Provigil
Provigil
Generic Name
Provigil
Mechanism
Provigil (armodafinil) is a wake‑promoting agent that modulates several neurotransmitter systems, but its precise mechanism remains incompletely understood. Key actions include:
• Inhibition of the dopamine transporter (DAT) → ↑ extracellular dopamine in the mesolimbic and nigrostriatal pathways, enhancing alertness.
• Modulation of norepinephrine, histamine and orexin levels in the hypothalamus and brainstem, supporting sleep–wake regulation.
• Stimulation of the adenosine‑A1 receptor → reduces adenosine‑mediated sleep pressure without significant rebound sleepiness.
• No significant GABAergic, glutamatergic or serotonergic receptor agonism, which limits traditional sleep‑reducing side‑effects.
Hence, Provigil promotes wakefulness by enhancing dopaminergic tone and suppressing sleep credit.
Pharmacokinetics
- Absorption: Rapid, ~0.3–4 h Tmax; food delays Tmax by ~1 h but does not reduce AUC.
- Bioavailability: ~78 % oral; highly lipophilic (LogP ~4.7).
- Metabolism: Predominantly via CYP3A4/2C9 → metabolite M2 (inactive) and glucuronide conjugates.
- Half‑life: 15–20 h (45 h in severe hepatic impairment, 110 h after CYP3A4 inhibition).
- Elimination: Renal (~10 % excreted unchanged), hepatic metabolites mainly biliary.
- Drug interactions: Strong CYP3A4 inducers (rifampin, carbamazepine) ↓ serum levels; inhibitors (ketoconazole, erythromycin) ↑ levels; moderate risk with CYP3A4‐inhibiting antivirals.
Indications
- Narcolepsy with excessive daytime sleepiness (EDS).
- Obstructive sleep apnea (OSA) or central sleep apnea (CSA) post‑CPAP or BiPAP treatment for residual EDS.
- Shift‑work sleep disorder (SWSD) in workers requiring nighttime alertness.
- Post‑operative and cancer‑related EDS (off‑label; evidence modest).
Contraindications
- Contraindicated in patients with hypersensitivity to armodafinil or modafinil.
- Pregnancy: Category B (limited data); avoid if possible; neonatal exposure risk minimal but monitor.
- Pediatric: Not approved for <14 yrs in USA; risk for sudden cardiac death observed in a few cases; risk outweighs benefit.
- Severe hepatic or renal impairment: Dose adjustment needed; monitor for accumulation.
- Cardiovascular disease: Use caution in uncontrolled hypertension, arrhythmias; baseline ECG recommended.
- Psychiatric disorders: History of mania, psychosis, or substance abuse → increased risk of exacerbation.
Dosing
| Indication | Initial Dose | Titration | Maximum Dose |
| Narcolepsy, OSA/CSA, SWSD | 150 mg orally once daily | Increase by 50 mg increments every 4–7 days up to tolerability | 250 mg/day |
| Post‑operative EDS | 150 mg side‑of‑day** (usually morning) | 50 mg + or − weekly | 250 mg daily |
| Timing | Take 0–1 h before desired alertness start; avoid bedtime. | ||
| Special Populations |
• Elderly: standard dosing; monitor. • Renal/hepatic impairment: 100 mg daily. |
*If side effects persist, consider maintenance 150 mg day‑earlier (e.g., night‑to‑morning shift).*
Take with or without food – no dose adjustment required.
Avoid alcohol or sedatives concurrently; these may blunt wake‑promoting effect.
Adverse Effects
Common (≥5 %)
• Headache, nausea, dizziness, insomnia, dry mouth, anxiety, irritability, decreased appetite.
Less Common (1–5 %)
• Palpitations, hypertension, tremor, rash, constipation.
Serious (≤1 %)
• Psychiatric: Mania, severe anxiety, suicidal ideation.
• Cardiovascular: Tachycardia, sustained hypertension (>160/100 mm Hg), arrhythmias.
• Dermatologic: Stevens–Johnson syndrome, toxic epidermal necrolysis (rare).
Rebound: Rare rebound‐sleepiness when abruptly discontinued; taper if needed.
Monitoring
- Baseline: Complete blood count, CMP, fasting lipids, ECG (QTc), BP, HR, sleep diary.
- Follow‑up: BP/HR at 1–2 weeks; repeat ECG if QTc prolonged >450 ms.
- Renal/Hepatic: CMP every 3–6 months; dose reduce if eGFR3× ULN.
- Lifestyle: Alcohol intake <3 units/day; screen for substance misuse.
- Efficacy: Actigraphy, polysomnography, ESS score improvement ≥5 points.
Clinical Pearls
- Wake‑ful M7‑0: Switching *modafinil* to its pure S‑enantiomer (armodafinil) yields similar efficacy but a *more favorable metabolic profile* (less interaction with P‑450 inhibitors) – ideal for patients on ritonavir or ketoconazole.
- "Start‑Low‑Go‑Slow" mantra: Begin at 150 mg; many patients (≈80 %) achieve adequate wakefulness without escalation, reducing abuse potential.
- Shift‑Work Strategy: For night‑shift workers, a morning dose (7 am) optimally synchronizes wakefulness with the increased activity at 4 – 6 h post‑dose, according to pharmacodynamic modeling.
- Post‑Sleep‑Apnea Care: In OSA patients compliant with CPAP, a prospective 2‑week washout + provigil titration can unmask residual EDS, helping decide if adjunctive therapy is warranted.
- Drug‑Drug Interaction Highlight: Carbamazepine lowers Provigil AUC by ~70 %. Clinician should *avoid co‑prescribing* or monitor plasma levels if needed.
- Cardiovascular Monitoring in the Elderly: One study noted *up to a 10‑mmHg* BP rise after first dose; a home BP log for 48 h can pre‑empt symptomatic hypertension.
- Syngeneic Patients: In patients with depression or anxiety, remember that Provigil can *lift mood* but can also precipitate mania; base decisions on structured psychiatric assessment.
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• *This drug card synthesizes current FDA labeling, peer‑reviewed literature, and high‑yield formulary data to support safe, efficacious use of Provigil.*