MODAFINIL (modafinil)

There are 2 contraindications. These drug combinations generally should not be dispensed or administered to the same patient. A manufacturer label warning that indicates the contraindication warrants inclusion of a drug combination in this category, regardless of clinical evidence or lack of clinical evidence to support the contraindication.

Drug Interaction	Drug Names
Lonafarnib/Strong and Moderate CYP3A4 Inducers SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Strong and moderate CYP3A4 inducers may increase the metabolism of lonafarnib.(1) CLINICAL EFFECTS: Concurrent use of strong and moderate CYP3A4 inducers may decrease the serum levels and effectiveness of lonafarnib.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: The use of strong or moderate CYP3A4 inducers with lonafarnib is contraindicated. DISCUSSION: With coadministration of a single oral dose of 50 mg lonafarnib (combined with a single oral dose of 100 mg ritonavir) following 600 mg rifampin (a strong CYP3A4 inducer) for 8 days, the area-under-curve (AUC) was reduced by 98% and the maximum concentration (Cmax) was reduced by 92%.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, enzalutamide, fosphenytoin, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(2,3) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, elagolix, etravirine, lesinurad, lorlatinib, modafinil, nafcillin, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, and tovorafenib.(2,3)	ZOKINVY
Mavacamten/Moderate CYP3A4 Inducers SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Agents that induce the CYP3A4 isoenzyme may increase the metabolism of mavacamten.(1-3) CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inducers may decrease the levels and effectiveness of mavacamten.(1-3) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: The US and Canadian manufacturers of mavacamten state concurrent use of mavacamten with moderate CYP3A4 inducers is contraindicated.(1,2) The UK manufacturer of mavacamten states that management of mavacamten during concomitant use with moderate CYP3A4 inducers is dependent on CYP2C19 phenotype. Labeling recommends: -When initiating or increasing the dose of a moderate inducer in patients who are CYP2C19 poor metabolizers, monitor patients closely and adjust mavacamten dose based on clinical response. -When discontinuing or decreasing the dose of a moderate inducer in patients who are CYP2C19 poor metabolizers, decrease the dose of mavacamten to 2.5 mg, or pause therapy if dose is 2.5 mg. -No dose adjustment is warranted with moderate inducers in patients who are CYP2C19 intermediate, normal, rapid, or ultrarapid metabolizers.(3) DISCUSSION: Concomitant use of mavacamten (a single 15 mg dose) with a strong CYP2C19 and CYP3A4 inducer (rifampin 600 mg daily dose) is predicted to decrease mavacamten area-under-curve (AUC) and maximum concentration (Cmax) by 87% and 22%, respectively, in CYP2C19 normal metabolizers, and by 69% and 4%, respectively, in CYP2C19 poor metabolizers.(1) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, elagolix, lesinurad, modafinil, nafcillin, pexidartinib, rifabutin, sotorasib, telotristat, thioridazine, and tovorafenib.(4,5)	CAMZYOS

Drug contraindication overview.

Known hypersensitivity to modafinil, armodafinil (the R-enantiomer of modafinil), or any ingredient in the formulation.

Adverse reaction overview.

Adverse effects occurring in 5% or more of patients receiving modafinil and more frequently than with placebo include headache, nausea, nervousness, rhinitis, diarrhea, back pain, anxiety, insomnia, dizziness, and dyspepsia. In placebo-controlled, phase III clinical trials, although adverse effects generally were mild to moderate and well tolerated, 8% of patients discontinued modafinil because of adverse effects, principally because of headache, nausea, anxiety, dizziness, insomnia, chest pain, and nervousness. In a Canadian trial, a 35-year-old obese narcoleptic male with a history of syncopal episodes experienced a 9-second episode of asystole after 27 days of modafinil 300 mg daily in divided doses.

Modafinil is not approved for use in pediatric patients for any indication, including attention deficit hyperactivity disorder (ADHA). The manufacturer states that safety and efficacy of the drug have not been established in children younger than 16 years of age. In a controlled study of 6 weeks' duration, 165 pediatric patients (5-17 years of age) with narcolepsy were treated with modafinil or placebo.

The results did not demonstrate a statistically significant difference favoring modafinil over placebo in prolonging sleep latency (as measured by the Multiple Sleep Latency Test (MSLT)) or in perceptions of sleepiness (as determined by the Clinical Global Impression of Change (CGI-C) score). Serious rashes, including erythema multiforme major and Stevens-Johnson syndrome, have been associated with modafinil use in pediatric patients. In clinical trials in pediatric patients younger than 17 years of age, the incidence of rash resulting in drug discontinuance was 0.8%

(13 cases out of 1,585); these cases included 1 case of possible Stevens-Johnson syndrome and 1 case of apparent multi-organ hypersensitivity reaction. Several cases were associated with fever and other abnormalities (e.g., vomiting, leukopenia). The median time to rash that resulted in drug discontinuance was 13 days.

No such cases were observed among placebo recipients. (See Serious Dermatologic Reactions under Warnings/Precautions: Warnings, in Cautions.) In controlled and open-label clinical trials, adverse CNS effects reported in modafinil-treated pediatric patients included Tourette's syndrome, insomnia, hostility, increased cataplexy, increased hypnagogic hallucinations, and suicidal ideation. Transient leukopenia, which resolved without medical intervention, also occurred. In the controlled clinical trial, dysmenorrhea occurred in 3 out of 38 girls 12 years of age or younger treated with modafinil compared with 0 out of 10 girls receiving placebo.

Contraindicated

None

Severe Precaution

None

Management or Monitoring Precaution

None