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modafinil (Provigil, Sparlon)

DEA-controlled substance: class 4. (racemic mixture) Indications: - narcolepsy [8] - hypersomnia (safe in children 6-15 years) - somnolence [11] - fatigue in patients with multiple sclerosis [10] - depression [3] - adjunctive therapy for obstructive sleep apnea [5] - shift-work sleep disorder Contraindications: - avoid in patients with: a) left ventricular hypertrophy b) ischemic heart disease c) clinically significant mitral valve prolapse - pregnancy: - increased risk for congenital malformations when used during 1st trimester [12] Dosage: 1) narcolepsy: 200 mg PO QAM 2) hypersomnolence: 200-300 mg PO QD 3) multiple sclerosis: 200 mg PO QAM Reduce dosage 50% with liver impairment Pharmacokinetics: 1) time to peak concentration: 2-4 hours 2) absorption not affected by food 3) protein binding is 60% 4) elimination 1/2life is 7-15 hours a) 1/2 life of L-isomer 3 times that of D-isomer b) no interconversion 5) metabolized in the liver by cyt P450 2C19 [3] 6) steady-state levels reached after 2-4 days 7) allow 1-2 weeks for clinical effect Adverse effects: 1) headache 2) nausea 3) hypersalivation 4) nervousness 5) anxiety 6) insomnia 7) euphoria 8) skin rash a) serious rash, including Stevens-Johnson syndrome [8] b) rare cases of toxic epidermal necrolysis c) drug rash with eosinophilia & systemic symptoms (rare) [8] 9) hypertension (rare) 10) tachycardia (rare) 11) tolerance & dependence have NOT been reported 12) anorexia [7] 13) psychiatric symptoms [8] 14) hypersensitivity reactions [8] - angioedema & multi-organ hypersensitivity reactions Drug interactions: 1) modafinil inhibits cyt P450 2C19 [3] - may increase levels of drugs metabolized by cyt P450 2C19 2) modafinil induces cyt P450 3A4 - may diminish levels of drugs metabolized by cyt P450 3A4 3) interactions with antidepressants - citalopram (Celexa), amitriptyline, desipramine, imipramine, clomipramine Mechanism of action: 1) unknown 2) does NOT bind to adrenergic, dopamine, serotonin, histamine-3, GABA, benzodiazepine or adenosine receptors 3) binds to dopamine reuptake site & causes an increase in extracellular dopamine

Interactions

drug adverse effects (more general classes)

Related

cytochrome P450 2C19 (cytochrome P450 2C17, cytochrome P450 11A, mephenytoin 4-hydroxylase, cytochrome P450 254C, CYP2C19) cytochrome P450 3A4 (cytochrome P450 C3, nifedipine oxidase, P450-PCN1, NF-25, CYP3A4)

Specific

armodafinil (Nuvigil)

General

analeptic (CNS stimulant)

Properties

MISC-INFO: elimination route LIVER 1/2life 7-14 HOURS protein-binding 60% pregnancy-category C/D/X? safety in lactation ?

Database Correlations

PUBCHEM cid=4236

References

  1. Micromedex
  2. Prescriber's Letter 7(7):41 2000
  3. Prescriber's Letter 8(3):16 2001
  4. Prescriber's Letter 13(3): 2006 Cytochrome P450 drug interactions Detail-Document#: 220233 (subscription needed) http://www.prescribersletter.com
  5. Journal Watch 22(2):17, 2002 Pack et al, Am J Respir Crit Care Med 164:1675, 2001
  6. Czeisler CA, Walsh JK, Roth T, Hughes RJ, Wright KP, Kingsbury L, Arora S, Schwartz JR, Niebler GE, Dinges DF; U.S. Modafinil in Shift Work Sleep Disorder Study Group. Modafinil for excessive sleepiness associated with shift-work sleep disorder. N Engl J Med. 2005 Aug 4;353(5):476-86. Erratum in: N Engl J Med. 2005 Sep 8;353(10):1078. PMID: 16079371 - Basner RC. Shift-work sleep disorder--the glass is more than half empty. N Engl J Med. 2005 Aug 4;353(5):519-21. No abstract available. PMID: 16079378
  7. Prescriber's Letter 13(2): 2006 Detail-Document#: 220214 (subscription needed) http://www.prescribersletter.com
  8. Morgenthaler TI et al, Practice parameters for the treatment of narcolepsy and other hypersomnias of central origin. Sleep 2007, 30:1705 PMID: 18246980
  9. FDA MedWatch Updates to the WARNINGS section of the prescribing information http://www.fda.gov/medwatch/safety/2007/safety07.htm#Provigil - Prescriber's Letter 14(12): 2007 Safety Warning with Modafinil Detail-Document#: 231210 (subscription needed) http://www.prescribersletter.com
  10. Medical Knowledge Self Assessment Program (MKSAP) 16 American College of Physicians, Philadelphia 2012
  11. Deprecated Reference
  12. Damkier P, Broe A. First-Trimester Pregnancy Exposure to Modafinil and Risk of Congenital Malformations. JAMA. 2020;323(4):374-376. PMID: 31990303 https://jamanetwork.com/journals/jama/article-abstract/2759460