Continuing Education Activity

Modafinil is a non-amphetamine central nervous system stimulant with wakefulness-promoting properties. It is used in the treatment of conditions which cause excessive daytime sleepiness. In the United States, modafinil is Food and Drug Administration-approved for the treatment of the following in adults: narcolepsy, sleep work shift disorder, and obstructive sleep apnea (adjunct to continuous positive airway pressure). It also has several off-label indications. This activity will highlight the mechanism of action, adverse event profile, pharmacology, monitoring, and relevant interactions of modafinil, pertinent for members of the interprofessional team in the treatment of patients with conditions where modafinil has a therapeutic purpose.

Objectives:

• Identify the mechanism of action of modafinil.

• Review the approved and off-label indications for modafinil.

• Summarize the adverse events to modafinil therapy.

• Outline the importance of collaboration and communication among interprofessional team members to improve outcomes and treatment efficacy for patients who might benefit from therapy with modafinil.

Indications

Modafinil is a non-amphetamine central nervous system stimulant with wakefulness-promoting properties. It is used in the treatment of conditions that cause excessive daytime sleepiness.

United States Food and Drug Administration-Approved Indications

• Narcolepsy: First-line treatment; Modafinil is used to treat the daytime fatigue associated with narcolepsy, and it has not been shown to improve symptoms of cataplexy.
• Sleep Work Shift Disorder: First-line treatment
• Obstructive sleep apnea: Adjunct to continuous positive airway pressure 

Off-Labeled Indications

• Attention-deficit hyperactivity disorder [1][2] 
  • Some evidence of efficacy exists in the pediatric population. A recent study of adult patients with attention-deficit hyperactivity disorder found no benefit of modafinil.[3]
• Acute unipolar and bipolar depressive episodes [4]
• Cocaine dependence
  • Evidence regarding the efficacy of modafinil for this purpose appears mixed.[5][6]
• Cancer-related fatigue
  • Evidence regarding the efficacy of modafinil for this use appears mixed.[7][8]
• Multiple sclerosis-related fatigues [9]

The use of modafinil as a “cognitive enhancer” in healthy subjects has been suggested in the literature; however, the precise benefits and risks associated with this use remain uncertain.[10][11]

Mechanism of Action

Modafinil is known to be a weak inhibitor of dopamine reuptake, which may be its primary clinically important property. It has little to no in vivo affinity for the serotonin (5HT) or norepinephrine (NE) transporters. However, elevated concentrations of NE and 5HT in the prefrontal cortex and hypothalamus have been observed following modafinil administration, possibly as an indirect effect of increased extracellular dopamine. Modafinil exists as a racemic mixture of S- and R-enantiomers. The R-enantiomer is thought to be the source of modafinil’s psychotropic properties and is marketed independently as armodafinil.[12] 

Additionally, modafinil has been postulated to increase signaling in the hypothalamic orexin and histamine neurotransmitter pathways,[13] and animal studies have also suggested a glutamatergic effect.[14] A potential advantage of modafinil is its very low observed propensity for causing euphoric effects associated with traditional psychostimulants (e.g., cocaine, amphetamine). This has been attributed to differences in its interaction with the dopamine transporter at the molecular level.[15] In several laboratory studies of healthy subjects, modafinil has also been shown to reduce the euphoric effects of cocaine.[16][17]

Pharmacokinetics

Absorption: Modafinil is readily absorbed after oral administration. It is insoluble in an aqueous solution and therefore cannot be administered intravenously. Maximum plasma concentration is reached 2 to 4 hours after administration. 

Metabolism: Modafinil undergoes hepatic metabolism via multiple pathways, including cytochrome (CYP) CYP3A4. 80% of the dose is recovered in the urine in the form of metabolites.

Elimination: The elimination half-life of a single dose in healthy subjects is approximately 15 hours.[18] Severe renal and/or hepatic impairment is known to cause significantly increased steady-state drug concentrations. Dose reduction is recommended in patients with severe hepatic impairment.

Administration

Modafinil is available exclusively in the form of 100 mg and 200 mg oral tablets; the usual dose is 200 mg once daily. It is classified as a control substance class IV drug. 

Adult Dosing

The recommended dose of modafinil tablets in the treatment of narcolepsy or obstructive sleep apnea is  200 mg orally administered once a day in the morning. For the treatment of shift work disorder, modafinil 200 mg once a day is taken about one hour before the start of the work shift.

Specific Patient Population 

Pediatric use: Effectiveness and safety in pediatric patients are not established. Modafinil is not United States Food and Drug Administration (FDA)-approved for use in the pediatric population for any indication. Serious skin rashes, including Stevens-Johnson syndrome and erythema multiforme major, have been reported with modafinil use in pediatric patients.

Geriatric use: In older patients, modafinil and metabolite elimination might be reduced, so consider using lower doses and closely monitor patients.

Pregnancy: It is classified as pregnancy category C medicine by the FDA. There is no evidence to suggest or exclude harm to the human fetus associated with modafinil. However, an increased risk of abortion and intrauterine growth restriction has been observed in some animal studies. The risks and benefits of therapy during pregnancy should be carefully considered.[19]

Lactating women: It is unknown if modafinil is excreted in breast milk. Use with caution, especially if the newborn infant is exclusively breastfed.[20]

Hepatic impairment: In patients with severe hepatic impairment, modafinil dose should be reduced by one-half of the usual dosage indicated for the patients. A dose reduction to a maximum of 100 mg daily is recommended in patients with severe hepatic impairment.

Renal Impairment: Modafinil should be used with caution in patients with severe renal impairment. However, no recommendations for renal dosing exist.

Adverse Effects

Modafinil is generally a well-tolerated stimulant. The most commonly reported adverse effects of modafinil (less than 10% of users) are headache, nausea, and decreased appetite. Other commonly reported adverse effects (5% to 10% of users) include anxiety, insomnia, dizziness, diarrhea, and rhinitis.[1] Regarding serious adverse effects, cases of Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug rash with eosinophilia and systemic symptoms have been reported in postmarketing surveillance. These life-threatening rashes associated with modafinil appear extremely rare, although the precise incidence rates are not known. Most of the reported cases have occurred within six weeks of drug initiation. Therefore, any patient who develops a rash during this time frame is advised to notify the prescribing physician immediately.[21]

Abuse Potential: In clinical trials, modafinil use produces euphoric and psychoactive effects, altering thinking, mood, feelings, and perception like other central nervous system stimulants. Assess the risk of potential abuse and use it with caution in patients with a history of drug abuse.

Withdrawal: In one placebo-controlled clinical trial, after nine weeks of modafinil use, the effects of modafinil withdrawal were observed. No withdrawal symptoms were observed in patients with modafinil treatment cessation during 14 days of observation, but in patients with narcolepsy, sleepiness returned. 

Contraindications

There are few if any, absolute contraindications to the use of modafinil. However, the following is a list of relative contraindications, cautions, and special considerations: 

• Dermatological reaction: If a serious rash including Stevens-Johnson syndrome develops, discontinue modafinil at the first sign of rash, unless the rash is clearly not drug-related.
• Angioedema and Anaphylaxis Reactions: If suspected, discontinue modafinil.
• Multiorgan Hypersensitivity Reactions: If suspected, discontinue modafinil.
• Persistent Sleepiness: Monitor patients frequently for a degree of sleepiness and, if appropriate, recommend patients avoid engaging or driving in any other potentially dangerous activity.
• Cardiovascular disease: In patients with preexisting cardiovascular conditions, consider increased monitoring. Modafinil is not recommended in patients with documented left-ventricular hypertrophy or a history of previous cardiotoxicity related to psychostimulant use. It should be used with caution in patients with uncontrolled hypertension, unstable angina, or recent myocardial infarction.
• Psychiatric disorders: Modafinil should be used with caution in patients with a history of psychosis and/or mania. Such patients should be monitored for hallucinations, delusions, mania, aggression, and suicidal ideation upon starting modafinil. Discontinuation is advised if these symptoms develop.
• Tic disorders: Limited evidence suggests that all central nervous system stimulants may exacerbate tics in patients with pre-existing tic disorders. A baseline assessment of tics is recommended before initiating treatment.[22]

Monitoring

There is no requirement for specific monitoring of patients receiving modafinil. However, a variety of drug-drug interactions are possible. Modafinil is a substrate of hepatic CYP3A4, a moderate inducer of CYP3A4, and a weak inhibitor of CYP2C19.[18]

Modafinil may decrease serum concentrations of other drugs to a clinically significant extent, including the following:

• Antihepaciviral combination products
• Antiretroviral combination products
• Clarithromycin
• Clozapine
• Cyclosporine
• Estrogen Derivatives: In patients using combined oral contraceptive pills (OCP), the manufacturer recommends that patients use an alternative method of contraception, instead of or in addition to OCP, during and until one month after completing modafinil therapy.
• Guanfacine
• Lurasidone
• Nimodipine
• Opioid medications (eg, codeine, fentanyl, hydrocodone)
• Ranolazine
• Zolpidem

Serum concentrations of modafinil may be decreased to a clinically significant extent in the presence of drugs that induce CYP3A4. These include rifampin, phenytoin, St John Wort, and efavirenz. Conversely, serum concentrations of modafinil may be increased to a clinically significant extent in the presence of drugs that inhibit CYP3A4. These include azole antifungals (ketoconazole, itraconazole), ritonavir, and clarithromycin.

Toxicity

Case reports of modafinil overdose/toxicity are rare. Clinical manifestations of modafinil overdose are relatively mild but may include hypertension, tachycardia, agitation, and/or psychosis.[23] The most frequently reported clinical effects were tachycardia, insomnia, agitation, dizziness, and anxiety. About 20% of overdose cases require medical treatment. Symptoms typically respond to supportive therapy, although augmentation with benzodiazepines is occasionally required. Other treatments include diphenhydramine, beta-blockers, haloperidol, IV fluid hydration, nitroglycerin, epinephrine, benztropine, and promethazine based on precipitating symptoms.[24]

Enhancing Healthcare Team Outcomes

Modafinil is a stimulant medication that is generally safe, well-tolerated, and carries a low potential for abuse and dependence. It is used to treat excessive daytime sleepiness associated with narcolepsy, sleep work shift disorder, and obstructive sleep apnea. It is often used in conjunction with other medical and lifestyle treatments for these conditions. Most patients can safely receive modafinil, although it should be used cautiously in patients with structural cardiac disease, severe hepatic impairment, or a history of psychosis/mania. Although no specific monitoring is recommended for patients on modafinil, nurses, pharmacists, and physicians should be aware of the possible drug-drug interactions, including oral contraceptive pills. That is why the prescriber should consult with a pharmacist and conduct a thorough evaluation of all existing medications. Nurses should monitor patient results and also check for signs of adverse reactions at each visit. This interprofessional approach will optimize therapy with modafinil.