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DRUG RECORD

 

MODAFINIL, ARMODAFINIL

OVERVIEW
Modafinil, Armodafinil

 

Introduction

Modafinil and its R-enantiomer armodafinil are central nervous system stimulants used to improve wakefulness in patients with excessive sleepiness.  Both modafinil and armodafinil are associated with a low rate of serum aminotransferase elevations during therapy, but they have not been implicated in cases of clinically apparent acute liver injury.

 

Background

Modafinil (moe daf' i nil) is a non-amphetamine central nervous system (CNS) stimulant whose mechanism of action is not entirely clear.  Modafinil is structurally unrelated to the amphetamines, and it does not appear to affect release of CNS norepinephrine or dopamine.  Modafinil is a racemic mixture of S and R enantiomers, whereas armodafinil (ar" moe daf' i nil) is the R enantiomer only.  Both enantiomers have CNS activating actions, but they differ in pharmacokinetics and half-life.  Modafinil and armodafinil increase wakefulness and both have been shown to be helpful in conditions with excessive sleepiness (narcolepsy, obstructive sleep apnea and shift-work sleep disorder), and have been studied off label to treat fatigue associated with chronic illness such as cancer, Parkinson’s disease, HIV/AIDs and multiple sclerosis.  Modafinil was approved for use in the United States in 1998 and armodafinil in 2007.  Modafinil is available in tablets of 100 and 200 mg in generic forms and under the brand name Provigil, the usual dose in adults being 200 mg once daily in the morning or an hour before a work shift.  Armodafinil is available in tablets of 50, 150 and 250 mg under the brand name Nuvigil, the usual dose in adults being 150 to 250 mg once daily.  Armodafinil is also approved for treatment of sleepiness due to jet lag, a lower dose of 50 to 150 mg being recommended.  The most common side effects of both agents include headache, anxiety nervousness, nausea, decreased appetite, palpitations and disturbed sleep.  Modafinil and armodafinil are now classified as category IV controlled substances, indicating that they have a potential for abuse and can lead to physical or psychological dependence.

 

Hepatotoxicity

In clinical trials, modafinil and armodafinil were associated with a low rate of serum aminotransferase and alkaline phosphatase elevations (<1%).  Furthermore, despite widescale use, there have not been reports of clinically apparent liver injury due to modafinil or armodafinil.  Rare instances of hypersensitivity reactions and even Stevens Johnson syndrome have been reported after modafinil use and these reactions may be accompanied by evidence of hepatic involvement or injury. 

 

Likelihood score: E (unlikely causes of clinically apparent liver injury).

 

Mechanism of Injury

The mechanism by which modafinil and armodafinil might cause liver injury is unknown.  Modafinil is extensively metabolized in the liver, but has few drug-drug interactions.

Central nervous system stimulants used for attention deficit disorder, narcolepsy or excessive sleepiness include methylphenidate, atomoxetine, modafinil, armodafinil and the amphetamines.  Stimulants that are no longer used for medical conditions but that are abused include cocaine and methylenedioxymetamphetamine, which is also known as ecstasy.

 

Drug Class:  CNS Stimulants

 

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PRODUCT INFORMATION
Modafinil, Armodafinil

 

REPRESENTATIVE TRADE NAMES
Modafinil – Generic, Provigil®


DRUG CLASS
Central Nervous System Stimulants


COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH


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CHEMICAL FORMULAS AND STRUCTURES
Modafinil, Armodafinil
DRUG CAS REGISTRY NUMBER MOLECULAR FORMULA STRUCTURE
Modafinil 68693-11-8 C15-H15-N-O2-S Chemical Structure for Modafini
Armodafinil 112111-43-0 C15-H15-N-O2-S Chemical Structure for Armodafinil

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REFERENCES
Modafinil, Armodafinil

 

References updated: 20 July 2017

  1. Zimmerman HJ. Methylphenidate. Miscellaneous drugs and diagnostic chemicals. In, Zimmerman, HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp. 712.  (Expert review of hepatotoxicity published in 1999; modafinil is not mentioned).

  2. Larrey D, Ripault MP. Hepatotoxicity of psychotropic drugs and drugs of abuse. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 443-62.  (Review of hepatotoxicity of psychotropic agents does not discuss modafinil and armodafinil).

  3. Wesfall TC, Westfall DP. Narcolepsy and related syndromes. Adrenergic agonists and antagonists. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman’s the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 303.  (Textbook of pharmacology and therapeutics).

  4. Randomized trial of modafinil for the treatment of pathological somnolence in narcolepsy. US Modafinil in Narcolepsy Multicenter Study Group. Ann Neurol 1998; 43: 88-97. PubMed Citation  (Controlled trial of modafinil [200 or 400 mg] vs placebo for 9 weeks; modafinil demonstrated an excellent safety profile for up to 40 weeks of open label treatment; “there were few clinically meaningful changes in laboratory values”).

  5. Randomized trial of modafinil as a treatment for the excessive daytime somnolence of narcolepsy. US Modafinil in Narcolepsy Multicenter Study Group. Neurology 2000; 54: 1166-75. PubMed Citation  (Controlled 9 week trial of two doses of modafinil [200 and 400 mg] vs placebo in 271 patients with narcolepsy: “There were no meaningful differences among treatment groups at week 9 in clinical laboratory test results”).

  6. Mitler MM, Harsh J, Hirshkowitz M, Guilleminault C. Long-term efficacy and safety of modafinil (PROVIGIL((R))) for the treatment of excessive daytime sleepiness associated with narcolepsy. Sleep Med 2000; 1: 231-243. PubMed Citation  (478 adults with narcolepsy were enrolled in two 40-week, open label extension studies using 200 to 400 mg of modafinil daily; common side effects were headache, nervousness, and nausea; clinically significant elevations in ALT occurred in 6 [1.5%] and total bilirubin in 1 patient, but no other details given).

  7. Moldofsky H, Broughton RJ, Hill JD. A randomized trial of the long-term, continued efficacy and safety of modafinil in narcolepsy. Sleep Med 2000; 1: 109-16. PubMed Citation  (69 patients with narcolepsy were treated for 16 weeks in an open label extension study; mean ALT levels did not change, only 2 patients had concurrent increase in ALT and AST, but none developed jaundice).

  8. Hoover-Stevens S, Kovacevic-Ristanovic R. Management of narcolepsy in pregnancy. Clin Neuropharmacol 2000; 23: 175-81. PubMed Citation  (Review of the efficacy of medications for narcolepsy and their safety during pregnancy and breast feeding; modafinil is not discussed).

  9. New indications for modafinil(Provigil). Med Lett Drugs Ther 2004; 46: 34-5. PubMed Citation  (Brief review of modafinil and its expanded indications for sleepiness due to work-shift sleep disorder and sleep apnea syndrome; “Increases in aminotransferase activity have been reported”).

  10. Stankoff B, Waubant E, Confavreux C, Edan G, Debouverie M, Rumbach L, Moreau T, et al.; French Modafinil Study Group. Modafinil for fatigue in MS: a randomized placebo-controlled double-blind study. Neurology 2005; 64: 1139-43. PubMed Citation  (Controlled trial of escalating doses of modafinil vs placebo for 5 weeks in 115 patients with multiple sclerosis; “There was no major safety concern”).

  11. Wigal SB, Biederman J, Swanson JM, Yang R, Greenhill LL. Efficacy and safety of modafinil film-coated tablets in children and adolescents with or without prior stimulant treatment for attention-deficit/hyperactivity disorder: pooled analysis of 3 randomized, double-blind, placebo-controlled studies. Prim Care Companion J Clin Psychiatry 2006; 8: 352-60. PubMed Citation  (Of 638 children or adolescents treated with modafinil or placebo, side effects were insomnia, headache and decreased appetite; no mention of liver related side effects).

  12. Roth T, Schwartz JR, Hirshkowitz M, Erman MK, Dayno JM, Arora S. Evaluation of the safety of modafinil for treatment of excessive sleepiness. J Clin Sleep Med 2007; 3: 595-602. PubMed Citation  (Summary of results from 6 randomized controlled trials of modafinil for excessive sleepiness in 1529 patients treated for up to 12 weeks; elevations of ALT above 3 times the ULN occurred in <1% of patients; one serious adverse event was listed as abnormal liver enzymes and probably due to modafinil).

  13. Janeiro M, Camblor E, Fernández R, Núñez D. [Narcolepsy and anesthesia]. Rev Esp Anestesiol Reanim 2007; 54: 198-9. Spanish. PubMed Citation  (24 year old man with narcolepsy receiving modafinil and chlorimipramine requiring surgery was found to have serum enzyme elevations; tolerated reintroduction of modafinil without recurrence; no details given).

  14. Kumar R. Approved and investigational uses of modafinil : an evidence-based review. Drugs 2008; 68: 1803-39. PubMed Citation  (Review of pharmacology, clinical efficacy and safety of modafinil; a single case of fatal, multiorgan [including liver] hypersensitivity has been reported).

  15. Lankford DA. Armodafinil: a new treatment for excessive sleepiness. Expert Opin Investig Drugs 2008; 17: 565-73. PubMed Citation  (Systematic review of armodafinil for excessive sleepiness; no discussion of liver related adverse events; 1 case of Stevens Johnson syndrome and 1 of severe hypersensitivity response reported with modafinil).

  16. Rabkin JG, McElhiney MC, Rabkin R, McGrath PJ. Modafinil treatment for fatigue in HIV/AIDS: a randomized placebo-controlled study. J Clin Psychiatry 2010; 71: 707-15. PubMed Citation  (115 patients with HIV/AIDs were treated with modafinil or placebo for 4 weeks; no mention of liver adverse events).

  17. Rosenberg RP, Bogan RK, Tiller JM, Yang R, Youakim JM, Earl CQ, Roth T. A phase 3, double-blind, randomized, placebo-controlled study of armodafinil for excessive sleepiness associated with jet lag disorder. Mayo Clin Proc 2010; 85: 630-8. PubMed Citation  (427 adults were treated with armodafinil [50 or 150 mg] or placebo for 3 days after flight from US to France; side effects were headache, nausea and diarrhea; no mention of serum enzyme results). 

  18. Davies M, Wilton L, Shakir S. Safety profile of modafinil across a range of prescribing indications, including off-label use, in a primary care setting in England: results of a modified prescription-event monitoring study. Drug Saf 2013; 36: 237-46. PubMed Citation  (Among 1096 patients prescribed modafinil by UK primary care physicians who filled out a questionnaire regarding its effects, indications were narcolepsy in 24%, "lassitude" in 24% and sleep apnea in 10%, while adverse reactions were uncommon [27 in 17 patients: 1.7%]; no mention of ALT elevations or hepatotoxicity).

  19. Spathis A, Fife K, Blackhall F, Dutton S, Bahadori R, Wharton R, O'Brien M, et al. Modafinil for the treatment of fatigue in lung cancer: results of a placebo-controlled, double-blind, randomized trial. J Clin Oncol 2014; 32: 1882-8. PubMed Citation  (Among 160 patients with lung cancer treated with modafinil or placebo for 28 days, fatigue scores improved to the same degree in both groups and adverse event rates were similar as well; no mention of ALT elevations or hepatotoxicity).

  20. Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-52.e7. PubMed Citation  (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, none were attributed to modafinil or armodafinil).

  21. Silveira MG, Gossard AA, Stahler AC, Jorgensen RA, Petz JL, Ali AH, Lindor KD. A randomized, placebo-controlled clinical tTrial of efficacy and safety: modafinil
    in the treatment of fatigue in patients with primary biliary cirrhosis. Am J Ther 2017; 24: e167-76. PubMed Citation  (Among 40 patients with primary biliary cirrhosis and fatigue who were treated with modafinil or placebo for 12 weeks, fatigue scores improved in a similar percentage of both groups [18% and 13%] and adverse events included headache, rash and diarrhea, while liver test results did not change in either group).

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Modafinil, Armodafinil
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