PROLERT 100

Indications

• Narcolepsy
• Excessive daytime sleepiness
• Hypersomnia

Dosage

Children: Refer to the BNF for Children for specific dosing information.

Adults: The usual initial dose for adults is 200 mg daily, taken in the morning. This may be adjusted based on clinical response.

Mechanism of action

The exact mechanism of action of modafinil is not fully understood. However, it is believed to inhibit the reuptake of dopamine by binding to the dopamine reuptake pump, leading to increased extracellular dopamine levels. Additionally, modafinil activates glutamatergic circuits and inhibits GABA, thereby promoting wakefulness. It may also exert partial alpha 1B-adrenergic agonist effects. Modafinil's wakefulness-promoting actions are similar to those of sympathomimetic agents, although its pharmacologic profile differs significantly.

Pharmacodynamics

Modafinil primarily functions as a stimulant, marketed as a wakefulness-promoting agent. It addresses conditions like narcolepsy, where dysfunction in wakefulness-promoting peptides, such as orexins, occurs. Modafinil is not indicated for general fatigue and has been noted for its potential benefits in managing hypersomnia and aiding recovering cocaine addicts in their rehabilitation.

Pharmacokinetics

Modafinil is orally administered and has a bioavailability that can vary. It is metabolized primarily in the liver, and its half-life may range from 12 to 15 hours, allowing for once-daily dosing. The drug is primarily excreted in the urine as metabolites. It is advisable to monitor patients with hepatic or renal impairment, as dose adjustments may be necessary.

Adverse effects

• Headache
• Nausea
• Dizziness
• Insomnia
• Anxiety
• Dry mouth
• Diarrhea
• Rash

Interactions

• modafinil+mobocertinib: Severe (decreases exposure)
• modafinil+voxilaprevir: Severe (decreases concentration)
• modafinil+zanubrutinib: Severe (decreases exposure)
• modafinil+osimertinib: Moderate (decreases exposure)
• modafinil+cyproterone with ethinylestradiol: Unknown (decreases efficacy)
• modafinil+co-cyprindiol: Unknown (decreases efficacy)
• modafinil+avacopan: Unknown (decreases exposure)
• modafinil+bosutinib: Unknown (decreases exposure)
• cobicistat+modafinil: Unknown (increases exposure)
• modafinil+combined hormonal contraceptives: Unknown (decreases efficacy)

Precautions

• Caution in hepatic impairment
• Caution in renal impairment
• Monitor for psychiatric symptoms
• Use with caution in patients with a history of substance abuse

Pregnancy

Manufacturer advises to avoid unless potential benefit outweighs risk due to toxicity in animal studies.

Breast-feeding

Manufacturer advises to avoid due to presence in milk in animal studies.

Storage

Store in a cool, dry place away from direct sunlight.

Formulations

• Tablet 100 mg
• Tablet 200 mg
• Oral solution 500 mg/ml

Mechanism of action

The exact mechanism of action is unclear, although <i>in vitro</i> studies have shown it to inhibit the reuptake of dopamine by binding to the dopamine reuptake pump, and lead to an increase in extracellular dopamine. Modafinil activates glutamatergic circuits while inhibiting GABA. Modafinil is thought to have less potential for abuse than other stimulants due to the absence of any significant euphoric or pleasurable effects. It is possible that modafinil acts by a synergistic combination of mechanisms including direct inhibition of dopamine reuptake, indirect inhibition of noradrenalin reuptake in the VLPO and orexin activation. Modafinil has partial alpha 1B-adrenergic agonist effects by directly stimulating the receptors. The precise mechanism(s) through which modafinil promotes wakefulness is unknown. Modafinil has wake-promoting actions similar to sympathomimetic agents like amphetamine and methylphenidate, although the pharmacologic profile is not identical to that of sympathomimetic amines. Modafinil has weak to negligible interactions with receptors for norepinephrine, serotonin, dopamine, GABA, adenosine, histamine-3, melatonin, and benzodiazepines. Modafinil also does not inhibit the activities of MAO-B or phosphodiesterases II-V. Modafinil-induced wakefulness can be attenuated by the á1-adrenergic receptor antagonist prazosin; however, modafinil is inactive in other in vitro assay systems known to be responsive to á-adrenergic agonists, such as the rat vas deferens preparation. Modafinil is not a direct- or indirect-acting dopamine receptor agonist. However, in vitro, modafinil binds to the dopamine transporter and inhibits dopamine reuptake. This activity has been associated in vivo with increased extracellular dopamine levels in some brain regions of animals. In genetically engineered mice lacking the dopamine transporter (DAT), modafinil lacked wake-promoting activity, suggesting that this activity was DAT-dependent. However, the wake-promoting effects of modafinil, unlike those of amphetamine, were not antagonized by the dopamine receptor antagonist haloperidol in rats. In addition, alpha-methyl-p-tyrosine, a dopamine synthesis inhibitor, blocks the action of amphetamine, but does not block locomotor activity induced by modafinil. Modafinil is a well-tolerated medication for excessive sleepiness, attention-deficit disorder, cocaine dependence and as an adjunct to antidepressants with low propensity for abuse. ... The modafinil action on identified dopaminergic and GABAergic neurons in the ventral tegmental area (VTA) and substantia nigra (SN) of rat brain slices /was examined/. Modafinil (20 microM) inhibited the firing of dopaminergic, but not GABAergic neurons. This inhibition was maintained in the presence of tetrodotoxin and was accompanied by hyperpolarization. Sulpiride (10 microM), a D2-receptor antagonist, but not prazosine (20 microM, an alpha1-adrenoreceptor blocker) abolished the modafinil action. Inhibition of dopamine reuptake with a low dose of nomifensine (1 microM) reduced the firing of DA neurons in a sulpiride-dependent manner and blunted the effect of modafinil. On acutely isolated neurons, modafinil evoked D2-receptor-mediated outward currents in tyrosine-hydroxylase positive cells, identified by single-cell RT-PCR, which reversed polarity near the K(+) equilibrium potential and were unchanged in the presence of nomifensine. Thus modafinil directly inhibits DA neurons through D2 receptors. Modafinil is a wakefulness-promoting drug that improves the alertness levels in narcolepsy; however, the molecular mechanism of action remains to be elucidated. We found that after a single icv injection of modafinil (10 ug/5 uL) the extracellular levels of dopamine (DA) and l-DOPA collected from the nucleus accumbens were increased and decreased, respectively. Separately, the icv administration of modafinil (10 microg/5 uL) to rats enhanced wakefulness (W) whereas diminished sleep during 4hr. Lastly, the

Pharmacodynamics

Modafinil is a stimulant drug marketed as a 'wakefulness promoting agent' and is one of the stimulants used in the treatment of narcolepsy. Narcolepsy is caused by dysfunction of a family of wakefulness-promoting and sleep-suppressing peptides, the orexins, whose neurons are activated by modafinil. The prexin neuron activation is associated with psychoactivation and euphoria. Modafinil is not indicated for complaints of lack of energy or fatigue; but it appears to be very helpful for some patients. Also, it has been used in the treatment of hypersomnia, a disorder in which patients lack the capacity for meaningful sleep and may require ten or more hours per day. Recent studies have have found that modafinil may help recovering cocaine addicts fight their addiction.