose studies, there was no difference in the incidence of reliably estimate their frequency or establish a causal relationship to drug discontinuation due to adverse events between FANAPT-treated (5%) and placebo-treated (5%) patients. The types of adverse events that led to dis- 7 DRUG INTERACTIONS
continuation were similar for the FANAPT- and placebo-treated patients.
Given the primary CNS effects of FANAPT, caution should be used when it Demographic Differences in Adverse Reactions in Clinical Trials
is taken in combination with other centrally acting drugs and alcohol. Due An examination of population subgroups in the four placebo-controlled, to its α1-adrenergic receptor antagonism, FANAPT has the potential to 4- or 6-week, fixed- or flexible-dose studies did not reveal any evidence of enhance the effect of certain anti hypertensive agents.
differences in safety on the basis of age, gender or race [see Warnings and 7.1 Potential for Other Drugs to Affect FANAPT
Iloperidone is not a substrate for CYP1A1, CYP1A2, CYP2A6, CYP2B6, Laboratory Test Abnormalities in Clinical Trials
CYP2C8, CYP2C9, CYP2C19, or CYP2E1 enzymes. This suggests that an There were no differences between FANAPT and placebo in the incidence interaction of iloperidone with inhibitors or inducers of these enzymes, or of discontinuation due to changes in hematology, urinalysis, or serum other factors, like smoking, is unlikely.
Both CYP3A4 and CYP2D6 are responsible for iloperidone metabolism.
In short-term placebo-controlled trials (4- to 6-weeks), there were 1.0% Inhibitors of CYP3A4 (e.g., ketoconazole) or CYP2D6 (e.g., fluoxetine, paroxetine) can inhibit iloperidone elimination and cause increased blood (13/1342) iloperidone-treated patients with hematocrit at least one time below the extended normal range during post-randomization treatment, compared to 0.3% (2/585) on placebo. The extended normal range for low- Ketoconazole: Co-administration of ketoconazole (200 mg twice daily for 4
ered hematocrit was defined in each of these trials as the value 15% below days), a potent inhibitor of CYP3A4, with a 3 mg single dose of iloperidone the normal range for the centralized laboratory that was used in the trial.
to 19 healthy volunteers, ages 18-45, increased the AUC of iloperidone and its metabolites P88 and P95 by 57%, 55% and 35%, respectively.
Other Reactions During the Pre-marketing Evaluation of FANAPT
Iloperidone doses should be reduced by about one-half when administered The following is a list of MedDRA terms that reflect treatment-emergent with ketoconazole or other strong inhibitors of CYP3A4 (e.g., itraconazole).
adverse reactions in patients treated with FANAPT at multiple doses ≥4 mg/day Weaker inhibitors (e.g., erythromycin, grapefruit juice) have not been stud- during any phase of a trial with the database of 3210 FANAPT-treated ied. When the CYP3A4 inhibitor is withdrawn from the combination therapy, patients. All reported reactions are included except those already listed in the iloperidone dose should be returned to the previous level.
Table 7, or other parts of the Adverse Reactions (6) section, those consid- ered in the Warnings and Precautions (5), those reaction terms which Fluoxetine: Co-administration of fluoxetine (20 mg twice daily for 21 days),
were so general as to be uninformative, reactions reported in fewer than 3 a potent inhibitor of CYP2D6, with a single 3 mg dose of iloperidone to 23 patients and which were neither serious nor life-threatening, reactions that healthy volunteers, ages 29-44, who were classified as CYP2D6 extensive are otherwise common as background reactions, and reactions considered metabolizers, increased the AUC of iloperidone and its metabolite P88, by unlikely to be drug related. It is important to emphasize that, although the about 2-3 fold, and decreased the AUC of its metabolite P95 by one-half.
reactions reported occurred during treatment with FANAPT, they were not Iloperidone doses should be reduced by one-half when administered with necessarily caused by it.
fluoxetine. When fluoxetine is withdrawn from the combination therapy, the iloperidone dose should be returned to the previous level. Other strong Reactions are further categorized by MedDRA system organ class and listed inhibitors of CYP2D6 would be expected to have similar effects and would in order of decreasing frequency according to the following definitions: fre- need appropriate dose reductions. When the CYP2D6 inhibitor is withdrawn quent adverse events are those occurring in at least 1/100 patients (only from the combination therapy, iloperidone dose could then be increased to those not listed in Table 7 appear in this listing); infrequent adverse reac- the previous level.
tions are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients.
Paroxetine: Co-administration of paroxetine (20 mg/day for 5-8 days), a
potent inhibitor of CYP2D6, with multiple doses of iloperidone (8 or 12 mg Blood and Lymphatic Disorders: Infrequent – anemia, iron deficiency ane- twice daily) to patients with schizophrenia ages 18-65 resulted in increased mia; Rare – leukopenia mean steady-state peak concentrations of iloperidone and its metabolite Cardiac Disorders: Frequent – palpitations; Rare – arrhythmia, atrioventric- P88, by about 1.6 fold, and decreased mean steady-state peak concentra- ular block first degree, cardiac failure (including congestive and acute) tions of its metabolite P95 by one-half. Iloperidone doses should be reduced Ear and Labyrinth Disorders: Infrequent – vertigo, tinnitus by one-half when administered with paroxetine. When paroxetine is with- Endocrine Disorders: Infrequent – hypothyroidism drawn from the combination therapy, the iloperidone dose should be returned to the previous level. Other strong inhibitors of CYP2D6 would be Eye Disorders: Frequent – conjunctivitis (including allergic); Infrequent – dry expected to have similar effects and would need appropriate dose reduc- eye, blepharitis, eyelid edema, eye swelling, lenticular opacities, cataract, tions. When the CYP2D6 inhibitor is withdrawn from the combination ther- hyperemia (including conjunctival) apy, iloperidone dose could then be increased to previous levels.
Gastrointestinal Disorders: Infrequent – gastritis, salivary hypersecretion, Paroxetine and Ketoconazole: Co-administration of paroxetine (20 mg
fecal incontinence, mouth ulceration; Rare – aphthous stomatitis, duodenal once daily for 10 days), a CYP2D6 inhibitor, and ketoconazole (200 mg ulcer, hiatus hernia, hyperchlorhydria, lip ulceration, reflux esophagitis, twice daily) with multiple doses of iloperidone (8 or 12 mg twice daily) to patients with schizophrenia ages 18-65 resulted in a 1.4 fold increase in General Disorders and Administrative Site Conditions: Infrequent – edema steady-state concentrations of iloperidone and its metabolite P88 and a (general, pitting, due to cardiac disease), difficulty in walking, thirst; Rare – 1.4 fold decrease in the P95 in the presence of paroxetine. So giving iloperidone with inhibitors of both of its metabolic pathways did not add to Hepatobiliary Disorders: Infrequent – cholelithiasis the effect of either inhibitor given alone. Iloperidone doses should therefore Investigations: Frequent: weight decreased; Infrequent – hemoglobin be reduced by about one-half if administered concomitantly with both a decreased, neutrophil count increased, hematocrit decreased CYP2D6 and CYP3A4 inhibitor.
Metabolism and Nutrition Disorders: Infrequent – increased appetite, dehy- 7.2 Potential for FANAPT to Affect Other Drugs
dration, hypokalemia, fluid retention In vitro studies in human liver microsomes showed that iloperidone does not substantially inhibit the metabolism of drugs metabolized by the follow- ing cytochrome P450 isozymes: CYP1A1, CYP1A2, CYP2A6, CYP2B6, 1211PT206400ASH.indd 32 CHILD AND ADOLESCENT PSYCHIATRY CHILD AND ADOLESCENT PSYCHIATRY PSYCHIATRIC TIMES 33 11. American Medical Association, American Acad-
13. Giedd JN. The teen brain: insights from neuro-
17. Lynam DR, Caspi A, Moffitt TE, et al. Longitudinal
8. Zimring FE. Penal proportionality for the young of-
emy of Child and Adolescent Psychiatry. Brief for the imaging. J Adolesc Health. 2008;42:335-343.
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cence predict adult psychopathy. J Abnorm Psychol. ished responsibility. In: Grisso T, Schwartz RG, eds. emy of Child and Adolescent Psychiatry as Amici turity and the brain: the promise and pitfalls of neu- Youth on Trial: A Developmental Perspective on Juve Curiae in Support of Neither Party, in Miller v. Ala- roscience research in adolescent health policy. 18. Marsteller FA, Brogan D, Smith I, et al. The Prev
nile Justice. Chicago: University of Chicago Press; bama, US Supreme Court Cases Nos. 109646, 10 J Adolesc Health. 2009;45:216-221.
alence of Psychiatric Disorders Among Juveniles 9647; 2012.
15. Raznahan A, Shaw P, Lalonde F, et al. How
Admitted to Department of Children and Youth Ser 9. Ash P. But he knew it was wrong: evaluating ado-
12. American Psychological Association. Brief of the
does your cortex grow? J Neurosci. 2011;31:7174- vices Regional Youth Detention Centers: Technical lescent culpability. J Am Acad Psychiatry Law. American Psychological Association, American Psy Report. Atlanta: Georgia Dept of Juvenile Justice; chiatric Association, National Association of Social 16. Fagan J. Contexts of choice by adolescents in
10. Cauffman E, Steinberg L. (Im)maturity of judg-
Workers, and Mental Health America as Amici Curiae criminal events. In: Grisso T, Schwartz RG, eds. Youth 19. Teplin LA, Abram KM, McClelland GM, et al.
ment in adolescence: why adolescents may be less Supporting Petitioners, in Graham v . Florida and Sul- on Trial: A Developmental Perspective on Juvenile culpable than adults. Behav Sci Law. 2000;18:741- livan v. Florida, Psychiatric disorders in youth in juvenile detention. US Supreme Court Case Nos. 08 Justice. Chicago: University of Chicago Press; 7412 and 087621; 2009.
Arch Gen Psychiatry. 2002;59:1133-1143. r CYP2C8, CYP2C9, or CYP2E1. Furthermore, in vitro studies in human liver Studies of elderly patients with psychosis associated with Alzheimer's dis- microsomes showed that iloperidone does not have enzyme inducing prop- ease have suggested that there may be a different tolerability profile (i.e., erties, specifically for the following cytochrome P450 isozymes: CYP1A2, increased risk in mortality and cerebrovascular events including stroke) in CYP2C8, CYP2C9, CYP2C19, CYP3A4 and CYP3A5.
this population compared to younger patients with schizophrenia [see Dextromethorphan: A study in healthy volunteers showed that changes in
Boxed Warning and Warnings and Precautions (5.1)]. The safety and effi- the pharma cokinetics of dextromethorphan (80 mg dose) when a 3 mg cacy of FANAPT in the treatment of patients with psychosis associated with dose of iloperidone was co-administered resulted in a 17% increase in total Alzheimer's disease has not been established. If the prescriber elects to treat exposure and a 26% increase in C such patients with FANAPT, vigilance should be exercised.
max of dextromethorphan. Thus, an inter- action between iloperidone and other CYP2D6 substrates is unlikely.
8.6 Renal Impairment
Fluoxetine: A single 3 mg dose of iloperidone had no effect on the pharma-
Because FANAPT is highly metabolized, with less than 1% of the drug excreted cokinetics of fluoxetine (20 mg twice daily).
unchanged, renal impairment alone is unlikely to have a significant impact on 7.3 Drugs that Prolong the QT Interval
the pharmaco kinetics of FANAPT. Renal impairment (creatinine clearance FANAPT should not be used with any other drugs that prolong the QT inter- <30 mL/min) had minimal effect on maximum plasma concentrations val [see Warnings and Precautions (5.2)].
(Cmax) of iloperidone (given in a single dose of 3 mg) and its metabolites P88 and P95 in any of the three analytes measured. AUC 8 USE IN SPECIFIC POPULATIONS
0–∞ was increased by 24%, decreased by 6%, and increased by 52% for iloperidone, P88 and P95, respectively, in subjects with renal impairment.
Pregnancy Category C 8.7 Hepatic Impairment
FANAPT caused developmental toxicity, but was not teratogenic, in rats and A study in mild and moderate liver impairment has not been conducted.
FANAPT is not recommended for patients with hepatic impairment.
In an embryo-fetal development study, pregnant rats were given 4, 16, or 8.8 Smoking Status
64 mg/kg/day (1.6, 6.5, and 26 times the maximum recommended human Based on in vitro studies utilizing human liver enzymes, FANAPT is not a dose [MRHD] of 24 mg/day on a mg/m2 basis) of iloperidone orally during substrate for CYP1A2; smoking should therefore not have an effect on the the period of organogenesis. The highest dose caused increased early intra - pharmacokinetics of FANAPT.
uterine deaths, decreased fetal weight and length, decreased fetal skeletal ossification, and an increased incidence of minor fetal skeletal anomalies and variations; this dose also caused decreased maternal food consumption 10.1 Human Experience
and weight gain.
In pre-marketing trials involving over 3210 patients, accidental or inten- tional overdose of FANAPT was documented in eight patients ranging from In an embryo-fetal development study, pregnant rabbits were given 4, 10, or 48 mg to 576 mg taken at once and 292 mg taken over a three-day period.
25 mg/kg/day (3, 8, and 20 times the MRHD on a mg/m2 basis) of iloperidone No fatalities were reported from these cases. The largest confirmed single during the period of organogenesis. The highest dose caused increased ingestion of FANAPT was 576 mg; no adverse physical effects were noted early intrauterine deaths and decreased fetal viability at term; this dose also for this patient. The next largest confirmed ingestion of FANAPT was 438 mg caused maternal toxicity.
over a four-day period; extrapyramidal symptoms and a QTc interval of In additional studies in which rats were given iloperidone at doses similar to 507 msec were reported for this patient with no cardiac sequelae. This the above beginning from either pre-conception or from day 17 of gestation patient resumed FANAPT treatment for an additional 11 months. In general, and continuing through weaning, adverse reproductive effects included reported signs and symptoms were those resulting from an exaggeration of prolonged pregnancy and parturition, increased stillbirth rates, increased the known pharmacological effects (e.g., drowsiness and sedation, tachy- incidence of fetal visceral variations, decreased fetal and pup weights, cardia and hypotension) of FANAPT.
and decreased post-partum pup survival. There were no drug effects on 10.2 Management of Overdose
the neurobehavioral or reproductive development of the surviving pups.
There is no specific antidote for FANAPT. Therefore appropriate supportive No-effect doses ranged from 4 to 12 mg/kg except for the increase in still- measures should be instituted. In case of acute overdose, the physician birth rates which occurred at the lowest dose tested of 4 mg/kg, which is should establish and maintain an airway and ensure adequate oxygenation 1.6 times the MRHD on a mg/m2 basis. Maternal toxicity was seen at the and ventilation. Gastric lavage (after intubation, if patient is unconscious) higher doses in these studies.
and administration of activated charcoal together with a laxative should be The iloperidone metabolite P95, which is a major circulating metabolite of considered. The possibility of obtundation, seizures or dystonic reaction of iloperidone in humans but is not present in significant amounts in rats, was the head and neck following overdose may create a risk of aspiration with given to pregnant rats during the period of organogenesis at oral doses of induced emesis. Cardiovascular monitoring should commence immediately 20, 80, or 200 mg/kg/day. No teratogenic effects were seen. Delayed skele- and should include continuous ECG monitoring to detect possible arrhythmias.
tal ossification occurred at all doses. No significant maternal toxicity was If antiarrhythmic therapy is administered, disopyramide, procainamide and produced. Plasma levels of P95 (AUC) at the highest dose tested were 2 quinidine should not be used, as they have the potential for QT-prolonging times those in humans receiving the MRHD of iloperidone.
effects that might be additive to those of FANAPT. Similarly, it is reasonable There are no adequate and well-controlled studies in pregnant women. to expect that the alpha-blocking properties of bretylium might be additive to Non-Teratogenic Effects those of FANAPT, resulting in problematic hypotension. Hypotension and Neonates exposed to antipsychotic drugs, during the third trimester of circulatory collapse should be treated with appropriate measures such as pregnancy are at risk for extrapyramidal and/or withdrawal symptoms fol- intravenous fluids or sympathomimetic agents (epinephrine and dopamine lowing delivery. There have been reports of agitation, hypertonia, hypotonia, should not be used, since beta stimulation may worsen hypotension in the tremor, somnolence, respiratory distress and feeding disorder in these setting of FANAPT-induced alpha blockade). In cases of severe extrapyrami- neonates. These complications have varied in severity; while in some cases dal symptoms, anticholinergic medication should be administered. Close symptoms have been self-limited, in other cases neonates have required medical supervision should continue until the patient recovers.
intensive care unit support and prolonged hospitalization.
FANAPT should be used during pregnancy only if the potential benefit justi- Store FANAPT tablets at controlled room temperature, 25°C (77°F); excur- fies the potential risk to the fetus.
sions permitted to 15°-30°C (59°-86°F) [See USP Controlled Room Tem- perature]. Protect FANAPT tablets from exposure to light and moisture.
8.2 Labor and Delivery
The effect of FANAPT on labor and delivery in humans is unknown.
Fanapt® is a registered trademark of Vanda Pharmaceuticals Inc. and is used by 8.3 Nursing Mothers
Novartis Pharmaceuticals Corporation under license.
FANAPT was excreted in milk of rats during lactation. It is not known whether FANAPT or its metabolites are excreted in human milk. It is recom- Novartis Pharmaceuticals Corporation mended that women receiving FANAPT should not breast feed.
East Hanover, NJ 07936 8.4 Pediatric Use
Safety and effectiveness in pediatric and adolescent patients have not been established.
8.5 Geriatric Use
Clinical Studies of FANAPT in the treatment of schizophrenia did not include sufficient numbers of patients aged 65 years and over to determine whether or not they respond differently than younger adult patients. Of the 3210 patients treated with FANAPT in pre-marketing trials, 25 (0.5%) were ≥65 years old and there were no patients ≥75 years old.
1211PT206400ASH.indd 33 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
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