NUVIGIL ARMODAFINIL 150MG 30 TABLETS

Description Contents hide 1 NUVIGIL ARMODAFINIL 150MG 30 TABLETS 1.1 Based on preclinical 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. 1.2 Specific populations: 1.3 More information about clinical studies: NUVIGIL ARMODAFINIL 150MG 30 TABLETS Mechanism of action: The mechanism(s) through which armodafinil promotes wakefulness is unknown. Armodafinil (R-modafinil) exhibits pharmacological properties similar to those of modafinil (a mixture of R- and S-modafinil) as far as it has been evaluated 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 those of sympathomimetic agents including amphetamine and methylphenidate, although their pharmacological profile is not identical to that of sympathomimetic amines. Modafinil-induced wakefulness can be attenuated by the α1-adrenergic receptor antagonist prazosin; However, modafinil is inactive in other in vitro test systems known to respond to α-adrenergic agonists such as rat vas deferens preparation. Armodafinil is an indirect dopamine receptor agonist; both armodafinil and modafinil show in vitro binding to the dopamine transporter and inhibit dopamine reuptake. In the case of modafinil, this activity has been associated in vivo with increased levels of extracellular dopamine in some regions of the brain of animals. In genetically modified mice lacking the dopamine transporter (DAT), modafinil did not exhibit wake-promoting activity, suggesting that this activity is 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 to the above, alpha-methyl-p-tyrosine, an inhibitor of dopamine synthesis, blocks the action of amphetamine, but does not block the locomotor activity induced by modafinil. In addition to its wake-promoting effects and its ability to increase locomotor activity in animals, modafinil produces psychoactive and euphoric effects, alterations in mood, perception, and thinking and feelings that are typical of other CNS stimulants. human beings. Modafinil has reinforcing properties as evidenced by its self-administration in monkeys previously trained to self-administer cocaine; modafinil was also partially discriminated as similar to a stimulant. Based on preclinical 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. Pharmacokinetics: Armodafinil exhibits time-independent linear kinetics following administration of single and multiple oral doses. The increase in systemic exposure is proportional within the dose range of 50 to 400 mg. No time-dependent change in kinetics was observed during 12 weeks of administration. The apparent steady state for armodafinil was achieved within the first 7 days of administration. At steady state, the systemic exposure to armodafinil is 1.8 times the exposure observed after a single dose. The concentration-time profiles of the R-enantiomer after administration of a single dose of 50 mg of NUVIGIL® or 100 mg of Modiodal® (modafinil, a 1:1 mixture of the R and S enantiomers) are almost superimposable. However, the Cmax and AUC0-∞ of armodafinil at steady state were elevated by approximately 37% and 70%, respectively, after administration of 200 mg of NUVIGIL® compared to the corresponding values ​​of modafinil after administration of 200 mg of Modiodal® due to the faster clearance of the S-enantiomer (elimination half-life of approximately 4 hours) compared to the R-enantiomer. Absorption: NUVIGIL® is rapidly absorbed after oral administration. Absolute oral bioavailability was not determined due to the aqueous insolubility of armodafinil, which precluded intravenous administration. Peak plasma concentrations are reached after approximately 2 hours in the fasted state. The effect of food on the total bioavailability of NUVIGIL® is considered minimal; However, the time required to reach peak concentration (tmax) can be prolonged by approximately 2-4 hours in the postprandial state. Since prolongation of tmax is also associated with the presence of elevated plasma concentrations later in time, food may potentially affect the onset and time course of the pharmacological action of NUVIGIL®. Distribution: NUVIGIL® has an apparent volume of distribution of approximately 42 L. Specific data on the protein binding of armodafinil are not available. However, modafinil is moderately bound to plasma proteins (approximately 60%), mainly to albumin. The potential for interactions of NUVIGIL® with highly protein-bound drugs is considered to be minimal. Metabolism: In vitro and in vivo data show that armodafinil undergoes hydrolytic deamidation, S-oxidation and hydroxylation of the aromatic ring with subsequent glucuronide conjugation of the hydroxylated products. Amide hydrolysis is the most prominent metabolic pathway, followed in importance by the formation of sulfones by the cytochrome P450 (CYP) 3A4/5 enzyme. The other oxidative products are formed too slowly in vitro to allow identification of the responsible enzyme(s). Only two metabolites reach appreciable concentrations in plasma (R-modafinil acid and modafinil sulfone). No specific data on the disposition of NUVIGIL® are available. However, modafinil is eliminated primarily through metabolism, predominantly in the liver, with less than 10% of the parent compound being excreted in the urine. A total of 81% of the administered radioactivity was recovered within 11 days postdose, predominantly in urine (80% vs. 1.0% in feces). Elimination: Following oral administration of NUVIGIL®, armodafinil exhibits an apparent monoexponential decline from peak plasma concentration. The apparent terminal t½ is approximately 15 hours. The oral clearance of NUVIGIL® is approximately 33 mL/min. Specific populations: Age: In a clinical study, systemic exposure to armodafinil was approximately 15% higher in elderly subjects (≥ 65 years of age, N = 24), which corresponded to an oral clearance (CL/F) of approximately 12 % lower, compared to young subjects (18-45 years of age, N = 25). Systemic exposure to armodafinil acid (metabolite) was approximately 61% (Cmax) and 73% (AUC0-T) higher compared to young subjects. Systemic exposure to the sulfone metabolite was approximately 20% lower in elderly subjects compared to young subjects. A subgroup analysis of elderly subjects showed that subjects aged ≥75 years and subjects aged 65-74 years had approximately 21% and 9% lower oral clearance, respectively, compared to young subjects. Systemic exposure was approximately 10% higher in subjects 65-74 years of age (N = 17) and 27% higher in subjects ≥ 75 years of age (N = 7) compared to young subjects. The change is considered unlikely to be clinically significant for elderly patients; However, since some elderly patients have higher exposure to armodafinil, use of lower doses should be considered. Sex: Population pharmacokinetic analysis does not suggest an effect of sex on the pharmacokinetics of armodafinil. Race: The influence of race on the pharmacokinetics of armodafinil has not been studied. Impaired liver function: The pharmacokinetics and metabolism of modafinil were examined in patients with liver cirrhosis (6 men, 3 women). Three patients had stage B or B cirrhosis and 6 patients had stage C or C cirrhosis (according to the Child-Pugh score criteria). Clinically, 8 of 9 patients were jaundiced and all 9 had ascites. In this patient population, modafinil oral clearance was reduced by approximately 60% and the steady-state concentration was doubled compared to normal patients (see Dosage and Administration). Impaired renal function: In a single-dose study of 200 mg modafinil, severe chronic renal failure (creatinine clearance ≤ 20 mL/min) did not significantly influence the pharmacokinetics of modafinil, but exposure to renal acid modafinil (metabolite) increased 9-fold. More information about clinical studies: Obstructive sleep apnea (OSA): The efficacy of NUVIGIL® in improving wakefulness in patients with excessive sleepiness associated with OSA was established in two 12-week, multicenter, placebo-controlled, parallel-group, double-blind patient studies. outpatients who met the criteria for OSA. These criteria include either: 1) excessive sleepiness or insomnia plus frequent episodes of difficulty breathing during sleep and associated manifestations such as loud snoring, morning headaches, or dry mouth upon awakening or 2) excessive sleepiness or insomnia and polysomnography demonstrating one of the following: the following: more than five obstructive apneas (each lasting more than 10 seconds) per hour of sleep and one or more of the following: frequent awakenings associated with the apneas, bradychycardia, or arterial oxygen desaturation in association with the apneas. In addition to the above, to enter these studies, all patients had to present excessive sleepiness demonstrated by a score of ≥ 10 on the Epworth Sleepiness Scale despite treatment with continuous positive airway pressure (CPAP). Evidence of effectiveness of CPAP in reducing apnea/hypopnea episodes was required along with documentation of CPAP use. Patients were required to have CPAP adherence, defined as using CPAP for ≥ 4 hours/night on ≥ 70% of nights. CPAP use continued during the study. In both studies, the primary measures of effectiveness were 1) sleep latency assessed via the Maintenance of Wakefulness Test (MWT) and 2) change in patients’ global disease status measured via the Impression. Global Change Clinic (CGI-C) at the final visit. For the studies to be successful, both measures had to show a statistically significant improvement. The MWT measures the latency (in minutes) of sleep onset. An extended MWT was performed with testing sessions at 2-hour intervals between 9 a.m. and 2 p.m. and 7 p.m. The primary analysis focused on the average sleep latencies for the first four testing sessions (9 a.m. to 3 p.m.). For each test session, the subject was asked to try to stay awake without resorting to extraordinary measures. Each test session was terminated after 30 minutes if sleep did not occur or immediately after sleep occurred. The CGI-C is a 7-point scale centered on “No change” and ranging from “Much worse” to “Much better.” The evaluators did not receive specific guidance about the criteria they should apply when rating patients. In the first study, a total of 395 patients with OSA were randomly assigned to NUVIGIL® 150 mg/day, NUVIGIL® 250 mg/day, or the corresponding placebo. Patients treated with NUVIGIL® showed a statistically significant improvement in the ability to stay awake compared to patients receiving placebo based on MWT at the final visit. A significantly greater number of patients treated with NUVIGIL® showed an improvement in global clinical condition assessed through the CGI-C scale at the final visit. The average sleep latencies (in minutes) at baseline MWT for the studies are shown below in Table 3 along with the average change from baseline in final visit MWT. The percentages of patients who showed any degree of improvement in CGI-C in the clinical studies are shown below in Table 4. The two doses of NUVIGIL® produced statistically significant effects of similar magnitudes on MWT and also on CGI- c. In the second study, 263 patients with OSA were randomly assigned to NUVIGIL® 150 mg/day or placebo. Patients treated with NUVIGIL® showed a statistically significant improvement in the ability to stay awake compared to patients receiving placebo based on the MWT (Table 1). A significantly greater number of patients treated with NUVIGIL® showed an improvement in global clinical condition based on the CGI-C scale (Table 2). Nighttime sleep measured by polysomnography was not affected by the use of NUVIGIL® in either study. Narcolepsy: The efficacy of NUVIGIL ® in improving wakefulness in patients with excessive sleepiness associated with narcolepsy was established in a 12-week, multicenter, placebo-controlled, parallel-group, double-blind study of outpatients who met ICSD criteria for narcolepsy. A total of 196 patients were randomized to NUVIGIL ® 150 or 250 mg/day or matching placebo. The ICSD criteria for narcolepsy include either: 1) recurrent daytime naps or sleep attacks occurring almost daily for at least 3 months plus sudden bilateral loss of postural muscle tone in association with intense emotions (cataplexy) or 2) complaint of excessive sleepiness or sudden muscle weakness with associated features (sleep paralysis, hypnagogic hallucinations, automatic behaviors, and major sleep episode disturbance) and polysomnography demonstrating one of the following: sleep latency of less than 10 minutes or rapid eye movement (REM) sleep latency of less than 20 minutes and Multiple Sleep Latency Test (MSL T) demonstrating a mean sleep latency of less than 5 minutes and two or more REM periods at sleep onset in the absence of a medical or mental disorder to explain the symptoms. To enter this study, all patients were required to have objectively documented excessive daytime sleepiness (by MSLT with sleep latency of 6 minutes or less) and no other clinically significant active medical or psychiatric disorder. The MSLT, an objective polysomnographic assessment of a patient’s ability to fall asleep in a nonstimulating environment, measured sleep onset latency (in minutes) averaged over 4 test sessions performed at 2-hour intervals. For each test session, the subject was instructed to lie quietly and attempt to sleep. Each test session was terminated after 20 minutes if no sleep occurred or immediately after sleep occurred. The primary efficacy measures were 1) sleep latency as assessed by the Maintenance of Wakefulness Test (MWT) and 2) change in the patient’s global disease status as measured by the CGI-C at the final visit (see Clinical Studies for a description of these measures). Each MWT test session was terminated after 20 minutes if no sleep occurred or immediately after sleep occurred in this study. Patients treated with both doses of NUVIGIL ® showed statistically significant improvement in the ability to maintain wakefulness on the MWT compared to placebo at the final visit (Table 1). Significantly more patients treated with both doses of NUVIGIL ® showed improvement in global clinical condition as assessed by the CGI-C scale at the final visit (Table 2). Both doses of NUVIGIL ® produced statistically significant effects of similar magnitudes on the CGI-C. While a statistically significant effect on MWT was observed with each dose, the observed magnitude of the effect was greater for the higher dose. Nocturnal sleep as measured by polysomnography was not affected by the use of NUVIGIL ® . Shift Work Sleep Disorder (SWD): The efficacy of NUVIGIL ® in improving wakefulness in patients with excessive sleepiness associated with SWD was demonstrated in a 12-week, multicenter, double-blind, placebo-controlled, parallel-group clinical study. A total of 254 patients with chronic SWD were randomized to NUVIGIL ® 150 mg/day or placebo. All patients met ICSD criteria for chronic SWD (which are consistent with the American Psychiatric Association’s DSM-IV-TR criteria for Circadian Rhythm Sleep Disorder: Shift Work Type). These criteria include: 1) either a) a primary complaint of excessive sleepiness or insomnia in temporal association with a work period (usually nocturnal) that occurs during the usual sleep phase or b) polysomnographic and MSLT demonstration of loss of a normal sleep-wake pattern (i.e., altered chronobiological rhythmicity); and 2) the absence of another medical or mental disorder to explain the symptoms; and 3) symptoms that do not meet criteria for another sleep disorder causing insomnia or excessive sleepiness (e.g., jet lag ). It should be noted that not all patients who complain of sleepiness and also work shifts meet the criteria for a diagnosis of SWD. Only patients who had been symptomatic for at least 3 months were enrolled in the trial. Enrolled patients were also required to work a minimum of 5 night shifts per month, have excessive sleepiness at the time of their night shifts (score of ≤ 6 minutes on the MSLT), and have daytime insomnia documented by a daytime polysomnogram (PSG). The primary efficacy measures were: 1) sleep latency assessed by the MSLT performed during a simulated night shift at the final visit and 2) change in the patient’s global disease status as measured by the CGI-C at the final visit (see Clinical Studies for a description of these measures). Patients treated with NUVIGIL ® showed a statistically significant prolongation of sleep onset time compared to patients receiving placebo based on overnight MSLT performed at the final visit (Table 1). Significantly more patients treated with NUVIGIL ® showed improvement in global clinical condition as assessed by the CGI-C scale at the final visit (Table 2). Daytime sleep as measured by polysomnography was not affected by the use of NUVIGIL ® . NUVIGIL ARMODAFINIL 150MG 30 TABLETS