Atomoxetine

From Pubdrug

Jump to: navigation, search

This drug has a Black Box warning from the U.S. Food and Drug Administration.

Contents
image:pdred.GIF This page is not completed and has not been reviewed for accuracy.
You are reading a non-certified PubDrug document. This document is incomplete and not ready for final editing, review, and certification. Until this document is certified, any registered PubDrug user may edit its content.

Authored by: hevahue 1005, 23 August 2007 (PST)
Certified by:

Atomoxetine quick reference

Atomoxetine
Atomoxetine general drug information
 Pronunciation AT oh mox e teen (.wav file)
 Trade Name(s) Strattera
 How Supplied Capsules: 10 mg, 18 mg, 25 mg, 40 mg, 60 mg, 80 mg, 100 mg
 Generic Availability No generics available
 Patent Expiry Date November 26, 2016
 Classification Selective Norepinephrine Reuptake Inhibitor
 Schedule Rx
 Pregnancy Category C
 Breast-feeding Use caution if administered to breast-feeding women as it's unknown if atomoxetine is excreted into human milk.
Atomoxetine chemical information
 IUPAC Name (-)-N-Methyl-

3-phenyl-3-(o-tolyloxy)-propylamine hydrochloride.

 Empirical Formula C17H21NO•HCl
 Molecular Weight 291.82 g/mol
pharmacokinetic information  |  pharmacogenomic information
[edit]

Description

Atomoxetine is a selective norepinephrine reuptake inhibitor (SNRI) used for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) in patients age six and older. It differs from other ADHD treatments in that it is classified as a non-stimulant and is not a controlled substance. Although not considered first-line therapy behind such stimulants as methylphenidate or amphetamines, atomoxetine may be used when stimulants are contraindicated, not tolerated, fail to show benefit, or are not preferred by parents and/or caregivers. [1][2]

It is important to note that the FDA issued a notice in September 2005 warning of risks for suicidal ideation in children and adolescents taking atomoxetine. Patients should be closely monitored for unusual changes in behavior, suicidality (suicidal thinking and behavior), and clinical worsening when dosage changes occur or during the first few months after initiating atomoxetine pharmacotherapy. [1][2][3]


[edit]

Mechanism of Action

Although atomoxetine is a selective norepinephrine reuptake inhibitor, how it exerts its therapeutic effects in ADHD is unknown.[1] Animal studies have demonstrated increased norepinephrine and dopamine concentrations in the prefontal cortex of the brain, which mediates attention, judgement, and impulse control.[1][4] As a result, increased levels of norepinephrine may lead to improved attention and decreases in impulsive behavior.

[edit]

Time Required for Therapeutic Response

  • Initial: 1 week[1]
  • Maximum: Up to 4 weeks[1]
[edit]

Pharmacokinetics

Absorption

Atomoxetine has rapid oral absorption from the GI tract. The extent of atomoxetine absorption (AUC) is not affected by food, but the rate of absorption is decreased, with a 37% lower Cmax (maximal plasma concentrations) and a delayed Tmax of 3 hours. Nevertheless, atomoxetine may be administered without regard to food. The absolute bioavailability is 63% in extensive metabolizers (EM) and 94% in poor metabolizers (PM). The Cmax occurs 1-2 hours after dose administration.[1]

Distribution

After intravenous administration, the volume of distribution is 0.85 L/kg. Atomoxetine predominantly distributes into total body water. Protein binding consists of 98% of atomoxetine in plasma bound primarily to albumin.[1]

Metabolism

Metabolism of atomoxetine occurs through CYP2D6 via oxidative metabolism and subsequent glucuronidation. Compared to EMs, PMs have reduced CYP2D6 activity resulting in higher atomoxetine concentrations (AUC is approximately 10-fold). In addition, maximum steady-state plasma concentrations (Css,max) are approximately 5-fold greater in PMs. After metabolism, the major oxidative metabolite is 4-hydroxyatomoxetine. Although equipotent to the parent drug, this metabolite is present at much lower concentrations. In EMs, metabolism of atomoxetine occurs primarily through CYP2D6, whereas in PMs other cytochrome P450 enzymes play a role in the metabolism to 4-hydroxyatomoxetine (albeit at a slower rate). CYP2C19 also forms another metabolite, N-desmethylatomoxetine, in PMs, which has less activity and lower plasma concentrations than atomoxetine.[1]


Excretion

Mean plasma clearance of atomoxetine is 0.35 L/hr/kg and 0.03 L/hr/kg in adult EMs and PMs, respectively. The mean half-life is 5.2 hours and 21.6 hours in adult EMs and PMs, respectively. In EMs, the elimination half-life is similar between 4-hydroxyatomoxetine and N-desmethylatomoxetine (6-8 hours); however the half-life of N-desmethylatomoxetine is prolonged in PMs (34-40 hours). The majority of atomoxetine is excreted in the urine (>80%) as 4-hydroxyatomoxetine-O-glucuronide and the remainder is excreted in the feces (<17%). Complete biotransformation of atomoxetine is nearly achieved with less than 3% excreted unchanged.[1]



Back to top
[edit]

Special Population Pharmacokinetics

  • Renal insufficiency: Dosage adjustment of atomoxetine is not required for patients with renal insufficiency and end stage renal disease (ESRD). However, extensive metabolizers (EM) with ESRD had higher systemic exposure when compared to healthy patients, but there was no difference in exposure when adjusted for weight.[1]
  • Hepatic insufficiency: Patients (EMs) with moderate-severe hepatic impairment had higher AUCs than normal subjects. As a result, dosage adjusment of atomoxetine is recommended.[1]
  • Hemodialysis: The effects of hemodialysis on the pharmacokinetics of atomoxetine have not been studied.[1]
  • Geriatric: The pharmacokinetics of atomoxetine have not been studied in the elderly.[1]
  • Pediatric: In children less than 6 years of age, the pharmacokinetics of atomoxetine have not been studied. In children 6 years of age and older, the pharmacokinetics are similar to adults.[1]
  • Gender: Gender does not affect atomoxetine pharmacokinetics.[1]
[edit]

Indications and Dosages

[edit]

FDA Approved Indications

Attention-Deficit/Hyperactivity Disorder (ADHD)

  • Adults and children/adolescents weighing >70 kg:[1][2]
    • Initial dose: 40 mg PO daily as a single dose in the morning or 2 evenly divided doses in the morning and late afternoon/early evening.
    • Maintenance dose: 80 mg PO daily in 1-2 divided doses.
    • Titration schedule: After a minimum of 3 days, increase to a total daily dose of 80 mg PO daily in 1-2 divided doses. After 2-4 weeks, if response is suboptimal, may increase dose up to a maximum of 100 mg PO daily in 1-2 divided doses.
  • Children/adolescents weighing </=70 kg:[1][2]
    • Initial dose: 0.5 mg/kg/day PO as a single dose in the morning or 2 evenly divided doses in the morning and late afternoon/early evening.
    • Maintenance dose: 1.2 mg/kg/day PO in 1-2 divided doses.
    • Titration schedule: After a minimum of 3 days, increase to 1.2 mg/kg/day PO in 1-2 divided doses. Although no additional benefit has been shown, may increase up to a maximum of 1.4 mg/kg/day or 100 mg/day in 1-2 divided doses (whichever is less).
  • Children <6 years:[1][2]
    • Not FDA approved for this age group.
[edit]

Non-FDA Approved Indications

  • No non-FDA approved indications.
[edit]

Dosage Adjustment

Hepatic insufficiency: For moderate hepatic insufficiency (Child-Pugh Class B): initial and target doses should be reduced to 50% of normal dose. For severe hepatic insufficiency (Child-Pugh Class C): initial and target doses should be reduced to 25% of normal dose.[1]
Hemodialysis: No adjustment likely.[1]
Pediatric: See dosing above.[1]
Adults and children/adolescents >70 kg receiving a strong CYP2D6 inhibitor (paroxetine, fluoxetine, quinidine): Initiate at 40 mg/day and only titrate up to usual maintenance dose of 80 mg/day if no improvement after 4 weeks.[1]
Children and adolescents </=70 kg receiving a strong CYP2D6 inhibitor (paroxetine, fluoxetine, quinidine): Initiate at 0.5 mg/kg/day and only titrate up to usual maintenance dose of 1.2 mg/kg/day if no improvement after 4 weeks.[1]

[edit]

Dosage Limits

  • Adults: 100 mg/day[1]
  • Adolescents and children >70 kg: 100 mg/day[1]
  • Adolescents and children </=70 kg: 1.4 mg/kg/day or 100 mg/day (whichever is less).[1]


Back to top
[edit]

Administration

  • Route: Oral
  • Method:
    • Swallow capsule whole with a glass of water as prescribed. May take without regard to food.
    • Do not chew, crush, or open capsules.
    • Tapering is not required when discontinuing.[1]
[edit]

Monitoring Parameters[1]

  • No laboratory monitoring is required.
  • Patient growth (height and weight).
  • Blood pressure/pulse at baseline and periodically throughout treatment.
  • ADHD symptoms or aggressive behavior/hostility.
[edit]

Contraindications/Precautions

[edit]

Black box warning

FDA issued a black box warning in September 2005 advising patients and health care professionals of the increased risk for suicidal ideation in children or adolescents taking atomoxetine for ADHD. This advisory was based on reports and short-term studies of patients who experienced suicidal thoughts while taking atomoxetine. Patients should be monitored for suicidal thinking and behavior, clinical worsening, or unusual changes in behavior during the first few months of treatment or after dosage changes.[1][3]

In December 2004, the FDA issued a bolded warning for severe liver injury based on postmarketing reports of two patients who experienced remarkable elevations in hepatic enzymes and bilirubin. Patients should be monitored for jaundice or other signs of liver dysfunction (pruritis, dark urine, right upper quadrant pain), with follow-up laboratory testing. Patients with jaundice or laboratory evidence of liver injury should discontinue atomoxetine and not restart. Note: regular monitoring of liver function tests are not currently recommended.[1]

[edit]

Contraindications

  • Monoamine oxidase inhibitor (MAOI) therapy[1]
  • Narrow angle glaucoma[1]
[edit]

Precautions

  • Cardiac disease (cardiomyopathy, arrhythmias, congenital heart disease, hypertension).[1]
  • Psychiatric conditions (bipolar disorder, psychosis, depression).[1]
  • Urinary retention.[1]
  • Hepatic impairment.[1]
[edit]

Pregnancy indications

Category C

No well-controlled studies have been conducted in pregnant women. Atomoxetine should only be administered if the benefits for the mother outweigh the potential risks to the fetus.[1]

[edit]

Breast-feeding indications

Although atomoxetine and/or its metabolites are excreted into rat milk, it is unknown if they are excreted into human milk. Caution is recommended if used while breast-feeding.[1]

Back to top


[edit]

Drug-Drug, -Food, -Herb Interactions

Click the link above to go to the drug interactions page.

[edit]

Adverse Reactions/Side Effects

Atomoxetine Adverse Reactions Chart: Children and Adolescents (BID Dosing)[1]
Incidence Body System Adverse Reactions
>10% All Headache (27%), upper abdominal pain (20%), decreased appetite (14%), vomiting (11%), cough (11%).
1-10% CNS Somnolence (7%), dizziness (6%).
Dermatologic Dermatitis (4%).
GI Dyspepsia (4%), constipation (3%).
Respiratory Rhinorrhea (4%), influenza (3%).
Miscellaneous Decreased weight (2%), irritability (8%), ear infections (3%), mood swings (2%), crying (2%).
<1% All Seizures, aggressiveness, agitation, hostility, and rash.
Atomoxetine Adverse Reactions Chart: Adults[1]
Incidence Body System Adverse Reactions
>10% All Dry mouth (21%), headache (17%), insomnia and/or middle insomnia (16%), nausea (12%).
1-10% CNS Dizziness (6%), paraesthesia (4%), sinus headache (3%).
Cardiovascular Palpitations (4%).
Dermatologic Increased sweating (4%), dermatitis (2%).
GI Constipation (10%), dyspepsia (6%), flatulence (2%).
Genitourinary Urinary hesitation/urinary retention/difficulty in micturition (8%), dysmenorrhea (7%), erectile disturbance (7%), ejaculation failure/disorder (5%), impotence (3%), menstrual disorder (3%), prostatitis (3%), orgasm abnormal (2%), menses delayed/irregular (2%).
Neuromuscular/skeletal Myalgia (3%).
Respiratory Sinusitis (6%).
Miscellaneous Decreased appetite (10%), fatigue (7%), decreased libido (6%), sleep disorder (4%), abnormal dreams (4%), pyrexia (3%), rigors (3%), hot flushes (3%).
<1% All Seizures, aggressiveness, agitation, hostility, and rash.


[edit]

Overdosage Measures

Commonly reported symptoms of atomoxetine acute and chronic overdoses: somnolence, agitation, hyperactivity, gastrointestinal symptoms, and unusual behavior. Less frequently reported signs/symptoms include QT prolongation and mental changes (disorientation and hallucinations). [1]


Treatment:

  • Supportive/symptomatic treatment (establish patent airway, monitor cardiac/vital signs).
  • Gastric lavage (if initiated shortly after ingestion).
  • Activated charcoal.
  • Dialysis is NOT recommended due to extensive protein-binding of atomoxetine.[1]
Back to top
[edit]

Product Information and Distribution[1][2]

Note: appearance only available for brand-name product
Dose/form Drug color(s) Drug shape Markings or odor/flavor
10 mg capsule opaque-white capsule/cylindrical Lilly 3227
18 mg capsule gold/opaque-white capsule/cylindrical Lilly 3238
25 mg capsule opaque-blue/opaque-white capsule/cylindrical Lilly 3228
40 mg capsule opaque-blue capsule/cylindrical Lilly 3229
60 mg capsule opaque-blue/gold capsule/cylindrical Lilly 3239
80 mg capsule opaque-brown/opaque-white capsule/cylindrical Lilly 3250
100 mg capsule opaque-brown capsule/cylindrical Lilly 3251
  • Inactive ingredients in capsules:
    • Dimethicone, edible black ink, gelatin, pregelatinized starch, sodium lauryl sulfate, titanium dioxide, synthetic yellow iron oxide, FD&C Blue No. 2, red iron oxide.[1]


[edit]

Patient Information[1][2]

  • Swallow capsule whole with a glass of water as prescribed. May take without regard to food. Do not chew, crush, or open capsules.
  • If breakage of the capsule occurs, avoid touching the capsule and make sure to wash hands and other areas which came into contact with the broken capsule. Avoid contact with eyes.
  • If you miss a dose, do not double up on your next dose. Take your usual dose at the next regularly scheduled time.
  • Although rare, suicidal thoughts and actions have been reported in children and adolescents. The risk for this appears to be higher when atomoxetine is initiated or when your physician makes dose changes. It is important to monitor your child's behaviors, moods, and thoughts during treatment.
  • Atomoxetine may also cause liver injury in rare cases. Call your doctor immediately if any of the following occur: itching, right upper belly pain, dark urine, yellow eyes or skin, unexplained flu-like symptoms.
  • You should monitor your child's growth during atomoxetine treatment as there is a possibility that growth inhibition may occur.
  • Common Side Effects in Children and Adolescents: Upset stomach, decreased appetite, nausea or vomiting, dizziness, tiredness, and mood swings.
  • Common Side Effects in Adults: Constipation, dry mouth, nausea, decreased appetite, dizziness, trouble sleeping, sexual side effects, menstrual cramps, and problems passing urine.


Back to top
[edit]

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 1.15 1.16 1.17 1.18 1.19 1.20 1.21 1.22 1.23 1.24 1.25 1.26 1.27 1.28 1.29 1.30 1.31 1.32 1.33 1.34 1.35 1.36 1.37 1.38 1.39 1.40 1.41 1.42 1.43 1.44 1.45 Strattera (atomoxetine HCl) package insert. Indianapolis, IN; Eli Lilly and Company; 2007 Apr.
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 Clinical Pharmacology Website. Available at: http://www.clinicalpharmacology.com/. Accessed September 10, 2007.
  3. ↑ 3.0 3.1 U.S. Food and Drug Administration Web Site. Available at: http://www.fda.gov/cder/drug/infopage/atomoxetine/default.htm. Accessed September 28, 2007.
  4. ↑ Corman SL, Fedutes BA, Culley CM. Atomoxetine: the first nonstimulant for the management of attention-deficit/hyperactivity disorder. Am J Health-Syst Pharm 2004;61:2391-2399.
[edit]

PUBMED References

[edit]

Efficacy Trial Articles

  1. Kratochvil CJ, Vaughan BS, Mayfield-Jorgensen ML, March JS, Kollins SH, Murray DW, et al. A pilot study of atomoxetine in young children with attention-deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol 2007;17(2):175-85.
  2. Buitelaar JK, Michelson D, Danckaerts M, Gillberg C, Spencer TJ, Zuddas A, et al. A randomized, double-blind study of continuation treatment for attention-deficit/hyperactivity disorder after 1 year. Biol Psychiatry 2007;61(5):694-9.
  3. Adler LA, Spencer TJ, Milton DR, Moore RJ, Michelson D. Long-term, open-label study of the safety and efficacy of atomoxetine in adults with attention-deficit/hyperactivity disorder: an interim analysis. J Clin Psychiatry 2005;66(3):294-9.
  4. Gau SS, Huang YS, Soong WT, Chou MC, Chou WJ, Shang CY, et al. A randomized, double-blind, placebo-controlled clinical trial on once-daily atomoxetine in taiwanese children and adolescents with attention-deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol 2007;17(4):447-60.
  5. Weiss M, Tannock R, Kratochvil C, Dunn D, Velez-Borras J, Thomason C, et al. A randomized, placebo-controlled study of once-daily atomoxetine in the school setting in children with ADHD. J Am Acad Child Adolesc Psychiatry 2005;44(7):647-55.
  6. Michelson D, Adler L, Spencer T, Reimherr FW, West SA, Allen AJ, et al. Atomoxetine in adults with ADHD: two randomized, placebo-controlled studies. Biol Psychiatry 2003;53(2):112-20.
  7. Spencer T, Heiligenstein JH, Biederman J, Faries DE, Kratochvil CJ, Conners CK, et al. Results from 2 proof-of-concept, placebo-controlled studies of atomoxetine in children with attention-deficit/hyperactivity disorder. J Clin Psychiatry 2002;63(12):1140-7.
  8. Biederman J, Heiligenstein JH, Faries DE, Galil N, Dittmann R, Emslie GJ, et al.; Atomoxetine ADHD Study Group. Efficacy of atomoxetine versus placebo in school-age girls with attention-deficit/hyperactivity disorder. Pediatrics 2002;110(6):e75.
  9. Michelson D, Allen AJ, Busner J, Casat C, Dunn D, Kratochvil C, et al. Once-daily atomoxetine treatment for children and adolescents with attention deficit hyperactivity disorder: a randomized, placebo-controlled study. Am J Psychiatry 2002;159(11):1896-901.
  10. Michelson D, Faries D, Wernicke J, Kelsey D, Kendrick K, Sallee FR, et al. Atomoxetine ADHD Study Group. Atomoxetine in the treatment of children and adolescents with attention-deficit/hyperactivity disorder: a randomized, placebo-controlled, dose-response study. Pediatrics 2001;108(5):E83.
  11. Spencer T, Biederman J, Heiligenstein J, Wilens T, Faries D, Prince J, et al. An open-label, dose-ranging study of atomoxetine in children with attention deficit hyperactivity disorder. J Child Adolesc Psychopharmacol 2001;11(3):251-65.


Back to top
[edit]

Therapeutic Class Comparison Articles

  1. Wang Y, Zheng Y, Du Y, Song DH, Shin YJ, Cho SC, et al. Atomoxetine versus methylphenidate in paediatric outpatients with attention deficit hyperactivity disorder: a randomized, double-blind comparison trial. Aust N Z J Psychiatry 2007;41(3):222-30.
  2. Gibson AP, Bettinger TL, Patel NC, Crismon ML. Atomoxetine versus stimulants for treatment of attention deficit/hyperactivity disorder. Ann Pharmacother 2006;40(6):1134-42.
  3. Prasad S, Harpin V, Poole L, Zeitlin H, Jamdar S, Puvanendran K; The SUNBEAM Study Group. A multi-centre, randomised, open-label study of atomoxetine compared with standard current therapy in UK children and adolescents with attention-deficit/hyperactivity disorder (ADHD). Curr Med Res Opin 2007;23(2):379-94.


[edit]

Pharmacokinetics Articles

  1. Sauer JM, Ring BJ, Witcher JW. Clinical pharmacokinetics of atomoxetine. Clin Pharmacokinet 2005;44(6):571-90.
  2. Witcher JW, Long A, Smith B, Sauer JM, Heilgenstein J, Wilens T, et al. Atomoxetine pharmacokinetics in children and adolescents with attention deficit hyperactivity disorder. J Child Adolesc Psychopharmacol 2003;13(1):53-63.
  3. Chalon SA, Desager JP, Desante KA, Frye RF, Witcher J, Long AJ, et al. Effect of hepatic impairment on the pharmacokinetics of atomoxetine and its metabolites. Clin Pharmacol Ther 2003;73(3):178-91.


Back to top
[edit]

Drug Interaction Articles

  1. Sauer JM, Long AJ, Ring B, Gillespie JS, Sanburn NP, DeSante KA, et al. Atomoxetine hydrochloride: clinical drug-drug interaction prediction and outcome. J Pharmacol Exp Ther 2004;308(2):410-8.
  2. Belle DJ, Ernest CS, Sauer JM, Smith BP, Thomasson HR, Witcher JW. Effect of potent CYP2D6 inhibition by paroxetine on atomoxetine pharmacokinetics. J Clin Pharmacol 2002;42(11):1219-27.
  3. Ciccone PE, Ramabadran K, Jessen LM. Potential interactions of methylphenidate and atomoxetine with dextromethorphan. J Am Pharm Assoc 2006;46(4):472-8.


[edit]

Adverse Effects Articles

  1. Adler L, Dietrich A, Reimherr FW, Taylor LV, Sutton VK, Bakken R, et al. Safety and tolerability of once versus twice daily atomoxetine in adults with ADHD. Ann Clin Psychiatry 2006;18(2):107-13.
Back to top
[edit]

Compliance Articles

[edit]

Pharmacoeconomic Articles

  1. Scheffler RM, Hinshaw SP, Modrek S, Levine P. The global market for ADHD medications. Health Aff (Millwood) 2007;26(2):450-7.


Back to top
[edit]

External Links

Clinical treatment guidelines

Patient information pages

Other resources

Back to top
Retrieved from "http://www.smbrower.com/mediawiki/index.php/Atomoxetine"
Personal tools