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Nuvigil (Armodafinil) - Description and Clinical Pharmacology

 
 



DESCRIPTION

NUVIGIL™ (armodafinil) is a wakefulness-promoting agent for oral administration. Armodafinil is the R-enantiomer of modafinil which is a mixture of the R- and S-enantiomers. The chemical name for armodafinil is 2-[(R)-(diphenylmethyl)sulfinyl]acetamide. The molecular formula is C15H15NO2S and the molecular weight is 273.35.

The chemical structure is:

Armodafinil is a white to off-white, crystalline powder that is very slightly soluble in water, sparingly soluble in acetone and soluble in methanol. NUVIGIL tablets contain 50, 100, 150, 200, or 250 mg of armodafinil and the following inactive ingredients: croscarmellose sodium, lactose, magnesium stearate, microcrystalline cellulose, povidone, and pregelatinized starch.

CLINICAL PHARMACOLOGY

Mechanism of Action and Pharmacology

The precise mechanism(s) through which armodafinil (R-enantiomer) or modafinil (mixture of R- and S-enantiomers) promote wakefulness is unknown. Both armodafinil and modafinil have shown similar pharmacological properties in nonclinical animal and in vitro studies, to the extent tested.

At pharmacologically relevant concentrations, armodafinil does not bind to or inhibit several receptors and enzymes potentially relevant for sleep/wake regulation, including those for serotonin, dopamine, adenosine, galanin, melatonin, melanocortin, orexin-1, orphanin, PACAP or benzodiazepines, or transporters for GABA, serotonin, norepinephrine, and choline or phosphodiesterase VI, COMT, GABA transaminase, and tyrosine hydroxylase. Modafinil does not inhibit the activity of MAO-B or phosphodiesterases II-IV.

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 alpha-adrenergic agonists such as the rat vas deferens preparation.

Armodafinil is not a direct- or indirect-acting dopamine receptor agonist. However, in vitro, both armodafinil and modafinil bind 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.

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. 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.

Pharmacokinetics

The active component of NUVIGIL is armodafinil, which is the longer-lived enantiomer of modafinil. NUVIGIL 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 NUVIGIL was reached within 7 days of dosing. At steady state, the systemic exposure for NUVIGIL is 1.8 times the exposure observed after a single dose. The concentration-time profiles of the pure R-enantiomer following administration of 50 mg NUVIGIL or 100 mg PROVIGIL® (modafinil) are nearly superimposable.

Absorption

NUVIGIL is 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 NUVIGIL 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 levels later in time, food can potentially affect the onset and time course of pharmacologic action for NUVIGIL.

Distribution

NUVIGIL 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 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 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 NUVIGIL 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).

Elimination

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

Drug-Drug Interactions

The existence of multiple pathways for armodafinil metabolism, as well as the fact that a non-CYP-related pathway is the most rapid in metabolizing armodafinil, suggest that there is a low probability of substantive effects on the overall pharmacokinetic profile of NUVIGIL due to CYP inhibition by concomitant medications.

In vitro data demonstrated that armodafinil shows a weak inductive response for 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.

Chronic administration of NUVIGIL at 250 mg reduced the systemic exposure to midazolam by 32% and 17% after single oral (5 mg) and intravenous (2 mg) doses, respectively, suggesting that administration of NUVIGIL moderately induces CYP3A activity. Drugs that are substrates for CYP3A4/5, such as cyclosporine, may require dosage adjustment. (See PRECAUTIONS, Drug Interactions).

Chronic administration of NUVIGIL at 250 mg did not affect the pharmacokinetics of caffeine (200 mg), a probe substrate for CYP1A2 activity.

Coadministration of a single 400-mg dose of NUVIGIL with omeprazole (40 mg) increased systemic exposure to omeprazole by approximately 40%, indicating that armodafinil moderately inhibits CYP2C19 activity. Drugs that are substrates for CYP2C19 may require dosage reduction. (See PRECAUTIONS, Drug Interactions).

Gender Effect

Population pharmacokinetic analysis suggests no gender effect on the pharmacokinetics of armodafinil.

Special Populations

Data specific to armodafinil in special populations are not available.

Age Effect:

A slight decrease (~20%) in the oral clearance (CL/F) of modafinil was observed in a single dose study at 200 mg in 12 subjects with a mean age of 63 years (range 53 — 72 years), but the change was considered not likely to be clinically significant. In a multiple dose study (300 mg/day) in 12 patients with a mean age of 82 years (range 67 — 87 years), the mean levels of modafinil in plasma were approximately two times those historically obtained in matched younger subjects. Due to potential effects from the multiple concomitant medications with which most of the patients were being treated, the apparent difference in modafinil pharmacokinetics may not be attributable solely to the effects of aging. However, the results suggest that the clearance of modafinil may be reduced in the elderly (See DOSAGE AND ADMINISTRATION).

Race Effect:

The influence of race on the pharmacokinetics of modafinil has not been studied.

Renal Impairment:

In a single dose 200 mg modafinil study, severe chronic renal failure (creatinine clearance ≤20 mL/min) did not significantly influence the pharmacokinetics of modafinil, but exposure to modafinil acid was increased 9-fold (See PRECAUTIONS).

Hepatic Impairment:

The pharmacokinetics and metabolism of modafinil were examined in patients with cirrhosis of the liver (6 men and 3 women). Three patients had stage B or B+ cirrhosis and 6 patients had stage C or C+ cirrhosis (per the Child-Pugh score criteria). Clinically 8 of 9 patients were icteric and all had ascites. In these patients, the oral clearance of modafinil was decreased by about 60% and the steady state concentration was doubled compared to normal patients. The dose of NUVIGIL should be reduced in patients with severe hepatic impairment (See PRECAUTIONS and DOSAGE AND ADMINISTRATION).

CLINICAL TRIALS

The effectiveness of NUVIGIL in improving wakefulness has been established in the following sleep disorders: obstructive sleep apnea/hypopnea syndrome (OSAHS), narcolepsy and shift work sleep disorder (SWSD).

For each clinical trial, a p-value of ≤ 0.05 was required for statistical significance.

Obstructive Sleep Apnea/Hypopnea Syndrome (OSAHS)

The effectiveness of NUVIGIL in improving wakefulness in patients with excessive sleepiness associated with OSAHS was established in two 12-week, multi-center, placebo-controlled, parallel-group, double-blind studies of outpatients who met the International Classification of Sleep Disorders (ICSD) criteria for OSAHS (which are also consistent with the American Psychiatric Association DSM-IV criteria). These criteria include either, 1) excessive sleepiness or insomnia, plus frequent episodes of impaired breathing during sleep, and associated features such as loud snoring, morning headaches or dry mouth upon awakening; or 2) excessive sleepiness or insomnia; and polysomnography demonstrating one of the following: more than five obstructive apneas, each greater than 10 seconds in duration, per hour of sleep; and one or more of the following: frequent arousals from sleep associated with the apneas, bradytachycardia, or arterial oxygen desaturation in association with the apneas. In addition, for entry into these studies, all patients were required to have excessive sleepiness as demonstrated by a score ≥ 10 on the Epworth Sleepiness Scale, despite treatment with continuous positive airway pressure (CPAP). Evidence that CPAP was effective in reducing episodes of apnea/hypopnea was required along with documentation of CPAP use.

Patients were required to be compliant with CPAP, defined as CPAP use ≥ 4 hours/night on ≥ 70% of nights. CPAP use continued throughout the study. In both studies, the primary measures of effectiveness were 1) sleep latency, as assessed by the Maintenance of Wakefulness Test (MWT) and 2) the change in the patient's overall disease status, as measured by the Clinical Global Impression of Change (CGI-C) at the final visit. For a successful trial both measures had to show statistically significant improvement.

The MWT measures latency (in minutes) to sleep onset. An extended MWT was performed with test sessions at 2 hour intervals between 9AM and 7PM. The primary analysis was the average of the sleep latencies from the first four test sessions (9AM to 3PM). For each test session, the subject was asked to attempt to remain awake without using extraordinary measures. Each test session was terminated after 30 minutes if no sleep occurred or immediately after sleep onset. The CGI-C is a 7-point scale, centered at No Change, and ranging from Very Much Worse to Very Much Improved. Evaluators were not given any specific guidance about the criteria they were to apply when rating patients.

In the first study, a total of 395 patients with OSAHS were randomized to receive NUVIGIL 150 mg/day, NUVIGIL 250 mg/day or matching placebo. Patients treated with NUVIGIL showed a statistically significant improvement in the ability to remain awake compared to placebo-treated patients as measured by the MWT at final visit. A statistically significant greater number of patients treated with NUVIGIL showed improvement in overall clinical condition as rated by the CGI-C scale at final visit. The average sleep latencies (in minutes) in the MWT at baseline for the trials are shown in Table 1 below, along with the average change from baseline on the MWT at final visit. The percentages of patients who showed any degree of improvement on the CGI-C in the clinical trials are shown in Table 2 below. The two doses of NUVIGIL produced statistically significant effects of similar magnitudes on the MWT, and also on the CGI-C.

In the second study, 263 patients with OSAHS were randomized to either NUVIGIL 150 mg/day or placebo. Patients treated with NUVIGIL showed a statistically significant improvement in the ability to remain awake compared to placebo-treated patients as measured by the MWT [Table 1]. A statistically significant greater number of patients treated with NUVIGIL showed improvement in overall clinical condition as rated by the CGI-C scale [Table 2].

Nighttime sleep measured with polysomnography was not affected by the use of NUVIGIL in either study.

Narcolepsy

The effectiveness of NUVIGIL in improving wakefulness in patients with excessive sleepiness (ES) associated with narcolepsy was established in one 12-week, multi-center, placebo-controlled, parallel-group, double-blind study of outpatients who met the ICSD criteria for narcolepsy. A total of 196 patients were randomized to receive NUVIGIL 150 or 250 mg/day, or matching placebo. The ICSD criteria for narcolepsy include either 1) recurrent daytime naps or lapses into sleep that occur almost daily for at least three months, plus sudden bilateral loss of postural muscle tone in association with intense emotion (cataplexy), or 2) a complaint of excessive sleepiness or sudden muscle weakness with associated features: sleep paralysis, hypnagogic hallucinations, automatic behaviors, disrupted major sleep episode; and polysomnography demonstrating one of the following: sleep latency less than 10 minutes or rapid eye movement (REM) sleep latency less than 20 minutes and a Multiple Sleep Latency Test (MSLT) that demonstrates a mean sleep latency of less than 5 minutes and two or more sleep onset REM periods and no medical or mental disorder accounts for the symptoms. For entry into these studies, all patients were required to have objectively documented excessive daytime sleepiness, via MSLT with a sleep latency of 6 minutes or less and the absence of any other clinically significant active medical or psychiatric disorder. The MSLT, an objective polysomnographic assessment of the patient's ability to fall asleep in an unstimulating environment, measured latency (in minutes) to sleep onset averaged over 4 test sessions at 2-hour intervals. For each test session, the subject was told to lie quietly and attempt to sleep. Each test session was terminated after 20 minutes if no sleep occurred or immediately after sleep onset.

The primary measures of effectiveness were: 1) sleep latency as assessed by the Maintenance of Wakefulness Test (MWT) and 2) the change in the patient's overall disease status, as measured by the Clinical Global Impression of Change (CGI-C) at the final visit (See CLINICAL TRIALS,  OSAHS section above for a description of these measures). Each MWT test session was terminated after 20 minutes if no sleep occurred or immediately after sleep onset in this study.

Patients treated with NUVIGIL showed a statistically significantly enhanced ability to remain awake on the MWT at each dose compared to placebo at final visit [Table 1]. A statistically significant greater number of patients treated with NUVIGIL at each dose showed improvement in overall clinical condition as rated by the CGI-C scale at final visit [Table 2].

The two doses of NUVIGIL produced statistically significant effects of similar magnitudes on the CGI-C. Although a statistically significant effect on the MWT was observed for each dose, the magnitude of effect was observed to be greater for the higher dose.

Nighttime sleep measured with polysomnography was not affected by the use of NUVIGIL.

Shift Work Sleep Disorder (SWSD)

The effectiveness of NUVIGIL in improving wakefulness in patients with excessive sleepiness associated with SWSD was demonstrated in a 12-week, multi-center, double-blind, placebo-controlled, parallel-group, clinical trial. A total of 254 patients with chronic SWSD were randomized to receive NUVIGIL 150 mg/day or placebo. All patients met the ICSD criteria for chronic SWSD [which are consistent with the American Psychiatric Association DSM-IV criteria for Circadian Rhythm Sleep Disorder: Shift Work Type]. These criteria include 1) either: a) a primary complaint of excessive sleepiness or insomnia which is temporally associated with a work period (usually night work) that occurs during the habitual sleep phase, or b) polysomnography and the MSLT demonstrate loss of a normal sleep-wake pattern (i.e., disturbed chronobiological rhythmicity); and 2) no other medical or mental disorder accounts for the symptoms, and 3) the symptoms do not meet criteria for any other sleep disorder producing insomnia or excessive sleepiness (e.g., time zone change [jet lag] syndrome).

It should be noted that not all patients with a complaint of sleepiness who are also engaged in shift work meet the criteria for the diagnosis of SWSD. In the clinical trial, only patients who were symptomatic for at least 3 months were enrolled.

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 (MSLT score ≤ 6 minutes), and have daytime insomnia documented by a daytime polysomnogram (PSG).

The primary measures of effectiveness were 1) sleep latency, as assessed by the Multiple Sleep Latency Test (MSLT) performed during a simulated night shift at the final visit, and 2) the change in the patient's overall disease status, as measured by the Clinical Global Impression of Change (CGI-C) at the final visit. (See CLINICAL TRIALS, Narcolepsy and OSAHS sections above for description of these measures).

Patients treated with NUVIGIL showed a statistically significant prolongation in the time to sleep onset compared to placebo-treated patients, as measured by the nighttime MSLT at final visit [Table 1]. A statistically significant greater number of patients treated with NUVIGIL showed improvement in overall clinical condition as rated by the CGI-C scale at final visit [Table 2].

Daytime sleep measured with polysomnography was not affected by the use of NUVIGIL.

Table 1. Average Baseline Sleep Latency and Change from Baseline at Final Visit (MWT and MSLT in minutes)
Disorder Measure NUVIGIL
150 mg*
NUVIGIL
250 mg*
Placebo

*Significantly different than placebo for all trials (p<0.05)

Baseline Change
from Baseline
Baseline Change
from Baseline
Baseline Change from
Baseline
OSAHS I MWT 21.5 1.7 23.3 2.2 23.2 -1.7
OSAHS II MWT 23.7 2.3 - - 23.3 -1.3
Narcolepsy MWT 12.1 1.3 9.5 2.6 12.5 -1.9
SWSD MSLT 2.3 3.1 - - 2.4 0.4

Table 2. Clinical Global Impression of Change (CGI-C) (Percent of Patients Who Improved at Final Visit)
Disorder NUVIGIL
150 mg*
NUVIGIL
250 mg*
Placebo

*Significantly different than placebo for all trials (p<0.05)

OSAHS I 71% 74% 37%
OSAHS II 71% - 53%
Narcolepsy 69% 73% 33%
SWSD 79% - 59%

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