Modafinil

Pharmacogenomics:

Certain TCAs (e.g. clomipramine, desipramine) and SSRIs are primarily metabolised by CYP2D6 and have ancillary routes of elimination through CYP2C19. Modafinil may affect the pharmacokinetics of CYP2D6 substrates in patients with CYP2D6 gene polymorphism.

FDA-approved drug label for modafinil states that the levels of CYP2D6 substrates may be increased when co-administered with modafinil in patients who are deficient in CYP2D6 enzyme (poor metabolisers). The frequency of this phenotype may vary in different ethnic backgrounds. For example, the prevalence of CYP2D6 poor metabolisers is 7-10% in Caucasians which may be similar or lower in other populations. Product guidelines recommend dose adjustments for TCAs, SSRIs and drugs which are CYP2C19 substrates when used concomitantly with modafinil.

Severe: Reduce recommended dose to half.

May be taken with or without food.

Uncontrolled moderate to severe hypertension, cardiac arrhythmias. Pregnancy.

Patients with history of psychiatric disorders (e.g. psychosis, depression, mania, major anxiety, agitation, insomnia), alcohol, drug or illicit substance abuse; CV disease (e.g. recent history of MI, unstable angina, coronary artery disease). Hepatic or renal impairment. Elderly. Lactation. Not recommended in patients with a history of left ventricular hypertrophy or cor pulmonale, and in patients with mitral valve prolapse induced by previous CNS stimulant use.

Significant: Onset or worsening of anxiety, nervousness, insomnia, confusion, agitation, depression, suicide-related behaviour, psychotic or manic symptoms, aggressive or hostile behaviour, chest pain, palpitations, dyspnoea.
Cardiac disorders: Tachycardia.
Eye disorders: Blurred vision.
Gastrointestinal disorders: Abdominal pain, nausea, dry mouth, diarrhoea, dyspepsia, constipation.
General disorders and administration site conditions: Back pain.
Immune system disorders: Angioedema.
Investigations: Abnormal liver function test.
Metabolism and nutrition disorders: Decreased appetite.
Nervous system disorders: Headache, dizziness, paraesthesia.
Psychiatric disorders: Hallucinations, delusions, somnolence.
Respiratory, thoracic and mediastinal disorders: Rhinitis, pharyngitis.
Vascular disorders: Vasodilation, hypertension.
Potentially Fatal: Rarely, multi-organ hypersensitivity reactions, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms.

PO: C (Avoid using modafinil during pregnancy due to congenital malformations including increased risk of congenital cardiac anomalies, intrauterine growth restriction & spontaneous abortion.)

This drug may cause blurred vision or dizziness, if affected, do not drive or operate machinery.

Perform ECG before initiation of therapy. Monitor blood pressure, heart rate, development of severe skin reactions or psychiatric symptoms.

Symptoms: Insomnia, restlessness, disorientation, confusion, agitation, anxiety, excitation, hallucination, nausea, diarrhoea, tachycardia, bradycardia, hypertension, chest pain. Management: Supportive treatment. Induce emesis or perform gastric lavage. Monitor psychomotor status and CV status.

Altered plasma concentrations with CYP3A4 inducers (e.g. carbamazepine, phenobarbital, rifampicin) and CYP3A4 inhibitors (e.g. ketoconazole, itraconazole). Decreased clearance of phenytoin, warfarin, diazepam, propranolol, omeprazole. Reduced effectiveness of steroidal contraceptives.

Description:
Mechanism of Action: Modafinil is a central stimulant that selectively inhibits the reuptake of dopamine and noradrenaline. Although its exact mechanism of action is unclear, it appears to exert its stimulant effects by reducing GABA-mediated neurotransmission.
Pharmacokinetics:
Absorption: Well absorbed from the gastrointestinal tract. Time to peak plasma concentration: 2-4 hours.
Distribution: Volume of distribution: 0.9 L/kg. Plasma protein binding: Approx 60%, mainly to albumin.
Metabolism: Partially metabolised in the liver by CYP3A4 and CYP3A5 enzymes to form 2 major metabolites, acid modafinil and modafinil sulfone (both inactive).
Excretion: Via urine (80% as metabolites, <10% as unchanged drug); faeces (1%). Elimination half-life: Approx 15 hours.

Source: National Center for Biotechnology Information. PubChem Database. Modafinil, CID=4236, https://pubchem.ncbi.nlm.nih.gov/compound/Modafinil (accessed on Jan. 22, 2020)

Store between 20-25°C.

Thuốc TKTW khác & thuốc trị rối loạn tăng động giảm chú ý

N06BA07 - modafinil ; Belongs to the class of centrally-acting sympathomimetics. Used as CNS stimulant.

Annotation of FDA Label for Modafinil and CYP2D6. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 21/11/2019.

Anon. Modafinil. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 21/11/2019.

Buckingham R (ed). Modafinil. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 21/11/2019.

Do Not Use Modafinil in Pregnant Patients or Those Who May Become Pregnant. Medsafe. http://www.medsafe.govt.nz/. Accessed 03/12/2020.

Joint Formulary Committee. Modafinil. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 21/11/2019.

McEvoy GK, Snow EK, Miller J et al (eds). Modafinil. AHFS Drug Information (AHFS DI) [online]. American Society of Health-System Pharmacists (ASHP). https://www.medicinescomplete.com. Accessed 09/02/2016.

Modafinil Tablet (Actavis Pharma, Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 09/02/2016.

Modafinil Tablet (Alembic Pharmaceuticals Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 21/11/2019.

Provigil 100 mg Tablet (Teva Pharma B.V.). MHRA. https://products.mhra.gov.uk/. Accessed 03/12/2020.

Provigil Tablet (Bryant Ranch Prepack). U.S. FDA. https://www.fda.gov/. Accessed 21/11/2019.