Armodafinil 250 mg · Tablets

The mechanism(s) through which armodafinil promotes wakefulness is unknown. Armodafinil (R-modafinil) has pharmacological properties similar to those of modafinil (a mixture of R- and S-modafinil), to the extent tested in animal and in vitro studies. The R- and S-enantiomers have similar pharmacological actions in animals.

Armodafinil and modafinil have wake-promoting actions similar to sympathomimetic agents including amphetamine and methylphenidate, although their pharmacologic profile is not identical to that of the sympathomimetic amines.

Modafinil-induced wakefulness can be attenuated by the α1-adrenergic receptor antagonist, prazosin; however, modafinil is inactive in other in vitro assay systems known to be responsive to α-adrenergic agonists such as the rat vas deferens preparation.

Armodafinil is an indirect dopamine receptor agonist; both armodafinil and modafinil bind in vitro to the dopamine transporter and inhibit dopamine reuptake. For modafinil, 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.

In addition to its wake-promoting effects and ability to increase locomotor activity in animals, modafinil produces psychoactive and euphoric effects, alterations in mood, perception, thinking, and feelings typical of other CNS stimulants in humans. Modafinil has reinforcing properties, as evidenced by its self-administration in monkeys previously trained to self-administer cocaine; modafinil was also partially discriminated as stimulant-like.

Based on nonclinical studies, two major metabolites, acid and sulfone, of modafinil or armodafinil, do not appear to contribute to the CNS-activating properties of the parent compounds.

Armodafinil exhibits linear time-independent kinetics following single and multiple oral dose administration. Increase in systemic exposure is proportional over the dose range of 50 to 400 mg. No time-dependent change in kinetics was observed through 12 weeks of dosing. Apparent steady state for armodafinil was reached within 7 days of dosing. At steady state, the systemic exposure for armodafinil is 1.8 times the exposure observed after a single dose. The concentration-time profiles of the R-enantiomer following administration of a single-dose of 50 mg armodafinil tablets or 100 mg PROVIGIL® (modafinil, a 1:1 mixture of R- and S-enantiomers) are nearly superimposable. However, the Cmax and AUC0-∞, of armodafinil at steady state were approximately 37% and 70% higher, respectively, following administration of 200 mg armodafinil tablets than the corresponding values of modafinil following administration of 200 mg PROVIGIL due to the more rapid clearance of the S-enantiomer (elimination half-life approximately 4 hours) as compared to the R-enantiomer.

Armodafinil tablets are readily absorbed after oral administration. The absolute oral bioavailability was not determined due to the aqueous insolubility of armodafinil, which precluded intravenous administration. Peak plasma concentrations are attained at approximately 2 hours in the fasted state. Food effect on the overall bioavailability of armodafinil is considered minimal; however, time to reach peak concentration (tmax) may be delayed by approximately 2-4 hours in the fed state. Since the delay in tmax is also associated with elevated plasma concentrations later in time, food can potentially affect the onset and time course of pharmacologic action for armodafinil tablets.

Armodafinil has an apparent volume of distribution of approximately 42 L. Data specific to armodafinil protein binding are not available. However, modafinil is moderately bound to plasma protein (approximately 60%), mainly to albumin. The potential for interactions of armodafinil tablets with highly protein-bound drugs is considered to be minimal.

After oral administration of armodafinil tablets, armodafinil exhibits an apparent monoexponential decline from the peak plasma concentration. The apparent terminal t½ is approximately 15 hours. The oral clearance of armodafinil is approximately 33 mL/min.

In vitro and in vivo data show that armodafinil undergoes hydrolytic deamidation, S-oxidation, and aromatic ring hydroxylation, with subsequent glucuronide conjugation of the hydroxylated products. Amide hydrolysis is the single most prominent metabolic pathway, with sulfone formation by cytochrome P450 (CYP) 3A4/5 being next in importance. The other oxidative products are formed too slowly in vitro to enable identification of the enzyme(s) responsible. Only two metabolites reach appreciable concentrations in plasma (i.e., R-modafinil acid and modafinil sulfone).

Data specific to armodafinil disposition are not available. However, modafinil is mainly eliminated via metabolism, predominantly in the liver, with less than 10% of the parent compound excreted in the urine. A total of 81% of the administered radioactivity was recovered in 11 days post-dose, predominantly in the urine (80% vs. 1.0% in the feces).

In vitro data demonstrated that armodafinil weakly induces CYP1A2 and possibly CYP3A activities in a concentration-related manner and that CYP2C19 activity is reversibly inhibited by armodafinil. Other CYP activities did not appear to be affected by armodafinil. An in vitro study demonstrated that armodafinil is a substrate of P-glycoprotein.