Neurology/Psychiatry

Neurology/Psychiatry Naomi House, Pharm.D., BCPP Wolfson Children’s Hospital/Baptist Medical Center Jacksonville Jacksonville, Florida

Neurology/Psychiatry

Neurology/Psychiatry Naomi House, Pharm.D., BCPP Wolfson Children’s Hospital/Baptist Medical Center Jacksonville Jacksonville, Florida

ACCP Updates in Therapeutics® 2015: Pediatric Pharmacy Preparatory Review Course 1-71


Learning Objectives 1. Apply evidence-based medication therapy for acute and prophylactic treatment of migraines. 2. Distinguish between various seizure medications for type of seizure, age, drug interactions, and adverse effects. 3. Differentiate between the medication therapies for cerebral palsy symptoms of spasticity, drooling, and bone mineral density loss. 4. Evaluate between the medications for autism spectrum disorders for target symptoms and adverse effects. 5. Select appropriate medication therapy for pediatric bipolar depression based on symptoms, bipolar phase, and adverse events, including monitoring parameters. 6. Develop treatment plans for attention-deficit/ hyperactivity disorder, including medication recommendations, dose, adverse events, and dosage formulations. 7. Describe the medications used for various eating disorders and their place in therapy. 8. Differentiate between various substances of abuse by symptoms of intoxication, symptoms of withdrawal, and treatment options. 9. Identify treatment options and potential adverse effects of medications for pediatric depression.

Self-Assessment Questions Answers and explanations to these questions can be found at the end of this chapter. 1. R.H. is a 15-year-old female adolescent who presents to the emergency department (ED) with a headache. She describes her headache as a throbbing, pulsing pain in the front of her head. Bright lights seem to make it worse. She has been nauseated since the onset of the headache and has vomited twice in the past hour. Which medication is best, given R.H.’s symptoms? A. Almotriptan oral tablet. B. Hydrocodone/acetaminophen oral tablet. C. Hydromorphone intravenous injection. D. Sumatriptan nasal spray.

2. S.K. is a 5-year-old girl (weight 20 kg) with focal (partial onset) seizures. She was placed on carbamazepine 2 months ago. For the first month after the dose was titrated to 200 mg twice daily, she had no seizures. After the first month, however, the seizures recurred. A therapeutic level was drawn, which was 3.5 mg/mL (normal range 4–12 mg/mL). Which is the most likely reason for the low level? A. Carbamazepine binds to protein binding. B. Carbamazepine has displacement of the free fraction. C. Carbamazepine is an autoinducer. D. Carbamazepine has multi-phasal distribution. 3. C.F. is a 12-year-old boy (weight 45 kg) who has been having difficulty in school. He has been described as staring off into space and not paying attention. He seems to do this many times a day, but each episode lasts for only a few seconds. Which is the best medication for C.F.? A. Ethosuximide. B. Topiramate. C. Phenobarbital. D. Phenytoin. 4. M.M. is an 8-year-old boy with cerebral palsy. His primary symptoms are muscle tightness in his arm, a scissored gait, grimacing in his face, and an intermittent tremor. His mother brings a prescription for baclofen 5 mg every 8 hours. Which best reflects the target symptom in M.M. for which baclofen has been prescribed? A. Ataxia. B. Athetoid movements C. Dyskinesia movements. D. Spasticity. 5. M.P. is an 11-year-old boy with autism disorder. His current symptoms include inability to communicate verbally, inability to follow directions, irritability, self-injurious behavior, flat affect, and aggression. He often gets upset, and if his routine is disrupted, he will start rocking back and forth. Aripiprazole is prescribed. Which of his symptoms is aripiprazole most likely to improve? A. Poor verbal communication. B. Irritability. C. Flat affect. D. Inability to follow directions.



Questions 6 and 7 pertain to the following case: T.E. is a 15-year-old female adolescent with bipolar disorder. She presents with an expansive mood, grandiosity, and flight of ideas. She has not slept for more than 2 hours for at least 1 week. Her parents brought her to the hospital because she was communicating with her online boyfriend and told him she would wire him $10,000. 6. Which would be the most appropriate medication for T.E.? A. Olanzapine. B. Lamotrigine. C. Fluoxetine. D. Methylphenidate. 7. The physician would like to prescribe lithium for T.E. For which adverse effect is lithium most likely titrated with initiation? A. Leukopenia. B. Nausea/vomiting. C. Pancreatitis. D. Early jitteriness and anxiety. 8. K.C. is a 14-year-old male adolescent (weight 45 kg) who presents to the ED with hallucinations, paranoia, and aggression. On medication reconciliation, it is noted that the dose of his attentiondeficit/hyperactivity disorder (ADHD) medication was recently doubled. Of the medications indicated to treat ADHD, which is most likely causing these symptoms in K.C.? A. Atomoxetine. B. Clonidine XR. C. Guanfacine XR. D. Methylphenidate. 9. N.B. is a 12-year-old girl who was given a diagnosis of ADHD. The physician would like to use a methylphenidate product that will last at least 10 hours. Which medication would be best for N.B. because of its longer duration of action? A. Methylphenidate CD. B. Methylphenidate ER. C. Methylphenidate OROS. D. Methylphenidate SR.

10. L.R. is a 16-year-old female adolescent who binges on junk food and later purges. She is given a diagnosis of bulimia nervosa. Which best depicts the medication that is U.S. Food and Drug Administration (FDA) indicated for bulimia nervosa and may be useful in treating L.R.? A. Fluoxetine. B. Fluvoxamine. C. Paroxetine. D. Sertraline. 11. R.S. is a 17-year-old male adolescent with a history of alcohol use and binge drinking who received his first DUI (driving under the influence) after his 17th birthday. His parents bring him to the hospital for evaluation as having possible alcohol use disorder. It is determined that he meets the criteria for this disorder, and he is referred to an outpatient treatment center. Given the evidence for treating adolescents with substance use disorders, which would be best to initiate as first-line therapy in R.S.? A. Behavior therapy. B. Acamprosate. C. Naltrexone. D. Disulfiram. Questions 12 and 13 pertain to the following case: K.B. is a 13-year-old female adolescent who presents with depressed mood, insomnia, weight loss, feelings of guilt, and suicidal ideation. She has been feeling this way for the past 3 months. Several weeks ago, she almost tried to overdose on her mother’s oxycodone but then confessed to her mother her thoughts. At that time, she was admitted to the hospital, but no medications were prescribed. The current presentation began when she notified her mother of her suicidal thoughts, and her mother brought her immediately to the hospital for evaluation. This time, the physician would like to initiate an antidepressant. 12. Which medication is best for K.B.? A. Venlafaxine. B. Duloxetine. C. Escitalopram. D. Amitriptyline.



13. K.B. was stabilized at the hospital and discharged home with a prescription of an antidepressant. After doing well with her medication for 1 year, K.B. did not think she needed it any longer and abruptly stopped taking it. Two days later, her depression came back, and she felt worse than she had before. She had 2 nights of vivid dreams, felt that someone was trying to shock her, and had severe nausea. Which is most likely occurring? A. Rebound depression. B. Serotonin syndrome. C. Serotonin discontinuation syndrome. D. Onset of manic symptoms.

Abbreviations ADHD Attention-deficit/hyperactivity disorder ASD Autism spectrum disorder BED Binge eating disorder CBT Cognitive behavioral therapy ED Emergency department GABA γ-Aminobutyric acid RCT Randomized controlled trial SSRI Selective serotonin reuptake inhibitor TCA Tricyclic antidepressant



I. MIGRAINES/HEADACHES A. Epidemiology 1. Headache a. Prevalence for all children and adolescents younger than 20 years is estimated at 58.4% worldwide. b. Prevalence female-to-male ratio is 1.5/1 for all children and adolescents younger than 20 2. Migraine a. Prevalence for all children and adolescents younger than 20 is estimated at 7.7%. b. Prevalence for females is 9.7% and for males, 6%. c. Prevalence of migraines is the same for females as for males younger than 14, and migraines are more prevalent in adolescent females. 3. Abdominal migraine accounts for 4%–15% of chronic, recurrent abdominal pain. 4. Cluster headaches are rare in children younger than 10 years. 5. Comorbid conditions such as seizures and psychiatric diagnoses are common with headache and migraine. B. Classifications of Headache by the International Headache Society 1. Migraine without aura: At least five attacks of headache lasting 4–72 hours with at least two of the following characteristics: unilateral location, pulsating quality, moderate or severe pain intensity, aggravating or causing avoidance of routine physical activity. During headache, at least one of the following: nausea and/or vomiting, photophobia, phonophobia. Occipital headache in children is rare, and migraine headaches in general are usually frontotemporal. In young children, photophobia and phonophobia may be inferred from their behavior. 2. Migraine with aura: At least two attacks with at least three of the following: one or more fully reversible aura symptoms, at least one aura symptom for more than 4 minutes, or two or more symptoms occurring in succession; no single aura symptom lasts more than 60 minutes; headache follows aura within 60 minutes. Typical auras consist of visual, sensory, or speech symptoms. Examples include flickering lights or spots, feeling of pins or needles, and numbness. 3. Childhood periodic syndromes are commonly precursors of migraine. a. Cyclic vomiting: At least four attacks of intense nausea and vomiting lasting from 1 hour to 5 days; vomiting during attacks occurs at least four times per hour for at least 1 hour, and child is symptom free between attacks b. Abdominal migraine: At least five attacks that last 1–72 hours with abdominal pain that is midline, periumbilical, or poorly localized; dull or “just sore” quality; and moderate to severe intensity. For the abdominal pain attack criteria, at least two of the following must occur: anorexia, nausea, vomiting, or pallor. c. Benign paroxysmal vertigo of childhood: At least five attacks of vertigo occurring without warning and resolving spontaneously after minutes to hours, together with a normal neurologic examination and normal electroencephalogram (EEG). Benign paroxysmal vertigo is often associated with nystagmus or vomiting. 4. TTH (tension-type headache): At least 10 previous headaches, each lasting from 30 minutes to 7 days, with no nausea and vomiting and no more than one photophobia and phonophobia, with at least two of the following: pressing/tightening (nonpulsating) quality; mild to moderate intensity; bilateral location; no aggravation with physical activity C. Treatment of Pediatric Migraine 1. Acute treatment a. The goal is a rapid response resulting in a prompt return to normal activity and no relapse. ACCP Updates in Therapeutics® 2015: Pediatric Pharmacy Preparatory Review Course 1-75


b. Ibuprofen (Motrin, Advil) has been studied and is effective. Dose: 7.5–10 mg/kg/dose; maximum (max) per dose: 800 mg; max per day: 2400 mg c. Acetaminophen (Tylenol) is also listed in the guidelines as a treatment option. i. Ibuprofen was found to be more efficacious than acetaminophen and lasted longer, but both medications were well tolerated. ii. Dose: 10–15 mg/kg/dose; max per dose: 1000 mg; max per day: 3000 mg d. Triptans (5-hydroxytryptamine 1D-receptor agonists) i. Almotriptan (12–17 years old) and rizatriptan (6–17 years old) are the only FDA labelapproved treatment for pediatric migraine. ii. Sumatriptan nasal spray, zolmitriptan oral tablet and orally disintegrating tablet, rizatriptan oral tablet and orally disintegrating tablet, and eletriptan have all been studied in the adolescent population with some positive results. iii. Sumatriptan subcutaneously has positive open-label data with doses of 3–6 mg (0.06 mg/kg/ dose) for those 6–18 years of age. The oral formulation of sumatriptan was not statistically significantly different compared with placebo. iv. Naratriptan and frovatriptan have no efficacy studies for this population. D. Epidemiology 1. Headache a. Prevalence for all children and adolescents younger than 20 years is estimated at 58.4% worldwide. b. Prevalence female-to-male ratio is 1.5/1 for all children and adolescents younger than 20 2. Migraine a. Prevalence for all children and adolescents younger than 20 is estimated at 7.7%. b. Prevalence for females is 9.7% and for males, 6%. c. Prevalence of migraines is the same for females as for males younger than 14, and migraines are more prevalent in adolescent females. 3. Abdominal migraine accounts for 4%–15% of chronic, recurrent abdominal pain. 4. Cluster headaches are rare in children younger than 10 years. 5. Comorbid Table 1. Summary of Triptans Investigated for Pediatric Migraine Generic Name

Brand Name

Dosage Form

Time to Relief (hours)

Sumatriptan

Imitrex

Nasal spray

Zolmitriptan

Zomig

Rizatriptan

Almotriptan

Dose

Indication

2

10 mg: < 40 kg 20 mg: > 40 kg

12- to 17-year-old adolescents

Tablets, ODT, nasal spray

2

2.5–10 mg

Studies with mixed results of efficacy in 12to 17-year-old adolescents

Maxalt Maxalt MLT

Tablets, ODT

2

5–10 mg

For multiple attacks, some efficacy in 12- to 17-year-old adolescents

Amerge

Tablets

2

6.25–25 mg

FDA label approved for migraine in 12- to 17-year-old adolescents



Table 1. Summary of Triptans Investigated for Pediatric Migraine (continued) Generic Name

Brand Name

Dosage Form

Time to Relief (hours)

Dose

Indication

Eletriptan

Relpax

Tablets

2

40 mg

Studies show reduction in recurrent migraine in 12-to 17-year-old adolescents

ODT = orally disintegrating tablet.

a. Treatment with prochlorperazine has been shown to be more effective than that with ketorolac. b. Other antiemetics such as promethazine, metoclopramide, and ondansetron have been used for treatment and for nausea/vomiting associated with migraines. c. If nausea and vomiting are present, non-oral formulations should be tried first (e.g., injectable or nasal). d. Although studies have found that opioids are commonly used for abortive migraine treatment in practice, guidelines advise against using these agents for the management of migraine. Reasons against using opioids for migraine: Increased risk for abuse, increased risk of chronic daily headache or medication overuse headache, lack of evidence supporting superior efficacy and hyperalgesia e. Dihydroergotamine has been used for treatment-resistant migraine, but it is not mentioned in the guidelines. Mechanism of action: An ergot alkaloid α-adrenergic blocker directly stimulates vascular smooth muscle to vasoconstrict peripheral and cerebral vessels; may also affect serotonin receptors 6. Prophylactic treatment of pediatric migraine a. General principles i. Consider when headache frequency exceeds three or four episodes per month or if headaches interfere with school or normal activities. ii. Goals are to reduce the frequency, severity, and duration of attacks; improve responsiveness to treatment of acute attacks; improve function and quality of life; and reduce disability. iii. No treatment has been approved by the FDA. b. Medications with studies showing the efficacy of prophylaxis and included in guidelines: i. Amitriptyline – Starting dose: 5–10 mg at bedtime. May be increased to 1 mg/kg/day. Adverse events include arrhythmias, weight gain, anticholinergic effects, daytime sedation, and potential for overdose. Doses based on studies of children 6–12 years of age ii. Topiramate – Dose: 15–200 mg/day. Age 5–17 years. Adverse effects include anorexia, weight reduction, gastroenteritis, paresthesia, somnolence, and dulled cognition. iii. Valproic acid – Dose: 20–40 mg/kg/day; max dose 1000 mg. Age 12–17 years. Adverse effects include liver dysfunction, pancreatitis, somnolence, weight gain, alopecia, and menstrual irregularities. iv. Propranolol – Dose: 0.6–1.5 mg/kg/day or 10–40 mg three times daily. Max dose: 4 mg/kg/ day. Adverse effects include bradycardia, hypotension, syncope, dizziness, drowsiness, and wheezing. Contraindicated in asthma c. Other medications studied in pediatric patients with less evidence i. Levetiracetam – Dose: 125–250 mg three times daily or 20–40 mg/kg/day ii. Zonisamide – Dose: 5.8 mg/kg iii. Cyproheptadine – Dose: 4 mg d. Alternative therapies i. Magnesium has been studied in pediatric patients; may reduce the frequency of headaches, but patients tend to have gastrointestinal (GI) adverse effects. Dose: 9 mg/kg day divided three times daily ACCP Updates in Therapeutics® 2015: Pediatric Pharmacy Preparatory Review Course 1-77


ii. Butterbur, coenzyme Q10, ginkgolide B, and riboflavin all have potential efficacy in studies of pediatric patients; however, most of the studies had quality problems. Patient Cases Questions 1 and 2 pertain to the following case: A.M. is a 12-year-old girl (weight 50 kg) with a throbbing headache located in the front of her head that has lasted for 2 hours. She has phonophobia, but no nausea and vomiting. She describes this as the worst headache she has ever had. She has had “bad” headaches in the past, when acetaminophen has worked, but this headache did not go away with a 650-mg dose. 1. Which would be the next best step for her headache? A. Ibuprofen orally. B. Prochlorperazine orally. C. Sumatriptan orally. D. Topiramate orally. 2. After a few months, A.M. continues to have migraine headaches, consisting of about four per month. She has missed 1 week of school in the past month because of her migraines. Although the medications for acute treatment seem to be working, her mother is concerned about the amount of medications her daughter is taking and wonders whether there is anything her daughter could take for migraine prevention. Which scheduled medication would be best for migraine prophylaxis? A. Ibuprofen orally. B. Prochlorperazine orally. C. Sumatriptan orally. D. Topiramate orally. 3. A.K. is a 6-year-old boy who comes to the ED with nausea, vomiting, irritability, and restlessness and states that his head hurts. When asked where it hurts, he says “all over my head.” His mother states he has been acting like this for several hours. She tried acetaminophen several hours ago, but there appeared to be no change in his behavior or complaints. Which medication would best be tried next in A.K.? A. Morphine intravenously. B. Almotriptan orally. C. Sumatriptan nasal spray. D. Valproic acid orally.

II. SEIZURE DISORDERS (CHRONIC MANAGEMENT) A. Epidemiology 1. The estimated lifetime prevalence of childhood seizure disorders in the United States is 10 per 1000, or 1%. 2. About 10% of people in the United States will experience a seizure. 3. Febrile seizures are the most common type of seizure in children younger than 5 years, with a peak onset in those 14–18 months of age. B. Classifications of Seizures 1. The International League Against Epilepsy (ILAE) determines the classification of seizures. The most recent update was published in 2010. In this update, neonatal seizures are no longer a separate category but are included within the other classifications. ACCP Updates in Therapeutics® 2015: Pediatric Pharmacy Preparatory Review Course 1-78


2. Focal (formerly partial): Seizures begin in one hemisphere of the brain and may have the following subsequent descriptors: a. Without impairment of consciousness or awareness (roughly corresponding with simple seizures) b. Involving subjective sensory or psychic phenomena (corresponds with an aura) c. With impairment of consciousness or awareness (corresponds with complex seizures) d. Evolving to a bilateral, convulsive seizure (corresponds with secondarily generalized seizures) 3. Primary generalized seizures begin in both hemispheres of the brain. a. Absence: Brief and abrupt, last 10–30 seconds, occur in clusters. May have a short loss of consciousness or the patient may stare into space b. Myoclonic: Brief, lightning-like jerking movements of the entire body or the extremities c. Tonic: Flexion and/or extension phases of tonic-clonic. Tonic is a sustained contraction of muscles with progressive rigidity. d. Clonic: Rhythmic, repetitive, jerking muscle movements e. Tonic-clonic: Pattern of first the flexion, the extension phase, and then the tremor and clonic phase. A postictal phase may occur in which the patient is difficult to arouse and/or is somnolent or confused. f. Atonic: Loss of muscle tone. This may be described as a drop attack. 4. Unknown type – Epileptic spasms (formerly infantile spasms): Spasmodic clusters of jerking contractions of the extremities, head, and trunk. West syndrome is a disorder with infantile spasms, an abnormal EEG pattern called hypsarrhythmia, and developmental delay. The new classification system changed the terminology because spasms can last beyond infancy. 5. Epilepsies and syndromes a. Lennox-Gastaut syndrome is a mixture of intractable seizures and absence seizures. b. Benign epilepsy with centrotemporal spikes: Clonic movements that occur in the sleep. The seizures are usually benign, and the child outgrows them. c. Juvenile myoclonic epilepsy (aka Janz syndrome): Myoclonic jerks on awakening but patient may also have tonic-clonic seizures or absence seizures d. Febrile seizures: A seizure that is accompanied by a temperature of 100.4°F (38°C) in children between 6 months and 5 years of age without a diagnosis of central nervous system (CNS) infection. The seizures are related to the rate in rise in temperature, not the peak degree. C. Laboratory Data 1. EEG should be done after the second seizure. It can help determine the type of seizure, locate the site of the seizure, and therefore direct the type of medication. 2. MRI (magnetic resonance imaging) and CT (computed tomography) may be helpful in identifying structural abnormalities. D. Anticonvulsant Treatments 1. Medications a. Carbamazepine i. Mechanism of action: Blocks sodium and calcium voltage-dependent channels ii. Pharmacokinetics: Pan-enzyme inducer; autoinducer iii. Adverse effects: Rash (rarely may progress to Stevens-Johnson syndrome or toxic epidermal necrolysis), syndrome of inappropriate antidiuretic hormone release and hyponatremia, aplastic and other anemias, thrombocytopenia, leukopenia, blurred vision, diplopia, ataxia, nausea, headache, fatigue iv. Therapeutic levels: 4–12 mg/mL b. Clobazam i. Mechanism of action: Benzodiazepine; augments γ-aminobutyric acid (GABAA) chloride influx ii. Tolerance may develop. ACCP Updates in Therapeutics® 2015: Pediatric Pharmacy Preparatory Review Course 1-79


c.

d.

e.

f.

g.

h.

i.

j.

iii. Adverse effects: Somnolence, sedation, drooling, aggression, fatigue, suicidal behavior, and ideation iv. Controlled substance, schedule IV Ethosuximide i. Mechanism of action: T-type calcium channel blocker ii. Adverse effects: Nausea, headache, drowsiness, fatigue iii. Therapeutic levels: 40–100 mcg/mL Ezogabine i. Mechanism of action: Potassium channel blocker that stabilizes the channel open (potassium channel opener; voltage gate activation) ii. Adverse effects: Urinary retention; QT prolongation; psychiatric symptoms like increased suicidal ideation and hallucinations; fatigue; ataxia; and blue fingernails Felbamate i. Mechanism of action: Fast sodium channel blocker, enhances GABA, blocks NMDA (N-methyl-d-aspartate) receptors ii. Serious adverse effects: Aplastic anemia, acute hepatic failure. Guardian must sign consent form. iii. Other adverse effects: Anorexia, somnolence, insomnia, vomiting, weight loss, nausea, gait abnormality iv. Indicated for Lennox-Gastaut syndrome v. Used only for severe and refractory cases when other medications have failed Fosphenytoin i. Mechanism of action: Prodrug for phenytoin, fast sodium channel blocker ii. Parental formulation used for loading or maintenance. Preferred formulation because of less hypotension and lack of need for a central line iii. Primarily used for status epilepticus or in patients who cannot take oral phenytoin Gabapentin i. Mechanism of action: Inhibition of the α2δ subunit of voltage-dependent calcium channels. Increases GABA levels and synthesis. Modulates sodium and calcium channels. Inhibits monoamine neurotransmitter release ii. Pharmacokinetics: Not metabolized, eliminated renally. No dosing adjustments recommended for children younger than 12 years. For those 12 years and older, adjust dose when creatinine clearance is less than 60 mL/minute. iii. Adverse effects: Somnolence, fatigue, behavior changes, dizziness, weight gain Lacosamide i. Mechanism of action: Slow sodium channel blocker ii. Pharmacokinetics: Adjust dose when creatinine clearance is 30 mL/minute or less. iii. Adverse effects: PR-interval prolongation, dizziness, headache, diplopia Lamotrigine i. Mechanism of action: Blocks voltage-dependent sodium channels, increases GABA concentrations, decreases glutamate release ii. Black box warning: Rash. The rash can progress to Stevens-Johnson syndrome and toxic epidermal necrolysis. This is more common in pediatric patients within the first 8 weeks of treatment or when given with valproic acid. Slow titration of dose minimizes risk. When given with valproic acid, max dose is reduced to half or recommended dose when given as monotherapy. iii. Adverse effects: Drowsiness, diplopia, dizziness, headache, confusion Levetiracetam i. Mechanism of action: Unknown but may inhibit calcium channels, facilitate GABA transmission, or inhibit glutamate release



k.

l.

m.

n.

o.

p.

q.

ii. Pharmacokinetics: Not metabolized; adjust for renal dysfunction iii. Adverse effects: Dizziness, somnolence, behavior/personality changes, irritability, hostility, nervousness Oxcarbazepine i. Mechanism of action: Blocks sodium and calcium channel voltage-gated channels, fast sodium channel blocker ii. Pharmacokinetics: Active metabolite 10-monohydroxy oxcarbazepine; enzyme inducer, no autoinduction iii. Adverse effects: Hyponatremia more common than with carbamazepine, rash less common than with carbamazepine. Other adverse effects include dizziness, drowsiness, and nausea. iv. Therapeutic level: 10–40 mcg/mL Phenobarbital i. Mechanism of action: Increases GABA chloride influx ii. Pharmacokinetics: Pan-enzyme inducer iii. Adverse effects: Hyperactivity, cognitive impairment, drowsiness, lethargy, depression, apnea/ bradycardia (with rapid intravenous administration) iv. Controlled substance, scheduled as C-IV v. Therapeutic level: 15–40 mcg/mL. Toxic: greater than 40 mcg/mL Phenytoin/fosphenytoin i. Mechanism of action: Blocks voltage-gated sodium channels ii. Pharmacokinetics: Enzyme inducer, nonlinear kinetics iii. Adverse effects: Nystagmus, ataxia, drowsiness, cognitive impairment iv. Non–dose-related adverse effects: Gingival hyperplasia, hirsutism, acne, rash, hepatotoxicity, hypersensitivity reactions including rash v. Administer intravenously slow: Not to exceed 1–3 mg/kg/minute in neonates, 50 mg/minute in adults vi. Oral suspension: Must be shaken well; adheres to feeding tubes and is bound by enteral nutrition products vii. Therapeutic level: 10–20 mcg/mL; free phenytoin: 1–2.5 mcg/mL Pregabalin i. Mechanism of action: Inhibition of the α2δ subunit of voltage-dependent calcium channels; GABA analog ii. Pharmacokinetics: Not metabolized, reduce dose in renal dysfunction iii. Adverse effects: Drowsiness, ataxia, somnolence, weight gain, headache, blurred vision Rufinamide i. Mechanism of action: Unknown; fast sodium channel blocker ii. Pharmacokinetics: Absorption increased by food, administer with food iii. Adverse effects: Somnolence, dizziness, fatigue, nausea, headache, shortened QT interval Tiagabine i. Mechanism of action: Carbonic anhydrase inhibitor; inhibits GABA reuptake ii. Adverse effects: Dizziness, nervousness, fatigue, depressed mood, concentration difficulties Topiramate i. Mechanism of action: Fast sodium channel blocker; enhances GABA and blocks AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate) glutamate subtype ii. Pharmacokinetics: Not extensively metabolized iii. Adverse effects: Drowsiness, paresthesias, weight loss, renal stones, metabolic acidosis, decreased sweating, concentration and memory difficulties, behavior problems, acute angleclosure glaucoma



r. Valproic acid i. Mechanism of action: Blocks T-type calcium channels, blocks sodium channels, increases GABA activity ii. Pharmacokinetics: Enzyme inhibitor iii. Adverse effects: Hepatotoxicity (greater risk in children younger than 2 years) nausea/ vomiting, weight gain, thrombocytopenia, pancreatitis, alopecia, tremor, hyperammonemia iv. Depakote capsules can be opened and sprinkled on food. Do not chew sprinkles. v. Therapeutic levels: 50–100 mcg/mL. Efficacy may improve with higher levels,but toxicity can occur. s. Vigabatrin i. Mechanism of action: Irreversible inhibition of GABA transaminase ii. Pharmacokinetics: Induces cytochrome P450 (CYP) 2C9 iii. Adverse effects: Fatigue, somnolence, nystagmus, tremor, blurred vision, vision impairment, weight gain, arthralgia, ataxia, confusion t. Zonisamide i. Mechanism of action: Fast sodium channel blocker, blocks T-type calcium channels, weak carbonic anhydrase inhibitor ii. Adverse effects: Somnolence, dizziness, decreased sweating, hyperthermia, metabolic acidosis, anorexia. Chronic acidosis may lead to rash, Stevens-Johnson syndrome, and nephrolithiasis. Table 2. ILAE Summary of Medications for Types of Seizures in Children Type of Seizure

Established

Possible

Potential

Partial

Oxcarbazepine

Carbamazepine Phenobarbital Phenytoin Topiramate Valproic acid Vigabatrin

Clobazam Clonazepam Lamotrigine Zonisamide

Carbamazepine Phenobarbital Phenytoin Topiramate Valproic acid

Oxcarbazepine

Generalized tonic-clonic

Absence

Ethosuximide Valproic acid

Benign epilepsy with centrotemporal spikes

Lamotrigine Carbamazepine Valproic acid

Juvenile myoclonic epilepsy

Gabapentin Levetiracetam Oxcarbazepine Topiramate Valproic acid

ILAE = International League Against Epilepsy.



Table 3. Medications and Doses for Children in Seizures Drug Name

Dose

Formulations

Carbamazepine

< 6 years: Initial 10–20 mg/kg/day divided into two or three daily doses; suspension four times daily; max 35 mg/kg/day 6–12 years: Initial 100 mg twice daily, suspension 50 mg four times daily; increase by 100 mg/week, maintenance; 400–800 mg/day; max 1000 mg/day > 12 years: Initial 200 mg twice daily, suspension 100 mg four times daily, increase by 200 mg/week, maintenance: 800–1200 mg/day; max 12–13 years: 1000 mg/day; > 15 max 1200 mg/day

ER capsule, suspension, tablet, chewable tablet, ER tablet

Clobazam

< 2 years: 0.5–1 mg/kg/day >2 years: ≤ 30 kg: Initial 5 mg, increase by 10 mg each to a max of 40 mg/day > 30 kg: Initial 5–15 mg/day up to 40 mg/day Doses > 30 mg should be divided into two doses

Tablet

Ethosuximide

< 6 years: Initial: 15 mg/kg/day twice daily, increase every 4–7 days; maintenance: 15–40 mg/kg/day; max 1.5 g/day ≥ 6 years: 250 mg twice daily; increase by 250 mg every 4–7 days; maintenance 20–40 mg/kg/day; max 1.5 g/day

Capsule, solution, syrup

Ezogabine

Adult dosing only Initial: 100 mg three times daily. Increase weekly by 150 mg. Maintenance 300–400 mg three times daily; max 1200 mg/day

Tablet

Felbamate

Lennox-Gastaut syndrome 2–14 years: 15 mg/kg/day divided three or Suspension, tablet four times daily; increase by 15 mg/kg/day weekly; max 45 mg/kg/ day ≥ 14 years: Adjunct and conversion to monotherapy: 1200 mg/day divided three or four times daily; increase by 1200 mg/day weekly; max 3600 mg/day; monotherapy increase by 600 mg every 2 weeks

Gabapentin

3–12 years: Initial: 10–15 mg/kg/day divided three times daily; main- Capsule, solution, tenance: 3–4 years: 40 mg/kg/day divided three times daily; maintetablet nance 5–12 years: 25–35 mg/kg/day divided three times daily > 12 years: Initial 300 mg three times daily; maintenance: 900–1800 mg/day; max 3600 mg/day

Lacosamide

≥ 3 to ≤ 16 years: 1 mg/kg/day divided twice daily ≥ 17 years: Initial 50 mg twice daily; increase by 100 mg/week; maintenance 200–400 mg/day PO and IV doses are equivalent

Injection, solution, tablet



Table 3. Medications and Doses for Children in Seizures (continued) Drug Name

Dose

Formulations

Lamotrigine

Lamotrigine alone 2–12 years: 0.6 mg/kg/day initially; increase to 5–10 mg/kg/day divided twice daily Adults: 50 mg/day initially; increase to 300–500 mg/day divided twice daily Lamotrigine and valproic acid 2–12 years: 0.15 mg/kg/day initially; increase to 1–5 mg/kg/day divided twice daily Adults: 25 mg every other day initially; increase to 100–400 mg/day divided once or twice daily Lamotrigine and enzyme inducer 2–12 years: 0.6 mg/kg/day initially; increase up to 10–15 mg/kg/day divided twice daily Adults: 50 mg daily initially; increase to 300–500 mg divided twice daily

Tablet, chewable tablet, ER tablet, ODT, extemporaneous suspension

Levetiracetam

4–15 years: Initial 10 mg/kg/day twice daily; increase by 10 mg/kg every 2 weeks; max 30 mg/kg/day twice daily ≥ 16 years (PO/IV): Immediate release 500 mg twice daily, increase by 500 mg/dose every 2 weeks; max 1500 mg twice daily. ER; initial 1000 mg/day, increase by 1000 mg/day every 2 weeks, max 3000 mg/day IV daily dose = PO daily dose

Injection, solution, tablet, tablet ER

Oxcarbazepine

2–16 years for adjunctive: < 20 kg: Initiate at 16–20 mg/kg/day divided twice daily; > 20 kg: Initiate 8–10 mg/kg/day divided twice daily; increase over 2 weeks to maintenance Dose by weight: < 20 kg: 60 mg/kg/day, 20–29 kg; 900 mg/day; 29.1–39 kg: 1200 mg/day; > 39 kg: 1800 mg/day. > 16 years for adjunctive: Initial 300 mg twice daily, increase by 600 mg/day weekly; maintenance: 1200 mg/day divided twice daily 4–16 years for monotherapy: 8–10 mg/kg/day divided twice daily; increase by 5 mg/kg/day every third day; maintenance: 20–24.9 kg; 600–900 mg/day; 25 to < 35 kg: 900–1200 mg/day; 35 to < 45 kg: 900–1500 mg/day, 45 to < 50 kg: 1200–1500 mg/day; 50 to < 60 kg: 1200–1800 mg/day, 60 to < 70 kg: 1200–2100 mg/day, ≥ 70 kg: 1500–2100 mg/day > 16 years for monotherapy: Initial 300 mg twice daily; increase by 300 mg/day weekly; maintenance: 1200 mg//day divided twice daily

Suspension, tablet

Phenobarbital

Maintenance: < 1 year: 5–8 mg/kg/day divided into one or two doses; Elixir, injection, 1–5 years: 6–8 mg/kg/day divided into one or two doses; 5–12 years: tablet 3–6 mg/kg/day divided into one or two doses; > 12 years: 1–3 mg/kg/ day or 50–100 mg divided into two or three doses




Dose

Formulations

Phenytoin

Loading dose (IV/PO): 15–20 mg/kg/dose ER capsule, injecNeonates: Initial: 5 mg/kg/day divided twice daily; maintenance 5–8 tion, suspension, mg/kg/day divided twice daily; may require three times daily chewable tablet Infants/children: 5 mg/kg/day divided into two or three doses; maintenance: 6 months to 3 years: 8–10 mg/kg/day; 4–6 years: 7.5–9 mg/ kg/day; 7–9 years: 7–8 mg/kg/day; 10–16 years: 6–7 mg/kg/day; > 16 years: 300 mg/day or 4–6 mg/kg/day in two or three divided doses 92 mg of phenytoin (suspension/chewable) = 100 mg of phenytoin sodium

Pregabalin

Adult dosing only Initial 150 mg/day in two or three doses; max 600 mg/day

Capsule, solution

Rufinamide

≥ 4 years Initial 10 mg/kg/day divided into two doses, increase every other day by 10 mg/kg/day; maintenance: 45 mg/kg/day or 3200 mg/ day divided into two doses (whichever is lower) If taking valproic acid, initial dose is < 10 mg/kg/day Adults: Initial 400–800 mg/day divided into two doses; increase every other day by 400–800 mg/day; max 3200 mg/day in two doses

Tablet, suspension

Tiagabine

12–18 years: With enzyme-inducing agents: 4 mg/day for week 1; 4 mg twice daily for week 2, increase by 4–8 mg/day; max 32 mg/day in two to four doses

Tablet, suspension

Topiramate

2–16 years for adjunctive: Initial 25 mg/day or 1–3 mg/kg/day; increase by 1-3 mg/kg/day every 1 or 2 weeks; max 3–9 mg/kg day divided into two doses ≥ 17 years: Initial: 25 mg/day or twice daily for 1 week; increase by 25–50 mg/week; maintenance: 100–200 mg/day ≥ 10 years for monotherapy: Initial: 25 mg twice daily; increase by 50 mg/day weekly; up to 100 mg twice daily for week 4; may then increase by 100 mg/day weekly; max 200 mg twice daily

Sprinkle capsule, tablet, extemporaneous suspension

Valproic acid

Children and adults: Initial: 15 mg/kg/day; divided according to formulation; increase by 5–10 mg/kg/day weekly to therapeutic levels; immediate-release formulations are divided into three or four times daily; max 60 mg/kg/day Bioavailability of ER product is 8%–20% lower than that of other products

Capsule, sprinkle capsule, injection, solution, syrup, delayed-release tablet, ER tablet

Vigabatrin

Restricted access per REMS program Powder for solu1 month to 2 years: Initial 50 mg/kg/day divided twice daily. Increase tion, tablet by 25–50 mg/kg/day every 3 days; max 150 mg/kg/day




Dose

Formulations

Zonisamide

Infants and children: Initial: 1–2 mg/kg/day divided twice daily; increase by 0.5–1 mg/kg/day every 2 weeks; maintenance dose: 5–8 mg/kg/day; max for infantile spasms: 10–13 mg/kg/day ≥ 16 years: Initial: 100 mg/day; increase by 200 mg/day after week 2; may increase by 100 mg/day every 2 weeks; if no response, may increase to > 400 mg/day in one or two divided doses

Capsule, extemporaneous suspension

ER = extended release; IV = intravenous(ly); ODT =orally disintegrating tablet; PO = oral(ly); REMS = Risk Evaluation and Mitigation Strategies.

2. Nonpharmacologic treatment a. Ketogenic diet: A diet consisting of low-protein and low-carbohydrate and high-fat meals. The diet may reduce seizure frequency in refractory cases. Long-term adverse effects include weight loss, hyperlipidemia, hypoproteinemia, nephrolithiasis, renal tubular acidosis, constipation, growth retardation, and increases in hepatic and pancreatic enzymes. Monitor for QT prolongation and nutritional status. b. Vagal nerve stimulation: Used as adjunctive therapy in refractory epilepsy c. Surgery: Used for refractory focal seizures Patient Cases Questions 4 and 5 pertain to the following case: A.P. is a 13-year-old male adolescent (weight 55 kg) initiated on oxcarbazepine monotherapy for partial-onset seizures. His mother comes to the pharmacy to fill the prescription. His current prescription dose is 200 mg twice daily. His mother says that the physician told her the dose would most likely increase. 4. Which best reflects the max daily recommended dose for this patient? A. 600 mg. B. 900 mg. C. 1800 mg. D. 2400 mg. 5. A.P.’s mother has heard that antiepileptics have many adverse effects. Which adverse effect would the mother best be cautioned about regarding oxcarbazepine in A.P.? A. Gingival hyperplasia. B. Hirsutism. C. Hyponatremia. D. Renal failure.



Patient Cases (continued) 6. K.W. is a 15-year-old female adolescent (weight 54 kg) with generalized tonic-clonic seizures. She has been taking valproic acid 125 mg four times daily. Her serum level is 80 mcg/mL. She is still having seizures, but the family does not want to increase the dose because, on higher doses, K.W. becomes very drowsy, uncoordinated, and lethargic. The physician would like to add lamotrigine. Which would be the best initial dose of lamotrigine for K.W.? A. 25 mg daily. B. 50 mg twice daily. C. 25 mg every other day. D. 50 mg daily. 7. Which best reflects the lamotrigine adverse effect correlated with speed of titration? A. Rash. B. Tremor. C. Weight gain. D. Thrombocytopenia. 8. E.E. is a 16-year-old male adolescent who has been prescribed topiramate for juvenile myoclonic epilepsy. Which adverse event is most commonly associated with topiramate and is the one about which E.E. be counseled? A. Tremor. B. Rash. C. Weight gain. D. Memory/concentration difficulties. 9. N.P. is a 12-month-old female infant who was brought to the ED after having a seizure in the evening. She has reportedly not been feeling well and is irritable, crying, and restless. Her mother thought she was sick and checked her temperature earlier in the morning. She reports that N.P.’s temperature was normal. Now, N.P.’s temperature is 102.4°F. The seizure lasted less than 1 minute. Which type of seizure does N.P. most likely have? A. New-onset focal seizures. B. New-onset generalized seizures. C. Absence seizures. D. Febrile seizures.

III. CEREBRAL PALSY A. Epidemiology 1. Prevalence is two or three cases per 1000 in children. 2. Ratio of boys to girls is 1.4:1. B. Gross Motor Function Classification System 1. Level I: Walks without restriction: Limitations with more advanced gross motor skills 2. Level II: Walks without assistive devices: Limitations to walking outdoors and in the community 3. Level III: Walks with assistive devices: Limitations to walking outdoors and in the community 4. Level IV: Self-mobility with limitations: Children are transported, or they use power mobility outdoors and in the community. 5. Level V: Self-mobility is severely limited, even with the use of assistive technology. ACCP Updates in Therapeutics® 2015: Pediatric Pharmacy Preparatory Review Course 1-87


C. Classified by Type of Muscle Abnormality 1. Spasticity a. Stiff or tight muscles b. Increased deep tendon reflexes c. Scissored gait with toe-walking d. Unilateral or bilateral e. Upper and lower extremities may be affected. 2. Dyskinesia (dystonic or athetoid) a. Slow, uncontrollable writhing movements b. Grimacing or drooling caused by hyperactive muscles of the face and tongue 3. Ataxia a. Unsteady wide-based gait b. Intention tremor c. Difficulty with precise motions such as writing D. Treatment 1. Spasticity a. Baclofen (oral) i. Mechanism of action: GABA agonist. Binds to GABAB receptors in the spinal cord ii. Pharmacokinetics: Rapidly absorbed, metabolized in the liver Table 4. Dose Recommendations by Age for Baclofen Younger than 2 Years

2–7 years

Older than 7 Years

Adult 5 mg three times daily

Initial dose

2. 5 mg every 8 hours

5 mg every 8 hours

5 mg every 8 hours

Maintenance

10–20 mg/day in three divided doses

20–30 mg/day in three divided doses

30–40 mg/day in divided doses

Max dose

40 mg/day in divided doses



80 mg/day

Titration schedule

Every 3 days in increments of 5–15 mg/day

Every 3 days in increments of 5–15 mg/day

Every 3 days

Every 3 days

iii. Adverse events: Sedation, confusion. If abruptly discontinued, may cause withdrawal symptoms, including spasms, hallucinations, confusion, fever, and seizures iv. Special considerations: If discontinuation is warranted, taper the dose. b. Baclofen (intrathecal) i. Indicated when other oral medications have failed (oral baclofen, other muscle relaxants, and botulinum toxin A), the patient is adherent to the office visits, and the patient is older than 4 years ii. Administered by implantable pump with a continuous infusion. Pump is refilled by health care provider every 2–6 months. iii. Dose: (a) Screening – 50 mcg intrathecally for one dose and observe for 4–8 hours. If less than desired response, increase by 25 mcg and observe for another 4–8 hours. May increase ACCP Updates in Therapeutics® 2015: Pediatric Pharmacy Preparatory Review Course 1-88


c.

d.

e.

f.

once more to 100 mcg in 24 hours. If no response with 100 mcg, the patient is not a candidate for intrathecal baclofen. If screening dose is greater than 8 hours, then daily dose = effective screen dose. If screening dose is less than 8 hours daily dose = twice effective screen dosing. (b) Average daily dose: 12 years or younger: 100–300 mcg/day. Older than 12 years and adults: 300–800 mcg/day iv. Overdose symptoms: Hypotonia, drowsiness, unarousability, respiratory depression v. Monitor for infections around the pump area or meningitis as well as for signs of pump malfunctions or blockage. vi. Abrupt withdrawal symptoms include elevated temperature, paresthesias, altered mental status, rebound spasticity, and muscle rigidity. In rare cases, it can progress to rhabdomyolysis, malignant hyperthermia, multiple organ system failure, and death. Dantrolene i. Mechanism of action: Inhibits the release of calcium at the sarcoplasmic reticulum, resulting in muscle weakness. Directly affects the skeletal muscles ii. Dose: (a) Child: Initial 0.5 mg/kg/dose daily for 7 days; increase by 0.5 mg/kg/dose three times daily for 7 days; then 1 mg/kg/dose three times daily for 7 days; then 2 mg/kg/dose three times daily. Do not exceed 400 mg/day. (b) Adult: Initial 25 mg daily for 7 days; increase by 25 mg three times daily for 7 days; then 50 mg three times daily for 7 days; then 100 mg three times daily. Do not exceed 400 mg/day. iii. Adverse events: Drowsiness, irritability, hepatoxicity, and dose-dependent weakness Diazepam/clonazepam i. Mechanism of action: Benzodiazepine augments GABAA chloride influx. ii. Dose: (a) Clonazepam – Younger than 10 years or weight less than 30 kg: Initial: 0.01–0.03 mg/kg/ day divided into two or three doses daily. Increase no more than 0.5 mg every third day. Maintenance: 0.1–0.2 mg/kg/day divided into three doses per day. Not to exceed 0.2 mg/ kg/day. Older than 10 years or weight greater than 30 kg or adult: Initial not to exceed 0.5 mg three times daily; may increase by 0.5–1 mg every third day. Maintenance: 0.05–0.2 mg/kg/day. Not to exceed 20 mg/day (b) Diazepam – Child: 0.5–0.1 mg/kg/day divided into two to four doses/day. Max 0.8 mg/ kg/day. Adult: 2–10 mg/day divided into two to four doses per day iii. Adverse events: Sedation, weakness, and ataxia iv. Special considerations: May have risk of withdrawal if abruptly discontinued Tizanidine i. Mechanism of action: α2-Adrenergic agonist; reduces muscle tone through hyperpolarization of motor neurons with a decrease in excitability ii. Dose: Child to 15 years: 0.05 mg/kg/day. Initial dose for younger than 10 years: mg/day at bedtime. Initial dose for those 10 and older: 2 mg/day at bedtime Adult: Initial 4 mg/day. Increase to three times daily. Max dose: 36 mg/day iii. Adverse events: Sedation, hypotension, asthenia, dry mouth, dizziness, hallucinations, and hepatotoxicity iv. Special considerations: When given with food, absorption increases. Botulinum toxin A i. Mechanism of action: Acts as a denervation agent at the nerve terminal end plate by blocking acetylcholine release at the neuromuscular junction. Causes muscle paralysis ii. Given every 3 months as an intramuscular injection at the location of muscle involvement iii. Adverse events: Pain at the injection site, excessive weakness, unsteadiness, falls, and fatigue



iv. Special considerations: OnabotulinumtoxinA is approved in adults for upper limb spasticity in adults. It is not approved in children, but the practice parameter recommends it for localized or segmental spasticity. v. Potential for systemic toxicity from the spread of botulinum toxicity from the injection site g. Evidence for treating spasticity is older and inconclusive, but treatment options have been used historically. 2. Drooling a. Nonpharmacologic treatment should be tried first (e.g., good oral hygiene, attention to posture, training in oral motor skills). b. Glycopyrrolate/scopolamine: i. Anticholinergic that blocks the muscarinic receptors in the salivary glands ii. Adverse events include dry mouth, urinary retention, and constipation. iii. Glycopyrrolate is available as a solution. Scopolamine is available as a transdermal patch. c. Botulinum toxin A: Injected into the submandibular glands. Adverse events include pain, hematoma, swelling of the gland, and infection. Temporary swelling may cause swallowing difficulties. 3. Low bone mineral density a. Vitamin D and calcium supplementation may be used if levels place the patient at increased risk. b. Bisphosphonates may be considered if the patient has a history of fractures. Patient Cases Questions 10–12 pertain to the following case: J.N. is a 10-year-old girl (weight 28 kg) with cerebral palsy. Her symptoms of spasticity (muscle stiffness/tightness) are getting worse and are interfering with daily function. The physician prescribes tizanidine 2 mg at bedtime. 10. On which adverse event would J.N. and her family best receive counseling? A. Hypertension. B. Sedation. C. Renal dysfunction. D. Mania. 11. After several months, J.N. returns to the physician’s office with worsening symptoms. The physician switches the prescription to oral baclofen. Although this medication is well tolerated by J.N., the muscle tightness continues in her arms, interfering with writing and other activities. The physician decides to try onabotulinumtoxinA to be given every 3 months. Although rare, which potentially serious adverse effect would be best to notify J.N. and her family about? A. Hepatic failure. B. Renal failure. C. Systemic toxicity. D. Tardive dyskinesia.



Patient Cases (continued) 12. After about 1 year of treatment, J.N.’s family continues to report that the medications tried have not been that helpful for J.N.’s spasticity symptoms. The physician decides to try intrathecal baclofen. After 2 months of improved symptom control, J.N. suddenly becomes confused and irritated, with an elevated temperature. J.N. also is having terrible muscle rigidity, and her spasticity symptoms are worse. Which is the most likely cause of these symptoms? A. Injection site infection. B. Baclofen toxicity. C. Abrupt discontinuation. D. Inadequate dose.

IV. AUTISM SPECTRUM DISORDERS A. Epidemiology 1. Prevalence of autism spectrum disorders (ASDs) is 11.3 cases per 1000 births. 2. Asperger’s disorder is one-fifth as common as typical autism, although this disorder is no longer specified in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). 3. Autism is 4 times more common in males than in females. 4. Females with autism tend to have greater intellectual disability. B. Signs and Symptoms 1. DSM-5 criteria for ASDs changed from DSM-IV-TR criteria. DSM-5 ASDs now include autistic disorder, Asperger disorder, childhood disintegrated disorder, Rett’s disorder, and pervasive developmental disorder not otherwise specified. 2. Diagnostic domains were reduced from three to two. a. Deficits in social communication and interactions b. Restricted repetitive patterns of behaviors and interests 3. Associated behavioral difficulties a. Hyperactivity b. Obsessive-compulsive phenomena c. Self-injury d. Aggression e. Stereotypies (repetitive or ritualistic movements, posturing, or utterances) f. Tics g. Affective symptoms (depression, mania, mood lability, anxiety) 4. Attention difficulties are frequent in ASD, and DSM-5 allows for ADHD as an additional diagnosis. 5. 50% may have severe or profound intellectual disability. C. Treatment 1. Nonpharmacologic treatment such as structural education and behavioral interventions is effective; should be recommended 2. Pharmacotherapy should be recommended for a specific target symptom or comorbid condition. a. Second-generation or atypical antipsychotics: i. Risperidone and aripiprazole are FDA label approved for the treatment of irritability, consisting primarily of physical aggression and severe tantrum behavior associated with autism.



ii. One small study has been published investigating olanzapine. Improved group interactions were noted, but global improvement was not significant. Weight gain occurred significantly more often in the olanzapine group. Olanzapine is not FDA label approved. iii. Insufficient data exist for other atypical antipsychotics. b. First-generation or typical antipsychotics: Haloperidol used until second-generation antipsychotics were developed Table 5. Antipsychotics for Target Symptoms of Autism Drug Name

Age Approved

Dose

Target Symptom

Adverse Events

Aripiprazole

6–17 years

Initial: 2 mg/day Titrate by 5 mg/week Max: 15 mg/day

Irritability Hyperactivity Stereotypies (repetitive movements)

Weight gain Drooling Fatigue Somnolence Vomiting

Risperidone

5–16 years

< 20 kg: Initial: 0.25 mg/day Titrate: 0.25 mg/day every 2 weeks Max: 3 mg/day > 20 kg: Initiate: 0.5 mg/day Titrate by 0.5 mg/day every 2 weeks Max 3 mg/day

Severe aggression Temper tantrums Self-injury Hyperactivity Stereotypies Irritability Repetitive behaviors

EPS Weight gain Gynecomastia Fatigue Drowsiness Dizziness Hyperprolactinemia Drooling

Haloperidol

Not FDA label approved for autism

0.25–4 mg/day

Social isolation Stereotypies Hyperactivity Anger-related behaviors

Sedation EPS Irritability

EPS = extrapyramidal symptoms.

c. Anticonvulsants: Valproic acid, lamotrigine, and levetiracetam have inconsistent results with target symptoms of irritability and repetitive behaviors. Often used for comorbid seizure disorders d. Other medications often used in children with ASDs caused by comorbid conditions: i. i.Selective serotonin reuptake inhibitors (SSRIs) for depression/anxiety ii. α2-Agonists, stimulants, and/or atomoxetine for ADHD symptoms



Patient Cases Questions 13 and 14 pertain to the following case: E.A., a 9-year old boy with ASD presents with symptoms of hyperactivity, stereotypies, and self-injurious behavior. 13. A physician decides to prescribe risperidone for E.A. For which potential adverse effects would the patient and his family best receive counseling on risperidone use? A. Weight loss and/or anorexia. B. Anticholinergic symptoms like constipation, dry mouth, and blurred vision. C. Male breast tenderness. D. Antipsychotic withdrawal symptoms like seizures. 14. After several years of improved behavior, E.A. begins to have worsening irritability and aggression. The physician would like to change E.A.’s therapy. Which alternative medication would be the best option? A. Aripiprazole. B. Lurasidone. C. Asenapine. D. Iloperidone. 15. J.P. is a 12-year-old girl (weight 35 kg) with an ASD. For the past few months, the patient has become more irritable and aggressive, and she is having emotional outbursts. Her parents are frustrated and looking for help. The physician wants to prescribe an antipsychotic. Given J.P.’s diagnosis and symptoms, which is the best option? A. Olanzapine. B. Risperidone. C. Quetiapine. D. Ziprasidone.

V. PEDIATRIC BIPOLAR DISORDER A. Epidemiology 1. Lifetime prevalence of type 1 bipolar disorder in the general population: 0.4%–1.6% 2. Lifetime prevalence of type 2 bipolar disorder in the general population: 0.5% 3. Pediatric bipolar disorder estimated at 1.8% B. Definitions 1. Mania: Mood that is abnormally and persistently elevated, expansive, or irritable and the presence of abnormally increased goal-directed activity or energy that is persistent, lasting 1 week most of the day almost every day. Three or more of the following symptoms (four or more if the mood is simply irritable) are present: a. Inflated self-esteem or grandiosity b. Decreased need for sleep c. Hyperverbal or pressured speech d. Flight of ideas or racing thoughts e. Distractibility or continuously changing plans or activities f. Increase in goal-directed activity or psychomotor agitation/physical restlessness g. Excessive involvement in risky activities that may have negative consequences (e.g., spending sprees, sexually inappropriate behavior, or risky business ventures). The symptoms must be severe enough to cause functional impairment or hospitalization. ACCP Updates in Therapeutics® 2015: Pediatric Pharmacy Preparatory Review Course 1-93


2. Hypomania: Symptoms are similar to those of mania, but they are persistent, lasting at least 4 days most of the day almost every day. Three or more symptoms (four or more if the mood is simply irritable) are present. Risky activities are usually not so severe that they require hospitalization. 3. Major depressive episode (see Pediatric Depression section for symptoms) 4. Type 1 bipolar disorder: Criteria for one manic episode must be met. One lifetime manic episode must occur to have this diagnosis. A major depressive episode may or may not always occur. 5. Type 2 bipolar disorder – Criteria for one hypomanic episode and one major depressive episode must be met with no history of a manic episode. 6. Cyclothymic disorder – For children and adolescents: at least 1 year of several periods of hypomanic symptoms in those who have never met the criteria for manic episodes and in those with several periods of depressive symptoms who have never met the criteria for a major depressive episode. C. Treatment 1. Practice parameter defined in 2007 for treatment of children and adolescents a. Recommends using pharmacotherapy for mania b. Ongoing to prevent relapse and possibly lifelong c. Baseline and follow-up monitoring for symptoms, adverse effects, and laboratory monitoring d. ECT (electroconvulsive therapy) may be used if medications are not tolerated. 2. Treatment guidelines Table 6. Treatment Guideline Developed in 2005 for Children and Adolescents Manic or Mixed without Psychosis

Manic or Mixed with Psychosis

Stage 1

Second-generation antipsychotic (olanzapine, quetiapine risperidone) or mood stabilizer (lithium, valproic acid, carbamazepine) If partial response, may combine two (not two antipsychotics)

Mood stabilizer (lithium, valproic acid, carbamazepine) plus second-generation antipsychotic

Stage 2

Switch to another agent if monotherapy not already tried. If partial response, augment with second agent

Mood stabilizer (lithium, valproic acid, carbamazepine) plus second-generation antipsychotic Combination not tried in stage 1 Partial response: Use lithium and valproic acid or carbamazepine and a second-generation antipsychotic

Stage 3

Monotherapy agent not tried in stage 1 or 2

Alternative mood stabilizer or second-generation antipsychotic added to two-medication combination

Stage 4

Combination of two agents. If partial response, may add third agent

Combination of two mood stabilizers and secondgeneration antipsychotic

Stage 5

Monotherapy with oxcarbazepine, ziprasidone, or aripiprazole

Monotherapy with oxcarbazepine, ziprasidone, or aripiprazole

Stage 6

ECT (adolescents) or clozapine

ECT (adolescents) or clozapine

ECT = electroconvulsive therapy. Kowatch RA, Fristad M, Birmaher B, et al. Treatment guidelines for children and adolescents with bipolar disorder. J Am Acad Child Adolesc Psychiatry 2005;44:213-35.



3. Lithium a. Indicated for acute mania or mixed episode for children 12 years and older. Off-label indication for depression b. Mechanism of action: Unknown; normalizes or inhibits second messenger systems; decreases serotonin reuptake and increases postsynaptic serotonin receptor sensitivity; enhances GABA activity; reduces glutamate activity; modulates calcium metabolism c. Pharmacokinetics: Linear, not metabolized, half-life 24 hours, renal elimination d. Dose i. Acute mania in adults and adolescents 12 years and older: 600 mg three times daily or immediate release or 900 mg twice daily for sustained release. Start at lower doses to minimize adverse effects and improve tolerances. ii. Acute mania in children (6–12 years old): Start at 15–20 mg/kg/day in three or four divided doses. Usual dose is 15–60 mg/kg/day in divided doses. iii. Maintenance dose in adults and adolescents 12 years and older: Start at 900 mg/day in divided doses. Usual dosage range is 900–2400 mg/day in two to four divided doses. Once-daily doses up to 1800 mg are usually tolerated. iv. Maintenance dose in children (6–12 years old): Start at 10–20 mg/kg/day. Increase to 15–20 mg/kg/day. e. Therapeutic levels: 0.8–1.2 mEq/L for acute treatment. Maintenance treatment: 0.6–1.0 mEq/L. Draw levels 4–5 days after initiation. f. Adverse effects: i. Nausea, vomiting, diarrhea, hand tremor, impaired cognition, and drowsiness. ii. Mild toxicity: Nausea/vomiting, loose stools, lethargy, drowsiness, coarse hand tremor, muscular weakness ii. Moderate toxicity: Severe nausea, vomiting, diarrhea, confusion, dysarthria, nystagmus, ataxia, myoclonic twitches, electrocardiographic (ECG) changes iii. Severe toxicity: Severe nausea, vomiting, diarrhea, impaired consciousness, increased deep tendon reflexes, seizures, syncope, coma, ECG changes, renal insufficiency 4. Valproic acid (see Seizure Disorders section for mechanism of action, adverse events, and doses) – Approved in adults for mania and mixed episodes Not FDA label approved in children and adolescents for mania 5. Carbamazepine (see Seizure Disorders section for mechanism of action, adverse events, and doses) – Approved for adults for manic or mixed episodes. Not FDA label approved for children and adolescents 6. Lamotrigine (see Seizure Disorders section for mechanism of action, adverse events, and doses) – Approved in adults for long-term maintenance treatment. Not helpful for mania. Not FDA label approved in children and adolescents for bipolar disorder 7. Second-generation antipsychotics a. Mechanism of action: Dopamine-2 and serotonin-2A receptor blockers postsynaptically b. Olanzapine i. FDA indicated in those 13–17 of years of age for manic and mixed episodes ii. Dose: (a) Children 4–5 years: Initial 1.25 mg daily. Increase dose weekly. Max 10 mg/day (b) Children 6–18 years: Initial 2.5 mg daily. Titrate to target 10 mg/day. Max 20 mg/day iii. Adverse effects: Sedation, weight gain, hyperlipidemia, hyperglycemia, increased liver function test, extrapyramidal symptoms c. Quetiapine i. FDA indicated in those 10–17 years of age for mania ii. Dose: Start with 25 mg twice daily. Increase to 200 mg twice daily by day 5. Max dose 300 mg twice daily. Extended-release formulation is dosed once daily. iii. Adverse effects: Sedation, weight gain, anticholinergic effects, orthostatic hypotension ACCP Updates in Therapeutics® 2015: Pediatric Pharmacy Preparatory Review Course 1-95


d. Risperidone i. FDA indicated in those 10–17 years of age for mania and mixed episodes ii. Dose: Initial 0.5 mg once daily. Increase by 0.5–1 mg/day. Max dose 6 mg/day. However, doses greater than 2.5 mg/day have not shown extra benefit in this age group. iii. Adverse effects: Sedation, extrapyramidal effects, hyperprolactinemia, weight gain, orthostatic hypotension e. Aripiprazole i. FDA indicated for those 10–17 years of age for type 1 bipolar disorder acute episodes ii. Dose: Initial 2 mg daily for 2 days; then 5 mg daily for 2 days. Increase to 10 mg daily by day 5. Max dose 30 mg/day iii. Adverse effects: Orthostatic hypotension, agitation, drooling, drowsiness, extrapyramidal symptoms, fatigue, hypersomnia, lethargy, sedation f. Other antipsychotics are approved in adults (ziprasidone, lurasidone, asenapine). Patient Cases Questions 16–18 pertain to the following case: M.W. is a 16-year-old female adolescent who presents to the ED with flight of ideas, rapid speech, irritability, and hyperactivity. She is wearing a silver top with sequins and heavily applied makeup. She flirts with the young male resident covering the ED. Her parents are concerned with her behavior, especially with her overt sexual conduct. This seems to be a new development in the past few weeks, and it has caused marked impairment in her functioning at school. No psychotic symptoms are present. Laboratory tests reveal no abnormalities, and her toxicology screen is negative. She denies using drugs or alcohol. After a thorough workup, M.W. is given a diagnosis of type 1 bipolar disorder, current episode mania. 16. According to the treatment guidelines, which is the most appropriate first-stage recommendation? A. Lithium. B. Lithium plus olanzapine. C. Olanzapine plus risperidone. D. Valproic acid plus quetiapine. 17. The physician decides to prescribe lithium for M.W. After a few days, her lithium dose is 600 mg twice daily. A lithium level is ordered after 5 days at this dose. Which most accurately represents the target range for this therapeutic level? A. 0.2–0.5 mEq/L. B. 0.6–0.8 mEq/L. C. 0.8–1.2 mEq/L. D. 1.3–1.5 mEq/L. 18. After M.W. is stabilized on lithium, she is discharged home with instructions to follow up in 1 month and repeat another lithium level. Two weeks later, during her menstrual cycle, she starts taking over-the-counter ibuprofen and presents to the ED. Which symptom would she most likely present with? A. Ataxia and a coarse tremor. B. Liver failure and jaundice. C. Pancreatitis and abdominal pain. D. Hyperactivity and hallucinations.



Patient Cases (continued) 19. L.T. is a 15-year-old female adolescent with a diagnosis of bipolar disorder, current episode of acute depression. She presents to the ED after overdosing on 10 lorazepam tablets. After being medically cleared, she is admitted to the pediatric behavioral health care unit. Which medication may be most appropriate for L.T. at this time? A. Valproic acid. B. Lamotrigine. C. Oxcarbazepine. D. Carbamazepine.

VI. ATTENTION-DEFICIT/HYPERACTIVITY DISORDER A. Epidemiology 1. Estimated at 6%–9% in school-aged children 2. More commonly diagnosed in boys than in girls by 4:1 B. Symptoms 1. Inattention: Six or more (five or more for 17 years or older) that affect function a. Does not pay attention to details or makes careless mistakes in schoolwork b. Difficulty sustaining attention in tasks or play activity c. Does not seem to listen when spoken to directly d. Does not follow through on instructions or does not finish schoolwork, chores, or work duties e. Difficulty organizing tasks and activities f. Avoids, dislikes, or is reluctant to engage in tasks that require sustained mental efforts g. Loses items necessary for tasks or activities h. Easily distracted by external stimuli i. Forgetful in daily activities 2. Hyperactivity and impulsivity: Six or more (five or more for 17 years or older) that affect function a. Fidgets with or taps hands or feet or squirms in seat b. Leaves seat in situations when remaining seated is required c. Runs about or climbs in situations where it is unacceptable d. Difficulty playing or engaging in leisure activities quietly e. Is often “on the go” acting as if “driven by a motor” f. Talks excessively g. Blurts out answers before questions have been completed h. Has difficulty waiting his or her turn i. Interrupts or intrudes on others 3. Symptoms must be present before the patient is 12 years of age and must occur in two settings. C. Treatment 1. Treatment guidelines



Table 7. Two Guidelines for Attention Deficit Hyperactivity Disorder Level of Intervention

AACAP (2007)

AAP (2011)

One

Methylphenidate, amphetamine

Age 4–5: Behavior therapy Age 6–18: methylphenidate or amphetamine

Two

Atomoxetine

Age 4–5: Methylphenidate Age 6–18: Atomoxetine, guanfacine XR or clonidine XR

Three

If none of the above is satisfactory, review diagnosis; consider behavior therapy

Four

Bupropion, TCA, or α2-agonist

AACAP = American Academy of Child and Adolescent Psychiatry; AAP = American Academy of Pediatrics; TCA = tricyclic antidepressant. American Academy of Child and Adolescent Psychiatry. Practice parameter for the assessment and treatment of children and adolescent with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 2007;46:894-921. American Academy of Pediatrics (AAP). ADHD: clinical practice guideline for the diagnosis, evaluation, and treatment of attention deficit/ hyperactivity disorder in children and adolescents. Pediatrics 2011;128:1007-22.

2. Nonpharmacologic treatment a. BPT (behavioral parent training) b. Behavioral interventions c. School-focused interventions d. Child-focused interventions e. Cognitive-behavioral therapy (CBT) 3. Pharmacologic treatment a. Methylphenidate stimulants – Mechanism of action: Dopamine transport blockers resulting in sympathomimetic activity in the CNS Table 8. Methylphenidate Products Dosing Recommendations Generic Name

Initial Dose

Titrate Weekly

Dosing Range

Max Dose

Methylphenidate IR

Children 3–5 years: 1.25 mg twice daily (8 a.m. and noon)

1.25 mg

3.75–30 mg/day in two, or three divided doses TID (8 a.m., noon, and 4 p.m.)

30 mg/day

Children 6 and older: 0.3 mg/kg/dose or 2.5–5 mg/dose Twice daily (8 a.m. and noon)

0.1 mg/kg/dose 5–10 mg/day

0.3–1 mg/kg/day or 20–60 mg/day in two or three divided doses TID (8 a.m., noon, and 4 p.m.)

≤ 50 kg 2 mg/kg/day or 60 mg/day > 50 kg: 100 mg/ day



Table 8. Methylphenidate Products Dosing Recommendations (continued) Generic Name

Initial Dose

Titrate Weekly

Dosing Range

Max Dose

Methylphenidate ER

10 mg a.m.

10 mg

1060 mg once or twice daily

≤ 50 kg: 2 mg/kg/day or 60 mg/day > 50 kg: 100 mg/ day

Methylphenidate SR

20 mg morning

20 mg

20–60 mg once or twice daily


Methylphenidate OROS

18 mg once daily

18 mg

18–108 mg once daily

Children 6–12 years: 54 mg/day Adolescents ≤ 50 kg: 72 mg/day > 50 mg: 108 mg/ day

Methylphenidate CD Methylphenidate XR

20 mg once daily

10–20 mg

20–60 mg once daily


Methylphenidate LA

10–20 mg once daily in the morning

10 mg

10–60 mg


Methylphenidate transdermal

10 mg daily, apply in morning and remove after 9 hours

Each patch size

10- to 30-mg patch

30-mg patch

Dexmethylphenidate IR

2.5 mg twice daily (8 a.m. and noon)

2.5–5 mg

5–20 mg

20 mg

Dexmethylphenidate ER

5 mg once daily in the morning

5 mg/day

5–30 mg

30 mg



Table 9. Methylphenidate Formulations: Onset and Duration of Action Generic Name

Brand Name

Formulation

Onset

Duration of Action

Methylphenidate IR

Ritalin Methylin

Tablets: 5, 10, 20 mg Chewable tablet: 2.5, 5, 10 mg 5 mg/5 mL, 10 mg/10 mL

Clinical onset: 2060 minutes Time to peak: 1–4 hours

3–5 hours

Methylphenidate ER

Metadate ER Methylin ER

Tablets: 20 mg Tablets: 10–20 mg

Clinical onset: 20–60 minutes Time to peak: 5 hours

6–8 hours

Methylphenidate SR

Ritalin SR

Tablets 20 mg

Clinical onset: 6–8 hours 60–180 minutes Time to peak initial: 5 hours

Methylphenidate OROS

Concerta

Tablet: 18, 27, 36, and 54 mg Osmotic active trilayer controlled release 22/78 IR/ SR

Clinical onset: 1–2 hours Time to peak: 6–10 hours

12 hours

Methylphenidate CD

Metadate CD

Capsules: 10, 20, 30, 40, 50, 60 mg Biphasic 30/70 IR/ ER Can be sprinkled on food

Clinical onset: 30–60 minutes Time to peak: 1½ hours

6–8 hours

Methylphenidate XR

Quillivant XR

Suspension; 25 mg/5 mL (60, 120, 150, 160 mL)

Clinical onset: 30–60 minutes Time to peak; children: 4 hours Adolescents: 2 hours

6–8 hours

Methylphenidate LA

Ritalin LA

Capsules; 10, 20, 30, 40 mg Beaded controlled release 50/5 IR/ER beads Can be sprinkled

Clinical onset: 30–60 minutes Time to peak: 5 hours

6–8 hours



Table 9. Methylphenidate Formulations: Onset and Duration of Action (continued) Generic Name

Brand Name

Formulation

Onset

Duration of Action

Methylphenidate transdermal

Daytrana

Patch: 10, 15, 20, 30 mg *Patch is left on for 9 hours at a time

Clinical onset: 1 hour after patch placement Time to peak: 8 hours

11–12 hours Can be removed earlier for duration flexibility. Once removed, effect should be gone in 2–3 hours

Dexmethylphenidate IR

Focalin

Tablets: 2.5, 5, 10 mg

Clinical onset: 30 minutes Time to peak: 1-1½ hour

3–5 hours

Dexmethylphenidate XR

Focalin XR

Capsules: 5, 10, 15, 20, 25, 30, 35 mg Bimodal release 50/50 IR/ER Can be sprinkled

Clinical onset: 30 minutes Time to peak: Initial 1½ hours Second 6.5 hours

12 hours

IR = immediate release; TID = three times daily.

b. Amphetamine stimulants – Mechanism of action: Stimulates the release of dopamine and norepinephrine into the presynaptic nerve terminal Table 10. Amphetamine Products Dosing Recommendations Generic Name

Initial Dose

Titrate Weekly

Dosing Range

Max Dose

Amphetamine/dextroamphetamine

3–5 years: 2.5 mg daily ≥ 6 years: 5 mg once or twice daily

2.5 mg given in one or two divided doses 5 mg in one or two divided doses

10–40 mg

40 mg Patients > 50 kg: Max of 60 mg may be needed

Amphetamine/dextroamphetamine XR

6–12 years: 5–10 mg daily in the morning 13–17 years: 10 mg daily in the morning

5–10 mg 10 mg

5–30 mg


Dextroamphetamine

3–5 years: 2.5 mg daily ≥ 6 years: 5 mg daily

2.5 mg given in one or two divided doses 5 mg in one or two divided doses

5–40 mg

40 mg



Table 10. Amphetamine Products Dosing Recommendations (continued) Generic Name

Initial Dose

Titrate Weekly

Dosing Range

Max Dose

Dextroamphetamine ER

≥ 6 years: 5 mg once or twice daily

5 mg

5–20 mg


Lisdexamfetamine

≥ 6 years : 30 mg daily in the morning

10–20 mg

30–70 mg

70 mg

Table 11. Amphetamine Product Formulations: Onset and Duration of Action Duration of Action (hours)

Generic Name

Brand Name

Amphetamine/dextroamphetamine

Adderall

Tablets Onset of action: 30–60 5, 7.5, 10, 12.5, minutes 15, 20, 30 mg Time to peak: 3 hours

4–6

Amphetamine/dextroamphetamine XR

Adderall XR

Capsules 5, 10, 15, 20, 25, 30 mg

Onset of action: 30–60 minutes Time to peak: 7 hours

6–9

Dextroamphetamine

DextroStat Dexedrine

Tablets: 5, 10, 15 mg Solution: 5 mg/5 mL


4–6

Dextroamphetamine ER

Dexedrine Spansule

Spansule: 5 mg


8

Lisdexamfetamine (prodrug of dextroamphetamine)

Vyvanse

Capsules: 20, 30, 40, 50, 60, 70 mg May open and put in water

Onset of action: 1 hour Time to peak: l-dexamphetamine: 1 hour Dextroamphetamine: 3½ hours

10–12

Formulation

Onset

c. Adverse effects of stimulants i. Increase in blood pressure/heart rate ii. Psychosis or manic symptoms iii. Decreased appetite (a) Eat high-calorie breakfast and dinner. (b) Assess for weight loss. iv. Insomnia (give in morning or reduce afternoon dose) v. GI distress (take with high-fat meal) vi. Irritability vii. Headache ACCP Updates in Therapeutics® 2015: Pediatric Pharmacy Preparatory Review Course 1-102


viii. Growth suppression (a) Drug holidays: Discontinue use during the summer or on weekends. (b) Consider risks versus benefits. (c) Over time, patients seem to catch up. d. Selective norepinephrine reuptake inhibitor – Atomoxetine Table 12. Atomoxetine Properties Formulations

Dose

Pharmacokinetics

Adverse Events

10-, 18-, 25-, 40-, 60-, 80-, and 100-mg capsules

≤ 70 kg: Initial; 0.5 mg/kg/day Target: 1.2 mg/kg/day Titrate every 3 days Max: 1.4 mg/kg/day or 100 mg, whichever is less > 70 kg: Initial: 40 mg Target: 80 mg Titrate after 3 days Max: 100 mg

Time to peak: 1–2 hours Half-life: 5 hours Hepatically metabolized CYP2D6 and CYP2C19 Poor CYP2D6 metabolizers: 24 hours Active metabolite Half-life: 6–8 hours

GI discomfort Loss of appetite Nausea Headache Insomnia Irritability Fatigue Dizziness Increase in blood pressure (rare) Sedation Suicidal thinking Changes in behavior

e. α2-Adrenergic agonists i. Mechanism of action: Central α2-adrenergic receptor agonists inhibit presynaptic norepinephrine release and postsynaptically increase blood flow to the prefrontal cortex. ii. Extended-release guanfacine and clonidine are FDA label approved. Immediate-release formulations are NOT FDA label approved for ADHD. iii. Controlled data are limited for the immediate-release formulations. Table 13. α2-Adrenergic Agonists Generic Name

Formulations

Dose

Pharmacokinetics

Clonidine IR

Tablet: 0.1 mg 0.2 mg 0.3 mg Patch (TTS): 0.1 mg/24 hours, 0.2 mg/24 hours, 0.3 mg/24 hours

> 5 years: < 45 kg Initial: 0.05 mg at bedtime Titrate: 0.05 increments every 3–7 days > 45 kg: Initial: 0.1 mg bedtime Titrate: 0.1 mg every 3–7 days Max: 27–40 kg: 0.2 mg 41–45 kg; 0.3 mg > 45 kg: 0.4 mg/day Transdermal: May switch once stabilized on oral Switch to equivalent total daily oral dose

Time to peak: 3–5 hours Half-life: Children: 8–12 hours; adults: 12–16 hours Highly lipid soluble Hepatic metabolism Renally cleared



Table 13. α2-Adrenergic Agonists (continued) Generic Name

Formulations

Dose

Pharmacokinetics

Clonidine ER

Tablet: 0.1 mg, 0.2 mg

Initial: 0.1 mg at bedtime Titrate: 0.1 mg every 7 days Max: 0.4 mg/day

Time to peak: 7–8 hours Not bioequivalent to immediate release. 50% lower peak plasma concentrations than immediate release Half-life: Children 8–12 hours, adults 12–16 hours Highly lipid soluble Hepatic metabolism, renally cleared

Guanfacine IR

Tablet: 1 mg 2 mg

> 5 years and ≤ 45 kg: Initial: 0.5 mg at bedtime Titrate: 0.5 mg every 3–4 days > 45 kg: Initial: 1 mg at bedtime Titrate: 1 mg every 3–4 days Max: 27–40 kg: 2 mg 41–45 kg: 3 mg > 45 kg: 4 mg/day

Time to peak: 1–4 hours Half-life: 17 hours (range 10–30 hours) Hepatic metabolism by CYP3A4

TTS = transdermal therapeutic system.

f. Bupropion – Mechanism of action: Reuptake inhibitor of dopamine and norepinephrine Table 14. Bupropion Formulation

Dose

Max Dose

Adverse Events

Warnings/Precautions

Bupropion IR

Lesser of 3 mg/kg/day or 150 mg/day

Max: 300 mg/day with no single dose > 150 mg

Dry mouth, sedation, dizziness, tachycardia, anorexia, akinesia, auditory disturbance, anxiety

Suicidal ideation Activation of mania/hypomania, seizures, caution with cardiac disease

Bupropion SR

400 mg/day

Bupropion XL

450 mg/day

g. Tricyclic antidepressants (TCAs) historically have been used, but because of their potential adverse effects, they are not preferred. Patient Cases 20. W.B. is a 5-year-old boy (weight 25 kg) with a diagnosis of ADHD. According to the most recent guidelines published in 2011, which most accurately depicts first-line therapy? A. Behavior therapy. B. Atomoxetine. C. Guanfacine XR. D. Methylphenidate.



Patient Cases (continued) Questions 21 and 22 pertain to the following patient: R.K. is a 13-year-old female adolescent (weight 45 kg) with a diagnosis of ADHD. 21. According to the most recent guidelines published in 2011, which is best for first-line therapy? A. Behavior therapy. B. Atomoxetine. C. Guanfacine XR. D. Methylphenidate. 22. The physician believes there may be some substance abuse potential with R.K. and wants to prescribe an amphetamine-based product that is a prodrug. Which best reflects the product that is available as a prodrug? A. Amphetamine/dextroamphetamine. B. Dextroamphetamine. C. Lisdexamfetamine. D. Amphetamine/dextroamphetamine XR.

VII. EATING DISORDERS IN CHILDREN AND ADOLESCENTS A. Epidemiology – Lifetime prevalence for anorexia nervosa, bulimia nervosa, and binge eating disorder (BED) Table 15. Prevalence of Eating Disorders Anorexia Nervosa (%)

Bulimia Nervosa (%)

Binge Eating Disorder (%)

Total

0.3

0.9

1.6

Male

0.3

0.5

0.8

Female

0.3

1.3

2.3

B. Definitions 1. Anorexia nervosa: Three essential features, including persistent energy into intake restriction, intense fear of gaining weight or of becoming fat, or persistent behavior that interferes with weight gain; and a disturbance in self-perceived weight or shape 2. Bulimia nervosa: Three essential features include binge eating, recurrent inappropriate compensatory behaviors to prevent weight gain, and self-evaluation that is unduly influenced by body shape and weight. The binge eating and compensatory behaviors must occur at least once weekly for 3 months. 3. BED: Having on average one binge-eating episode per week for 3 months. Binge-eating episode is defined as eating, in a discrete period, an amount of food that is larger than what most people would eat in a similar period under similar consequences and as having a sense of lack of control over eating during the episode. C. Treatment 1. Anorexia nervosa a. Nonpharmacologic treatment is first line. ACCP Updates in Therapeutics® 2015: Pediatric Pharmacy Preparatory Review Course 1-105


i. Restore nutritional status. ii. Restore electrolytes. iii. Titrate calorie intake slowly. Increase weight by 1–2 pounds per week. iv. Avoid refeeding syndrome by slowing introducing normal quantities of food. v. Family-based therapy and CBT have been shown to be helpful. b. Pharmacologic treatment i. No FDA label-approved medications for anorexia nervosa ii. Most studies are of mixed populations of adolescents and adults with mixed results iii. Only olanzapine has shown efficacy in randomized controlled trials (RCTs) of adults. A placebo-controlled trial of adolescents showed no differences in BMI (body mass index) and had a large rate of dropouts and dissatisfaction with medication treatment. iv. Bupropion is contraindicated because of increased risk of seizures. v. Other medications may be helpful for comorbid conditions. Table 16. Medications Studied in Adult Populations in the Treatment of Anorexia Nervosa

Medications

Approved Use in Children and Adolescents for Other Conditions

Olanzapine

Yes

Schizophrenia Type 1 bipolar disorder, manic/mixed episodes

Weight gain, orthostatic hypotension, hyperglycemia, hyperlipidemia, QT prolongation tardive dyskinesia

Quetiapine

Yes

Schizophrenia Type 1 bipolar disorder, mania

Weight gain, signs of metabolic changes, tardive dyskinesia, orthostatic hypotension, sedation and somnolence

Fluoxetine

Yes

Depression Obsessive-compulsive disorder

Increased risk of suicidal thinking, nausea, sexual dysfunction, early jitteriness

Mirtazapine

No

Depression

Weight gain, risk of suicidal thinking, sedation

FDA-Approved Indications

Adverse Effects Requiring Caution

2. Bulimia nervosa a. Nonpharmacologic treatment i. CBT and interpersonal psychotherapy are helpful and considered first-line therapy. ii. Family-based therapy may be helpful, but more studies are needed. b. Pharmacologic treatment i. Antidepressants (monoamine oxidase inhibitors [MAOIs] and TCAs) have been shown to improve binging and purging behavior. ii. Fluoxetine 60 mg FDA label approved for adults with RCT data. Small open-label studies of children and adolescents showed a decrease in binging/purging behavior, and fluoxetine was tolerated. iii. Topiramate and ondansetron have been studied in adults. RCTs showed a reduction in binging and purging behavior. iv. Avoid bupropion use because the risk of seizures increases in this population. ACCP Updates in Therapeutics® 2015: Pediatric Pharmacy Preparatory Review Course 1-106


3. BED a. Nonpharmacologic treatment: CBT and interpersonal psychotherapy are helpful in eliminating binging and losing weight in a healthy manner and are considered first-line treatment. b. Pharmacologic treatment i. No medications have been studied in children or adolescent populations for BED. ii. SSRIs have been shown helpful, but CBT has been shown to be more effective. iii. Topiramate and zonisamide have been studied in adults, showing a reduction in binge-eating symptoms and reducing weight. iv. Orlistat reduces weight, but not binge-eating behavior, in adults. v. Atomoxetine reduced binge-eating behavior and increased weight loss in a small study of adults. Patient Cases 23. L.F. is a 17-year-old female adolescent with bulimia nervosa and depression. L.F. has tried two SSRIs for her depression, but neither worked. The physician would like to try an antidepressant with a different mechanism. Which best reflects the medication that is contraindicated for L.F.? A. Bupropion. B. Duloxetine. C. Mirtazapine. D. Venlafaxine. 24. A.O. is a 16-year-old female adolescent with BED. Which is the best first-line treatment for this disorder? A. CBT. B. Atomoxetine. C. Orlistat. D. Topiramate.

VIII. SUBSTANCE USE AND ADDICTIVE DISORDERS A. Epidemiology: Youth Risk Behavior Surveillance System – U.S. 2013 data Table 17. Prevalence Data for Various Substances of Abuse Substance

Prevalence

Tobacco

• • • • • • • • •

Ever smoked: 41.1% Before 13 years of age: 9.3% Current use (at least 1 day in past 30 days): 15.7% Frequent use (≥ 20 days in past 30 days): 5.6% Ever smoked daily: 8.9% Current daily use: 4% Smokeless tobacco current use: 8.9% Current use of tobacco products: 22.4% Prevalence decreasing in the past decade



Table 17. Prevalence Data for Various Substances of Abuse (continued) Substance

Prevalence

Alcohol

• • • • • •

Ever drank: 66.2% Before 13 years of age: 18.6% Current use (≥ 1 drink in the past 30 days): 34.9% ≥ 5 drinks in a row: 20.8% Largest number was ≥ 10 drinks in a row: 6.1% Prevalence decreasing since 1991

Marijuana

• • • •

Ever used: 40.7% Before 13 years of age: 8.6% Current use (once or more in the past 30 days): 23.4% Prevalence has not changed significantly since 2011

Cocaine

• Ever used: 5.5%

Hallucinogenic drugs (LSD, PCP, • Ever used: 7.1% angel dust, mushrooms) Inhalants

• Ever used: 8.9%

Ecstasy

• Ever used: 6.6%

Heroin

• Ever used: 2.2%

Methamphetamines

• Ever used: 3.2%

Steroids without a prescription

• Ever took: 3.2%

Injected illegal drug

• Ever injected: 1.7%

B. Substance Use Disorder Symptom 1. Substance taken in larger amounts or longer than intended 2. Persistent desire to cut down on or control use 3. Great deal of time spent in obtaining, using, or recovering from the substance 4. Craving 5. Recurrent use results in failure to meet major obligations (school, home). 6. Social and interpersonal problems caused by use 7. Social, occupational, or recreational activities given up 8. Recurrent use in situations in which it is physically hazardous 9. Continue use even though knowledge that the substance is causing problems 10. Tolerance 11. Withdrawal C. Specific Substances Symptoms of Intoxication and Withdrawal



Table 18. Intoxication and Withdrawal Symptoms Substance

Intoxication Symptoms

Withdrawal Symptoms

Alcohol

• Behavior changes (aggressive behavior, mood lability, impaired judgment) • Slurred speech • Incoordination • Unsteady gait • Nystagmus • Impaired attention/memory • Stupor/coma

• • • • •

Marijuana

• Behavior changes (euphoria, anxiety, impaired judgment, social withdrawal) • Impaired motor coordination • Sensation of slowed time • Conjunctival injection • Increased appetite • Dry mouth • Tachycardia

• • • • • • • • • •

Irritability, anger, aggression Nervousness/anxiety Insomnia, disturbing dreams Decreased appetite/weight loss Restlessness Depressed mood Abdominal pain Tremors Sweating/fever/chills Headache

Opioids

• • • • • • • •

• • • • • • • • • • •

Dysphoric mood Nausea/vomiting Muscle aches Lacrimation/rhinorrhea Pupillary dilation Sweating Piloerection Diarrhea Yawning Fever Insomnia

Phencyclidine

• Belligerence, assaultiveness, impulsiveness • Unpredictability • Agitation • Impaired judgment • Nystagmus • Hypertension, tachycardia • Numbness or decreased response to pain • Ataxia • Dysarthria • Muscle rigidity • Seizures or coma • Hyperacusis

Euphoria followed by apathy Dysphoria Agitation or slowing Impaired judgment Pupillary constriction Drowsiness or coma Slurred speech Impaired attention/memory

Autonomic hyperactivity Hand tremor Insomnia Nausea/vomiting Visual, tactile, or auditory hallucinations or illusions • Agitation • Anxiety • Seizures



Table 18. Intoxication and Withdrawal Symptoms (continued) Substance


Other hallucinogens • • • • •

Inhalants

Withdrawal Symptoms

• • • • • • •

Anxiety/depression Ideas of reference Paranoid ideation Impaired judgment Perceptual changes (hallucinations, illusions) Pupillary dilation Tachycardia Sweating Palpitations Blurred vision Tremors Incoordination

• • • • • • • • • • • • • • • •

Belligerence, assaultiveness Apathy Impaired judgment Dizziness Nystagmus Incoordination Slurred speech Unsteady gait Lethargy Depressed reflexes Psychomotor retardation Tremor Muscle weakness Blurred vision Stupor/coma Euphoria



Table 18. Intoxication and Withdrawal Symptoms (continued) Substance


Withdrawal Symptoms

Stimulants (cocaine, methamphetamine)

• • • • • • • • • • • • • •

• • • • • • • • •

Dysphoric mood Fatigue Vivid, unpleasant dreams Insomnia/hypersomnia Increased appetite Agitation Bradycardia Anhedonia Drug craving

• • • • • • •

Irritability, frustration, anger Anxiety Difficulty concentrating Increased appetite Restlessness Depressed mood Insomnia

Euphoria Hypervigilance Interpersonal sensitivity Anger, tension, or anxiety Impaired judgment Tachycardia/bradycardia Pupillary dilation Elevated or lowered blood pressure Perspiration/chills Nausea/vomiting Weight loss Agitation Muscular weakness Respiratory depression, chest pain, cardiac arrhythmias • Confusion, seizures, coma • Dyskinesias, dystonias

Tobacco

D. Treatment 1. Nonpharmacologic treatment has the most evidence for effectiveness. a. Behavioral approaches i. Adolescent Community Reinforcement Approach program ii. CBT iii. Contingency management iv. Motivational Enhancement Therapy program v. 12-step facilitation therapy b. Family-based approaches (evidence suggests that this is most effective) i. Brief strategic family therapy ii. Family behavior therapy iii. Multidimensional family therapy iv. Functional family therapy v. Multisystemic therapy c. Recovery support services are recommended after treatment, but mostly anecdotal supporting evidence (support groups, 12-step programs, recovery high schools) 2. Pharmacologic treatment a. No medications are FDA label approved in adolescents. b. No medications are FDA label approved for cocaine, marijuana, or methamphetamine in any age group. ACCP Updates in Therapeutics® 2015: Pediatric Pharmacy Preparatory Review Course 1-111


c. No evidence to determine impact on the developing brain d. Alcohol use disorders i. Alcohol withdrawal – 5%–10% of adolescents experience symptoms, and only a small portion need pharmacotherapy treatment. If medically necessary, benzodiazepines may be used. ii. Medications used for alcohol dependence are listed below, but they are not FDA indicated for children and adolescents. iii. Acamprosate: Reduces alcohol consumption and may extend abstinence time; adult dose is 666 mg three times daily iv. Naltrexone: Reduces alcohol consumption; adult dose: 50 mg/day v. Disulfiram: Aversion treatment or discourages drinking; adult dose: 250 mg/day; monitor with liver function testing e. Opiate use disorders i. Intoxication – Naloxone: 0.4–2 mg, repeat every 2–3 minutes; available as a pen for home use; severe opiate overdose may require an intravenous naloxone drip, particularly if secondary to longer-acting agents like methadone ii. Detoxification: Buprenorphine, clonidine, methadone iii. Maintenance: (a) Buprenorphine – For maintenance 24 mg/day. It is important to initiate this medication only after the patient is in withdrawal. It is indicated for adolescents 16 years and older. (b) Methadone – For maintenance, dose is flexible and titrated to individual response. Methadone used for opioid maintenance must be dispensed from a Drug Enforcement Agency (DEA)-licensed facility. f. Tobacco use disorders i. Bupropion: Reduces nicotine cravings and withdrawal symptoms. Dose: 150–300 mg/day. Some data for use in adolescents for 14 years and older with the bupropion SR dosage form ii. Varenicline: No data in pediatric populations. Caution indicated because of psychiatric adverse effects such as insomnia, headache, abnormal dreams, and suicidal ideation iii. Nicotine replacement therapy (a) Patch: For 1 pack/day, start with the 21-mg patch for 3 weeks. (b) Gum: One piece of gum with the urge to smoke; max 24 pieces/day (c) Lozenge (over the counter), nasal spray, and inhaler are also available but no adolescent data Patient Cases Questions 25 and 26 pertain to the following case: C.V. is a 16-year-old female adolescent who went to a party at her friend’s house while her parents were on vacation. At the party, C.V. had 5 drinks over 2 hours. This is not the first time she has had these behaviors. When C.V. arrived home, her parents noticed that she was slurring her words, could not walk straight, and was belligerent. They took her to the ED for further evaluation. In the ED, her blood alcohol level was 150 mg/dL. 25. Which treatment would be best to initiate for alcohol withdrawal? A. No treatment needed at this time. B. Chlordiazepoxide 25 mg four times daily. C. Fluids with vitamins. D. Naltrexone 50 mg.



Patient Cases (continued) 26. C.V. is referred for further evaluation for alcohol use disorder and outpatient treatment. Which is the most appropriate therapy for alcohol use disorder? A. CBT. B. Family-based therapy. C. Naltrexone 50 mg. D. Acamprosate 666 mg three times daily.

IX. PEDIATRIC DEPRESSION A. Epidemiology 1. About 11% of adolescents have a depressive disorder by age 18. 2. Estimated prevalence is 2% in children and 4%–8% in adolescents. 3. Male-to-female ratio of 1:1 during childhood and 1:2 during adolescence 4. The risk of depression increases as a child gets older; increases 2- to 4-fold after puberty, especially in females 5. According to the World Health Organization, major depression is the leading cause of disability among Americans 15–44 years of age. 6. In 2007, suicide was the third leading cause of death for youth 15–24 years of age. 7. 40%–90% of pediatric patients have comorbidities. B. Signs and Symptoms 1. DSM-5 criteria for major depressive disorder include five or more of the following symptoms, and patient must have either depressed mood or loss of interest or pleasure. Symptoms must occur almost every day for at least 2 weeks and result in a change in function. a. Depressed mood b. Lack of interest or pleasure in daily activities c. Significant changes in weight (increase or decrease) d. Significant changes in sleep (insomnia or hypersomnia) e. Psychomotor agitation or retardation f. Fatigue or decreased energy g. Feelings of worthlessness or inappropriate guilt h. Decreased concentration or difficulty making decisions i. Recurrent thoughts of death, suicidal ideation, or suicidal attempt 2. Signs and symptoms differences in children and adolescents from adults: a. Depressed mood may be expressed as more of an irritable mood. b. Mood lability c. Low frustration tolerance d. Temper tantrums e. More physical complaints or feeling sick f. Social withdrawal or refusing to go to school g. May not verbalize feelings of depression h. Tend to have fewer melancholic symptoms, delusions, and suicide attempts compared with adults C. Treatment 1. General treatment principles a. Treatment guidelines recommend supportive therapy and psychoeducation for mild depression. ACCP Updates in Therapeutics® 2015: Pediatric Pharmacy Preparatory Review Course 1-113


b. If, after 6–8 weeks, symptoms persist, antidepressants and/or psychotherapy is indicated. c. If, after another 6–8 weeks with no improvement, combination of antidepressants and psychotherapy should be considered if not already tried d. If improvement occurs, treatment should continue for 6–24 months. Monitoring should be done monthly for at least the first year. 2. SSRIs a. Mechanism of action: Inhibition of presynaptic serotonin reuptake by inhibition of the serotonin transporter in the neurons of the CNS b. Onset and duration of action: Some symptoms such as agitation or anxiety may improve within days to weeks. After 2–4 weeks of treatment, other target of systems such as depressed mood should improve, including the return of pleasurable experiences and the subsiding of suicidal thoughts. c. Adverse effects: Anxiety, insomnia, sedation, headache, nausea, diarrhea, anorexia, sexual dysfunction d. Serotonin syndrome: i. Occurs with the use of one or more serotonergic agents, particularly combinations of MAOIs and inhibitors of serotonin reuptake ii. Symptoms include mental status changes, autonomic hyperactivity, and neuromuscular abnormalities and can be life threatening. e. Serotonin discontinuation syndrome i. Risk with SSRIs with a shorter half-life (e.g., paroxetine) ii. Occurs when abruptly stopping the serotonergic agent iii. Symptoms: Anxiety, irritability, sadness, insomnia, headache, nausea, nightmares or vivid dreams, electric shock sensations; not life threatening iv. Prevent by slowly tapering the serotonergic antidepressant slowly over a few weeks. f. Fluoxetine is the only antidepressant that is FDA label approved for the treatment of depression in children younger than 12 years. g. Fluoxetine and escitalopram are the only two SSRIs with FDA label approval for use in adolescent depression. h. RCTs of sertraline and citalopram over placebo have shown positive results. i. Paroxetine has been studied, but only one of three studies showed positive results. j. Fluvoxamine is approved for obsessive-compulsive disorder in those 8 years and older but not for depression. Table 19. Selective Serotonin Antidepressant Doses and Pharmacokinetics Drug Name

Pediatric Indication

Dose

Half-life Active Metabolite

Oxidative Enzymes

Fluoxetine

FDA label approved for 8 and older

Initiate: 10 mg Range 10–20 mg (doses up to 60 mg may be used for anxiety disorders)

4–6 days Yes (half-life is 7–9 days)

2C9, 2D6

Escitalopram

FDA label approved for 12 and older

Initiate: 5 mg Range 10–20 mg

27–32 hours

3A4, 2C19

No



Table 19. Selective Serotonin Antidepressant Doses and Pharmacokinetics (continued) Pediatric Indication

Drug Name

Dose

Half-life Active Metabolite

Oxidative Enzymes

Citalopram

Not FDA approved

35 hours

No

3A4, 2C19, 2D6

Sertraline

Not approved for depression

26 hours

N-desmethylsertraline (half-life 66–80 hours)

2C9, 2C19, 2D6, 3A4

Paroxetine


24 hours

No

2D6

Fluvoxamine


16 hours

No

1A2, 2D6

3. Selective serotonin and norepinephrine inhibitors a. Mechanism of action: Inhibition of presynaptic serotonin and norepinephrine reuptake by inhibition of the serotonin and norepinephrine transporter in the neurons of the CNS b. Safety and efficacy have not been established for depression or anxiety disorders in pediatric patients. c. Studies have shown no difference between treatment and placebo for venlafaxine and duloxetine. d. Adverse events are similar to those of SSRIs. e. Monitor for high blood pressure. 4. Bupropion a. Studied in ADHD but not FDA indicated b. No RCTs for depression in pediatric patients 5. Mirtazapine: One study has shown no difference between mirtazapine and placebo. 6. TCAs a. Meta-analysis showed that SSRIs had better efficacy and were better tolerated. b. RCTs have not shown greater efficacy than placebo. c. Risk of overdose and death can occur with TCAs. ECG changes can occur with increased doses. 7. Suicide risk in children and adolescents a. All antidepressants have a black box warning for increased suicidal thinking and behavior in children, adolescents, and young adults. b. Meta-analysis of RCTs showed benefits of antidepressants. c. Risk of increased suicidality is about 2%. d. No evidence of increased suicide attempts Patient Cases Questions 27 and 28 pertain to the following case: B.B. is a 10-year-old boy who says that he is sick and does not want to go to school. On further questioning, he is unable to specify his symptoms. He has been irritable, has been throwing temper tantrums, has a low frustration tolerance, and has been drawing pictures of weapons. He has been preoccupied with thoughts of death. 27. He is given a diagnosis of depression. Which antidepressant is best for B.B.? A. Paroxetine. B. Fluoxetine. C. Sertraline. D. Bupropion. ACCP Updates in Therapeutics® 2015: Pediatric Pharmacy Preparatory Review Course 1-115


Patient Cases (continued) 28. Which best depicts the potential adverse effect that is listed as a black box warning and that the parents of B.B. must be counseled on and notified? A. Pancreatitis. B. Agranulocytosis. C. Diabetes insipidus. D. Suicidal ideation. 29. If, after 4 weeks of treatment, B.B. shows no response to treatment, which most accurately depicts the medication that has shown evidence in pediatric studies, even though it is not FDA indicated for pediatric depression? A. Venlafaxine. B. Mirtazapine. C. Sertraline. D. Bupropion.



REFERENCES Migraine/Headache 1. Abu-Arafeh I, Raak S, Sivaraman B, et al. Prevalence of headache and migraine in children and adolescents: a systematic review of population-based studies. Dev Med Child Neurol 2010;52:1088-97. A systematic review of the world literature using established methods to quantify the prevalence of headache and migraine in children because of the variability in the published studies.

2. Glauser T, Ben-Menachem E, Bourgeois B, et al. Updated ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia 2013;54:551-63. This is the most recent update on the evidence for the newer antiepileptics for both adults and children. Combines previous information with newer information to make new guidelines.

2. Lewis D, Ashwal S, Hershey A, et al. Practice parameter: pharmacological treatment of migraine headache in children and adolescents; report of the American Academy of Neurology Quality Standards Subcommittee and the Practice Committee of the Child Neurology Society. Neurology 2004;63:221524. U.S. guidelines outlining the evidence for the treatment and prophylaxis of migraine in children and adolescents, ranking recommendations according to the type of clinical studies and results.

Cerebral Palsy 1. Delgado MR, Hirtz D, Aisen M, et al. Quality Standards Subcommittee of the American Academy of Neurology, Practice Committee of the Child Neurology Society. Practice parameter: pharmacologic treatment of spasticity in children with cerebral palsy (an evidence-based review). Neurology 2010;74:336-43. Guideline for treatment, including medications for cerebral palsy with a focus on spasticity.

3. Papetti L, Paolino MC, Iannetti P. Migraine treatment in developmental age: guidelines update. J Headache Pain 2010;11:267-76. Combined guidelines from Italy, France, and the United States that reviewed the evidence since 2004. Provided similar recommendations according to newer clinical studies. 4. Sun H, Bastings E, Temech J, et al. Migraine therapeutics in adolescents: a systematic analysis and historic perspectives of triptan trials in adolescents JAMA Pediatr 2013;167:243-9. A review of the literature of the clinical trials for triptans recommending future directions for studies of adolescents. Seizure Disorders 1. Berg AT, Berkovic SF, Brodie MJ, et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology. 2005-2009. Epilepsia 2010;51:676-85. The most recent update on the classification and definitions of seizures and types of epilepsy.

2. Kirby RS, Wingate MS, Van Naarden Braun K, et al. Prevalence and functioning of children with cerebral palsy in four areas of the United States in 2006: a report from the Autism and Developmental Disabilities Monitoring Network. Res Dev Disabil 2011;32:4629. A report on the prevalence in various regions of the United States. Autism Spectrum Disorders 1. American Psychiatric Association (APA). Diagnostic and Statistical Manual of Mental Disorders, 5th ed. Arlington, VA: APA, 2013. The reference used to diagnose and classify mental disorders. The manual includes disorders from childhood to older adulthood. 2. Volkmar F, Siegel M, Woodbury-Smith M, et al. American Academy of Child and Adolescent Psychiatry Work Group on Quality Issues. Practice parameter for the assessment and treatment of children and adolescents with autism spectrum disorder. J Am Acad Child Adolesc Psychiatry 2014;53:237-57. Guidelines and review of autistic disorders, including diagnosis and treatment.



Pediatric Bipolar Disorder 1. American Psychiatric Association (APA). Diagnostic and Statistical Manual of Mental Disorders, 5th ed. Arlington, VA: APA, 2013. The reference used to diagnose and classify mental disorders. The manual includes disorders from childhood to older adulthood.

2. American Academy of Pediatrics (AAP). ADHD: clinical practice guideline for the diagnosis, evaluation, and treatment of attention deficit/hyperactivity disorder in children and adolescents. Pediatrics 2011;128:1007-22. The most recent guideline for ADHD, including recommendations for medication use.

2. Findling RL, Drury SS, Jensen PS, et al. American Academy of Child and Adolescent Psychiatry Work Group on Quality Issues. Practice parameter for the use of atypical antipsychotic medications in children and adolescents. Available at www.aacap.org/AACAP/Resources_for_Primary_Care/Practice_Parameters_and_Resource_Centers/Practice_Parameters. aspx. Accessed December 31, 2014. Review of the evidence and recommendations for the use of atypical antipsychotics for various disorders in children and adolescents.

3. American Psychiatric Association (APA). Diagnostic and Statistical Manual of Mental Disorders, 5th ed. Arlington, VA: APA, 2013. The reference used to diagnose and classify mental disorders. The manual includes disorders from childhood to older adulthood.

3. Kowatch RA, Fristad M, Birmaher B, et al. Treatment guidelines for children and adolescents with bipolar disorder. J Am Acad Child Adolesc Psychiatry 2005;44:213-35. Guidelines developed for the treatment of bipolar disorder. Guidelines include two treatment algorithms providing a stepwise approach to pharmacotherapy treatment. 4. McClellan J, Kowatch R, Findling R, et al.; American Academy of Child and Adolescent Psychiatry Work Group on Quality Issues. Practice parameter for the assessment and treatment of children and adolescents with bipolar disorder. J Am Acad Child Adolesc Psychiatry 2007;46:107-25. The practice parameter includes an update of the previous guidelines for children and adolescent bipolar disorders for diagnosis and treatment. It includes a discussion of the differences between children and adults. Attention-Deficit/Hyperactivity Disorder 1. American Academy of Child and Adolescent Psychiatry. Practice parameter for the assessment and treatment of children and adolescent with attentiondeficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 2007;46:894-921. An overview of the assessment and treatment for ADHD. Gives recommendations based on the evidence for medication use.

Eating Disorders 1. American Psychiatric Association (APA). Diagnostic and Statistical Manual of Mental Disorders, 5th ed. Arlington, VA: APA, 2013. The reference used to diagnose and classify mental disorders. The manual includes disorders from childhood to older adulthood. 2. Swanson SA, Crow SJ, Le Grange DL, et al. Prevalence and correlates of eating disorders in adolescents. Results from the National Comorbidity Survey Replication Adolescent Supplement. Arch Gen Psychiatry 2011;68:714-23. A study that estimated the lifetime prevalence of eating disorders in adolescents. The main outcomes measured wire prevalence and correlates of eating disorders and subthreshold conditions. Substance Use Disorders 1. American Psychiatric Association (APA). Diagnostic and Statistical Manual of Mental Disorders, 5th ed. Arlington, VA: APA, 2013. The reference used to diagnose and classify mental disorders. The manual includes disorders from childhood to older adulthood. 2. Burrell T, Cahalan C, Cimaglio B, et al. Principles of Adolescent Substance Use Disorder Treatment: A Research-Based Guide. Bethesda, MD: National Institute on Drug Abuse, January 2014. NIH Publication 14-953. A summary of the current principles and treatment options for substance use disorders in adolescents. This guide is written for the public.



3. Kann L, Kinchen S, Shanklin SL, et al. Youth Risk Behavior Surveillance-United States, 2013. MMWR 2014;64:1-172. A yearly survey of students in grades 9–12 at public and private schools that asks questions about all types of behavior. Included in this year report is substance use behavior. Pediatric Depression 1. American Psychiatric Association (APA). Diagnostic and Statistical Manual of Mental Disorders, 5th ed. Arlington, VA: APA, 2013. The reference used to diagnose and classify mental disorders. The manual includes disorders from childhood to older adulthood. 2. Birmaher B, Brent DA; American Academy of Child and Adolescent Psychiatry Work Group on Quality Issues. Practice parameter for the assessment and treatment of children and adolescents with depressive disorders. J Am Acad Child Adolesc Psychiatry 2007;46:1503-26. Review of children and adolescent depression disorders, including diagnosis, screening, and treatment.

3. Bridge JA, Iyengar S, Salary CB, et al. Clinical response and risk for reported suicidal ideation and suicide attempts in pediatric antidepressant treatment. A meta-analysis of randomized controlled trials. JAMA 2007;297:1683-96. A meta-analysis reviewing available RCTs for suicidal ideation and suicide attempts. The authors concluded that the benefits of antidepressants were greater than the risks from suicidal ideation and suicidal attempts. 4. Emslie GJ, Mayes T, Giovann P, et al. Treatment of resistant depression in adolescents (TORDIA): week 24 outcomes. Am J Psychiatry 2010;167:782-91. 5. National Institute for Health and Clinical Excellence (NICE). Depression in Children and Young People. May 2011. Available at https://www.nice.org.uk. Last updated March 2014. Accessed Dec, 2014. 6. National Institute of Mental Health. Depression in Children and Adolescents Fact Sheet. Bethesda, MD. Available at www.nimh.nih.gov. Accessed December 31, 2014. Summary of current information about child and adolescent depression for the National Institutes of Health. 7. Zuckerbrot RA, Cheung AH, Jensen PS, et al. Guidelines for adolescent depression in primary care (GLAD-PC). II. Treatment and ongoing management. Pediatrics 2007;120:1299-312.



ANSWERS AND EXPLANATIONS TO PATIENT CASES 1. Answer: A Of the choices, ibuprofen is the only one with clinical trials showing efficacy for acute treatment (Answer A is correct). Efficacy evidence for sumatriptan is available for the nasal spray and subcutaneous formulations but not for the oral formulation (Answer C is incorrect). Prochlorperazine may be beneficial even without nausea and vomiting present, but there is more evidence for ibuprofen (Answer B is incorrect). Topiramate is useful for prophylaxis but not for acute treatment (Answer D is incorrect). 2. Answer: D Topiramate is the only agent useful for prophylaxis (Answer D is correct). The other three agents are for acute treatment (Answers A and B are incorrect). Sumatriptan orally lacks sufficient evidence to support its use in adolescents (Answer C is incorrect). 3. Answer: C Because the patient is vomiting, a non-oral formulation is recommended (Answer B is incorrect). Sumatriptan nasal spray is the only choice with evidence of efficacy in a non-oral formulation (Answer C is correct). Valproic acid is for prophylaxis (Answer D is incorrect). Opioids should be avoided (Answer A is incorrect). 4. Answer: C The max dosing recommendation according to the manufacturer for a 55-kg child is 1800 mg (Answer C is correct). The other doses are either below or above the recommendation (Answers A, B, and D are incorrect). 5. Answer: C Gingival hyperplasia and hirsutism are both common adverse effects of phenytoin (Answers A and B are incorrect). Oxcarbazepine, which is hepatically cleared, does not affect renal function (Answer D is incorrect). Hyponatremia is more common with oxcarbazepine than with carbamazepine (Answer C is correct). 6. Answer: C The dosage recommendation according to the manufacturer is to initiate lamotrigine with an everyother-day schedule when used concurrently with valproic acid (Answer C is correct). A dose of 25 mg/day is for monotherapy (Answer A is incorrect). Initial 50 mg/day

doses are used when lamotrigine is used concurrently with enzyme inducers (Answers B and D are incorrect). 7. Answer: A Rash is the main concern with the concomitant use of valproic acid (Answer A is correct). The other three types of adverse events are common with valproic acid (Answers B–D are incorrect). 8. Answer: D Memory and concentration difficulties have been reported with topiramate (Answer D is correct). The other three adverse events are more common with other antiepileptics, including valproic acid, lamotrigine, phenytoin, and carbamazepine (Answers A–C are incorrect). 9. Answer: D Given the scenario and the rapid increase in the patient’s temperature, this is most likely a febrile seizure (Answer D is correct). The other diagnoses cannot be determined with just one seizure (Answers A–C are incorrect). 10. Answer: B One of the most common adverse effects of tizanidine is sedation (Answer B is correct). It is more likely to cause hypotension than hypertension (Answer A is incorrect). Renal dysfunction and mania are adverse effects of baclofen (Answers C and D are incorrect). 11. Answer: C Although rare, it is possible for the botulinum toxin to become systemic if it spreads from the injection site (Answer C is correct). It does not cause direct harm to either the liver or the kidney (Answers A and B are incorrect). Tardive dyskinesia is a long-term adverse effect associated with dopamine receptor blockers (Answer D is incorrect). 12. Answer: C This scenario probably suggests an abrupt discontinuation, and the family should make sure the pump is not empty (Answer C is correct). The symptoms may also reflect an infection but not the return of spasticity (Answer A is incorrect). Although an inadequate dose may explain the inadequate control of spasticity symptoms, it does not explain the change in the patient’s mental status or temperature (Answer D is incorrect). An overdose of



baclofen may explain the mental status changes, but not the change in temperature or inadequate control of spasticity symptoms (Answer B is incorrect). 13. Answer: C Risperidone can increase prolactin because of its dopamine receptor–blocking mechanism (Answer C is correct). Other second-generation antipsychotics may also increase prolactin, but not to the same extent as risperidone. Olanzapine, quetiapine, and ziprasidone have rates of prolactinemia similar to each other, but less than risperidone. Aripiprazole has the lower rate of prolactinemia. Antipsychotics are more likely to cause weight gain than weight loss (Answer A is incorrect). Risperidone has the lower rate of anticholinergic adverse effects compared with other antipsychotics (Answer B is incorrect). Seizures are not a common withdrawal symptom of antipsychotics (Answer D is incorrect). 14. Answer: A Aripiprazole is the only other antipsychotic indicated for autism among the choices (Answer A is correct). Lurasidone, iloperidone, and asenapine have not been studied in this population (Answers B–D are incorrect). 15. Answer: B Of the choices, risperidone is the only antipsychotic indicated for this patient’s symptoms (Answer B is correct). Olanzapine has been studied for this indication, but it lacks an FDA indication for these symptoms (Answer A is incorrect). Quetiapine and ziprasidone lack sufficient data for recommendation over risperidone and do not carry the indication for autism disorder (Answers C and D are incorrect). 16. Answer: A According to the treatment guidelines, monotherapy is recommended for the initial stage when treating mania without psychosis (Answer A is correct). Olanzapine may be added to lithium if a partial response occurs with lithium monotherapy (Answer B is incorrect). Valproic acid plus quetiapine may be tried after other treatment trials have failed (Answer D is incorrect). Regimens containing two antipsychotics are not recommended (Answer C is incorrect). 17. Answer: C The recommended therapeutic range for treating mania is 0.8–1.2 mEq/L (Answer C is correct). The therapeutic range of 0.6–0.8 mEq/L is recommended for maintenance

therapy (Answer B is incorrect). The range of 0.2–0.5 mEq/L is too low for an effect to occur (Answer A is incorrect). Toxic symptoms start to occur when the level rises above 1.2 mEq/L (Answer D is incorrect). 18. Answer: A Ataxia is a CNS symptom that can occur with moderate toxicity (Answer A is correct). Lithium is not metabolized and is therefore unlikely to cause liver or pancreatic problems (Answers B and C are incorrect). Hyperactivity is a symptom of mania (Answer D is incorrect). Toxic symptoms are more likely to be somnolence, syncope, seizures, and coma. 19. Answer: B Of these three mediations, lamotrigine is recommended for bipolar depression (Answer B is correct). The other three antiepileptics are recommended for mania or mixed episode symptoms (Answers A, C, and D are incorrect). 20. Answer: A According to the American Academy of Pediatrics (AAP) guidelines published in 2011, the first-line treatment for children 4–5 years of age is behavior therapy (Answer A is correct). Only methylphenidate is considered a secondline medication (Answer D is incorrect). The other agents are not recommended in this age group (Answers B and C are incorrect). 21. Answer: D According to the AAP guidelines published in 2011, the first-line treatment of 6- to 18-year-olds is methylphenidate or amphetamine products (Answer D is correct). Clonidine XR, guanfacine XR, and atomoxetine are second-line agents (Answers A–C are incorrect). 22. Answer: C Lisdexamfetamine is a prodrug that converts to amphetamine (Answer C is correct). The other three medications are not prodrugs (Answers A, B, and D). 23. Answer: A Bupropion is contraindicated in patients with bulimia nervosa and other eating disorders (Answer A is correct). In early studies when bupropion was studied for efficacy is this disorder, bupropion increased the risk of seizures. The other three agents are all appropriate for the treatment of depression, although none has the indication for treating eating disorders (Answers B–D are incorrect).



24. Answer: A Nonpharmacologic treatment is considered firstline therapy (Answer A is correct). Although orlistat, atomoxetine, and topiramate have all been studied in adults for symptoms of BED, none has an indication for this disorder (Answers B–D); also, none of these medications has been studied in children. 25. Answer: A Adolescents are unlikely to need treatment for alcohol withdrawal because most do not experience severe withdrawal symptoms (Answer A is correct). Naltrexone, which is used for treatment of the disorder, may decrease future alcohol consumption (Answer D is incorrect). Benzodiazepines and supportive care may be used if the adolescent is in severe withdrawal (Answers B and C are incorrect). 26. Answer: B Family-based therapy has the most evidence for treating adolescents (Answer B is correct). Although CBT may also be helpful, there is less evidence to support its use (Answer A is incorrect). Medications are not indicated in adolescents, and the long-term effects of these medications are unknown (Answers C and D are incorrect).

27. Answer: B Fluoxetine is the only FDA-indicated medication for depression in children younger than 12 (Answer B is correct). Sertraline has been studied in pediatric patients but does not have the FDA indication (Answer C is incorrect). Paroxetine was shown to be effective in only one of three studies (Answer A is incorrect). Bupropion has not been studied for depression (Answer D is incorrect). Because no other medications have been prescribed for this patient, it is reasonable to start with the antidepressant having the most evidence, which is fluoxetine. 28. Answer: D Suicidal ideation is the potential adverse effect that is listed as a black box warning (Answer D is correct). The other three, although serious adverse effects, are not associated with antidepressants (Answers A–C are incorrect). 29. Answer: C Although none of the choices is FDA indicated, sertraline has the most studies showing benefit over placebo (Answer C is correct). The other choices have either not shown positive results in studies (venlafaxine and mirtazapine) (Answers A and B are incorrect) or not been studied for depression in children (bupropion) (Answer D is incorrect).



ANSWERS AND EXPLANATIONS TO SELF-ASSESSMENT QUESTIONS 1. Answer: D Although almotriptan is the only FDA label-approved medication for the acute treatment of migraines in adolescents, this patient has nausea and vomiting (Answer A is incorrect). An alternative dosing form is recommended in this case; therefore, sumatriptan would be the best option (Answer D is correct). Narcotics are not recommended for migraines and should be avoided, if possible (Answers B and C are incorrect). 2. Answer: C The most likely reason for the patient’s low therapeutic level of carbamazepine is that carbamazepine is an autoinducer (Answer C is correct). After 1 month of treatment, carbamazepine would have reduced itself. The other three choices of protein binding, displacement of the free fraction, and multi-phasal distribution do not explain the patient’s decreasing carbamazepine level (Answers A, B, and D are incorrect). 3. Answer: A Of the possible choices, only ethosuximide is indicated for absence seizures (Answer A is correct). The other three agents are useful for generalized tonic-clonic seizures (Answers B–D are incorrect). 4. Answer: D Baclofen is a muscle relaxer indicated for spasticity (Answer D is correct). Although the other three choices are the classic symptoms of cerebral palsy, baclofen is not indicated for these symptoms and may not be helpful in relieving these symptoms (Answers A–C are incorrect).

Fluoxetine is an antidepressant and is not effective for mania (Answer C is incorrect). Methylphenidate, a stimulant, is indicated for ADHD; as such, it could exacerbate this patient’s manic symptoms (Answer D is incorrect). 7. Answer: B The most common adverse effect related to initial dosing with lithium is nausea and vomiting as well as other GI problems (Answer B is correct). Leukocytosis is a potential problem with the long-term use of lithium (Answer A is incorrect). Pancreatitis and liver enzyme elevation are more likely to occur with valproic acid use (Answer C is incorrect). Early jitteriness and anxiety are common with SSRIs (Answer D is incorrect). 8. Answer: D Because methylphenidate increases dopamine in the synaptic cleft, it can cause psychotic symptoms, including hallucinations and paranoia (Answer D is correct). Clonidine and guanfacine indirectly affect dopamine and are therefore less likely to cause psychotic symptoms (Answers B and C are incorrect). Atomoxetine weakly affects dopamine and is therefore less likely to cause psychotic symptoms (Answer A is incorrect). 9. Answer: C The methylphenidate OROS formulation has a duration of action of about 12 hours (Answer C is correct). The other three long-acting formulations have a duration of action of 6–8 hours (Answers A, B, and D are incorrect).

5. Answer: B Aripiprazole is indicated for irritability, aggression, and other tantrum-like behaviors (Answer B is correct). Aripiprazole does not improve communication skills such as following directions and verbal ability (Answers A and D are incorrect). Flat affect is also not an indication for aripiprazole and can be an adverse effect of some antipsychotics (Answer C is incorrect).

10. Answer: A Fluoxetine, an SSRI, is the only medication that is FDA label approved for bulimia in adults (Answer A is correct). However, fluoxetine is not indicated in children for bulimia, although it is approved for other anxiety disorders and depression in children. The other three medications are also SSRIs and are indicated for other types of anxiety disorders in children and adolescents, but not for bulimia nervosa (Answers B–D are incorrect).

6. Answer: A Of the choices, only olanzapine is indicated for the acute mania phase of bipolar disorder in adolescents (Answer A is correct). Lamotrigine may be helpful for maintenance treatment or the depression phase (Answer B is incorrect).

11. Answer: A Although medications have been studied in adults that show a reduction in alcohol use, binge drinking, and cravings (naltrexone, acamprosate, and disulfiram) (Answers B–D are incorrect), none is indicated in



children and adolescents (Answer A is correct). Different types of behavior therapy, including family therapy, are recommended. 12. Answer: C Escitalopram and fluoxetine are the only two antidepressants indicated for adolescent depression (Answer C is correct). Venlafaxine, duloxetine, and mirtazapine are not indicated for childhood and adolescent depression, and studies comparing these medications with placebo did not show a significant difference (Answers A, B, and D are incorrect).

13. Answer: C The scenario describes a case of serotonin discontinuation syndrome because symptom onset occurred only 2 days after the patient discontinued her medication (Answer C is correct). However, the patient may feel that this rebound depression is a result of discontinuing the medication abruptly and a return of her depression symptoms (Answer A is incorrect). It is possible that she can discontinue her medication at this time, but the medication should be reduced over weeks. Serotonin syndrome occurs when several serotonergic medications are used together (Answer B is incorrect). The patient’s symptoms do not reflect mania (Answer D is incorrect).
