FDA approved psychoactive medication for Children

Sep

2018

FDA approved psychoactive medication for Children

Posted On September 1, 2018 By Dr.Adel Serag And has No Comment

Fluoxetine for Pediatric Patients

US FDA Approved for Pediatric Use

Major depressive disorder (fluoxetine, ages 8 and older)

Obsessive compulsive disorder (fluoxetine, ages 7 and older)

Bipolar depression [in combination with olanzapine (Symbyax), ages 10 and older]

Off-Label for Pediatric Use But Approved in Adults

Panic disorder (fluoxetine, fluoxetine weekly)

Premenstrual dysphoric disorder (Sarafem)

Bulimia nervosa (fluoxetine, fluoxetine weekly)

Treatment-resistant depression [in combination with olanzapine (Symbyax)]

Other Off-Label Uses

Separation anxiety disorder

Social anxiety disorder (social phobia)

Generalized anxiety disorder

Posttraumatic stress disorder (PTSD)

Side Effects in Children

Mostly central nervous system side effects (insomnia but also sedation especially if not sleeping at night; agitation, tremors, headache, dizziness)

Treatment-emergent activation syndrome (TEAS) includes hypomania, agitation, anxiety, panic attacks, irritability, hostility/aggression, impulsivity, insomnia, and suicidality

TEAS can represent side effects, or can be the emergence of bipolar mania or the onset of suicidality and should be monitored and investigated with consideration of discontinuing or decreasing dose of fluoxetine or addition of another agent or switching to another agent to reduce these symptoms

Note: patients with diagnosed or undiagnosed bipolar or psychotic disorders may be more vulnerable to CNS-activating actions of SSRIs; pay particular attention to signs of activation in children with developmental disorders, autism spectrum disorders, or brain injury as they may not tolerate these side effects well

Gastrointestinal (decreased appetite, nausea, diarrhea, constipation, dry mouth)

Sexual dysfunction (boys: delayed ejaculation, erectile dysfunction; boys and girls: decreased sexual desire, anorgasmia)

Autonomic (sweating)

Bruising and rare bleeding, especially if combined with NSAIDS, aspirin, antiplatelet or anticoagulant drugs

SIADH (syndrome of inappropriate antidiuretic hormone secretion)

Rare seizures

Rare induction of mania

Rare activation of suicidal ideation and behavior (suicidality) (short-term regulatory studies did not show any actual suicides in any age group and also did not show an increase in the risk of suicidality with antidepressants compared to placebo beyond age 24)

What to Do About Side Effects

Wait, wait, wait: mild side effects are common, happen early, and usually improve with time, but treatment benefits can be delayed, and often begin just as the side effects wear off

May wish to try dosing every other day to deal with side effects, or wash out for a week and try again at half dose or every other day

May wish to give some drugs at night if not tolerated during the day, although this may not be useful for fluoxetine

For GI upset, try giving medication with a meal

Often best to try another monotherapy prior to resorting to augmentation strategies to treat side effects

What to Do For Activation (Jitteriness, Anxiety, Insomnia):

Administer dose in the morning

Consider a temporary dose reduction or a more gradual up-titration

Consider adding a 5HT2A antagonist such as trazodone or mirtazapine

Consider adding a benzodiazepine short term (caution in children and adolescents)

Consider switching to another antidepressant

Optimize behavioral interventions

Activation and agitation may represent the induction of a bipolar state, especially a mixed dysphoric bipolar II condition sometimes associated with suicidal ideation, and may require the addition of lithium, a mood stabilizer or an atypical antipsychotic, and/or discontinuation of ?uoxetine

Contraindications

If patient is taking an MAO inhibitor, thioridazine, pimozide, or tamoxifen

If there is a proven allergy to ?uoxetine

How to Dose in Children

Depression: initial dose 10 mg/day; after 2 weeks can increase to 20 mg/day; can go up to 80 mg/day if medically indicated and no side effects

In general, for doses higher than 20 mg/day, fluoxetine may be best administered in divided doses twice daily (in the morning and at noon)

OCD: initial dose 10 mg/day; after 2 weeks can increase to 20 mg/day (wait several weeks for lower weight children); consider additional dose increases up to 80 mg/day after several more weeks if there is insufficient response

Bipolar depression: initial 2.5 mg olanzapine/20 mg fluoxetine once daily in the evening; adjust based on tolerability/efficacy; usual dose 3 mg/25 mg–12 mg/50 mg once daily in the evening

How to Dose in Adolescents

Depression: initial dose 10 mg/day; after 1 week can increase to 20 mg/day; can go up to 80 mg/day if medically indicated and no side effects

In general, for doses higher than 20 mg/day fluoxetine may be best administered in divided doses twice daily (in the morning and at noon)

OCD: initial dose 10 mg/day; after 2 weeks can increase to 20 mg/day; consider additional dose increases after several more weeks if there is insufficient response; usual dose range is 20–60 mg/day

Bipolar depression: initial 2.5 mg olanzapine/20 mg fluoxetine once daily in the evening; adjust based on tolerability/efficacy; usual dose 3 mg/25 mg–12 mg/50 mg once daily in the evening

Options For Administration

Capsules 10 mg, 20 mg, 40 mg, 60 mg

Tablet 10 mg

Liquid 20 mg /5 mL–120 mL bottles

Weekly capsule 90 mg

Pulvules 10 mg, 20 mg 40 mg

Dosing Tips

Plasma levels are higher in lower weight children; therefore, starting and target doses may be lower and longer intervals between dose increases may be needed (see How to Dose)

If a child loses efficacy between daily doses, it may indicate rapid metabolism and the need to increase the dose or give twice daily even though fluoxetine has a long half-life (this is more common with other antidepressants with shorter half-lives)

Adolescents often need and receive adult doses

Be aware that metabolism changes during puberty and entry into adolescence and becomes more like adults (i.e., slower than in children)

If a child on a stable dose begins to lose tolerability with more side effects upon entering adolescence, this may signal the need for a dose reduction due to changing metabolism

The long half-lives of ?uoxetine and its active metabolites mean that dose changes will not be fully re?ected in plasma for several weeks, lengthening titration to ?nal dose and extending withdrawal from treatment

Liquid formulation easiest for doses below 10 mg when used for cases that are very intolerant to ?uoxetine or for very slow up and down titration needs

The more anxious and agitated the patient, the lower the starting dose, the slower the titration, and the more likely the need for a concomitant agent such as trazodone or even a benzodiazepine if warranted

If intolerable anxiety, insomnia, agitation, akathisia, or activation occur either upon dosing initiation or discontinuation, consider the possibility of activated bipolar disorder and switch to an atypical antipsychotic or a mood stabilizer

These symptoms may also indicate the need to evaluate for a mixed features episode and thus discontinuing fluoxetine and considering an atypical antipsychotic or a mood stabilizer or lithium

Pharmacokinetics

Active metabolite (nor?uoxetine) has a 2-week half-life (based on adult studies)

Parent drug has 2–3 day half-life (based on adult studies)

Inhibits CYP450 2D6, CYP450 3A4, and CYP450 2C19

Plasma levels of fluoxetine and norfluoxetine are higher in lower weight children than in adolescents or adults

Drug Interactions

Tramadol reported to increase the risk of seizures in patients taking an antidepressant

Can increase tricyclic antidepressant (TCA) levels; use with caution with tricyclic antidepressants or when switching from a TCA to ?uoxetine

Can cause a fatal “serotonin syndrome” when combined with MAO inhibitors, so do not use with MAO inhibitors or for at least 14 days after MAOIs are stopped

Do not start an MAO inhibitor for at least 5 weeks after discontinuing ?uoxetine

May displace highly protein bound drugs (e.g., warfarin)

Can rarely cause weakness, hyperre?exia, and incoordination when combined with sumatriptan, or possibly with other triptans, requiring careful monitoring of patient

Possible increased risk of bleeding, especially when combined with anticoagulants (e.g., warfarin, NSAIDs)

NSAIDs may impair effectiveness of SSRIs

Via CYP450 2D6 inhibition, could theoretically interfere with the analgesic actions of codeine, and increase the plasma levels of some beta blockers and of atomoxetine

Via CYP450 2D6 inhibition, ?uoxetine could theoretically increase concentrations of thioridazine and cause dangerous cardiac arrhythmias

Via CYP450 2D6 inhibition, may increase aripiprazole levels; consider up to 50% dose reduction of aripiprazole

May reduce the clearance of diazepam or trazodone, thus increasing their levels

Via CYP450 3A4 inhibition, may increase the levels of alprazolam, buspirone, and triazolam

Via CYP450 3A4 inhibition, ?uoxetine could theoretically increase concentrations of certain cholesterol lowering HMG CoA reductase inhibitors, especially simvastatin, atorvastatin, and lovastatin, but not pravastatin or ?uvastatin, which would increase the risk of rhabdomyolysis; thus, co-administration of ?uoxetine with certain HMG CoA reductase inhibitors should proceed with caution

Via CYP450 3A4 inhibition, ?uoxetine could theoretically increase the concentrations of pimozide, and cause QTc prolongation and dangerous cardiac arrhythmias

Caution when used with drugs metabolized by CYP450 2D6, 3A4 and 2C19, since plasma levels of those drugs may increase in patients also taking fluoxetine

Pearls

SSRIs show a small to medium effect in reducing childhood and adolescent anxiety in controlled clinical trials but may have more robust effects in clinical practice

Many SSRIs have an even smaller effect and sometimes no effect in controlled clinical trials of child and adolescent depression yet can show robust efficacy in clinical practice

Overall, adolescents respond better than children to SSRIs

Although fluoxetine has a more robust and consistent effect in child and adolescent depression than some other antidepressants, there are few head-to-head trials with other antidepressants

More recent studies with antidepressants newer than fluoxetine all tend to have lower drug-placebo differences than fluoxetine, but this may be due to changes in clinical trial methodologies and not to true differences in drug efficacy

Mood disorders can be associated with eating disorders, especially in adolescent females, and both can be treated successfully with ?uoxetine

Not as well tolerated as some other SSRIs for panic disorder and other anxiety disorders, especially when dosing is initiated, unless given with co-therapies such as benzodiazepines or trazodone

Developmental Aspects of Treatment

Clinical presentation of depression in children and adolescents may be different than in adults, i.e., with irritability, aggressive behaviors and school refusal

Diagnoses are less stable than in adults; at each follow-up visit look for morphing from one diagnosis to another and for emerging comorbidities that have changed since the last visit

Younger children tend to be more sensitive to adverse effects of SSRIs

However, younger children can also have faster hepatic and renal metabolism and excretion, leading to the need to use adult-like doses in children

For all SSRIs, and perhaps particularly for fluoxetine, children can have a two to three-fold higher incidence of behavioral activation and vomiting than adolescents, who have a somewhat higher incidence than adults

Hepatic enzyme activity develops early and the rate of drug metabolism is related to hepatic size, which is proportionately larger in children than in adults

Since liver parenchyma is also larger in children than in adults relative to body size, children generally require a larger dose per kilogram of body weight of drugs that are primarily metabolized by the liver, such as fluoxetine

Young children may also absorb some drugs faster than adults, leading to higher peak drug levels and peak dose side effects

For this reason, once a day drugs for adults may have to be given twice or three times a day in children

Simply decreasing adult doses on the basis of child weight can result in undertreatment because of faster drug elimination in children

Prepubescent children have more body water and less fat (where lipid soluble drugs are stored) compared to adults

Children tend to have less protein binding of drugs compared to adults, leaving a greater proportion of drug in the plasma biologically active

Be vigilant to increased side effects or otherwise unexplained loss of efficacy in spite of stable dosing and compliance, and be prepared to adjust the dose accordingly as the child progresses into adolescence, as metabolism and excretion may change and even slow down

Concerns About Suicidality

Suicide is alarmingly common in this age group: surveys by the CDC (Center for Disease Control) show that 15–20% of high school students have had in the past year serious thoughts of suicide and that 8–10% made a suicide attempt

Treating children and adolescents with antidepressants for depression, a leading cause of suicide in this age group, is one of the most controversial areas in psychopharmacology

The same class of drugs that has a black box warning for suicidality is also indicated as best practice standard for treatment of depression

Many prescribers and parents feel caught in a dilemma whether to treat with antidepressants or not; important to consider risks of not treating in addition to risks of treating

Suicidality is a confusing term that seems to imply a portfolio of symptoms that escalate until the ultimate act of suicide, that are potential predictors of suicide; however, symptoms of suicidality, especially those of TEAS (treatment emergent activation syndrome), are not proven to cause more completed suicides, and in controlled trials there were no actual completed suicides

Suicide is often impulsive and not predictable

Some studies show that the black box warning for suicidality by antidepressants has led to a decline in the diagnosis and treatment of child/adolescent depression with antidepressants and an increase in completed suicides in this age group

Other studies show that serious suicidal behavior is greatest in the month prior to treatment with antidepressants (especially in the week prior to treatment), so referral for antidepressant treatment can be too late and antidepressant treatment may need to be started earlier and urgently

These same studies also show that the risk of serious suicidal attempts may be higher during the first week of treatment with antidepressants, so vigilance to this behavior in the interval before antidepressants have a chance to start working is key to managing these patients

Conduct a thorough diagnostic evaluation and consider utilizing evidence-based psychosocial and behavioral interventions prior to psychotropic medications, especially in milder cases and when available and practical

However, the majority of children who receive psychosocial treatments that are not evidence-based interventions do not show improvement and may deteriorate

FDA approved psychoactive medication for Children

FDA approved psychoactive medication for Children

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