Nuvigil® [Armodafinil]

Pharmacological properties

Armodafinil is the (r) -enantiomer of modafinil, which is a 1: 1 mixture of (r) - and (s) -enantiomers. the mechanism by which armodafinil maintains wakefulness is unknown. the pharmacological properties of armodafinil are similar to those of modafinil, as follows from the results of animal and in vitro studies. in animals, the (r) - and (s) -enantiomers have the same pharmacological effect.

The action of armodafinil and modafinil maintains a wakeful state similarly to the action of sympathomimetic drugs, including amphetamine and methylphenidate, although their pharmacological profile differs from the profile of these sympathomimetic amines. Armodafinil is an indirect dopamine receptor agonist. Both in vitro armodafinil and modafinil bind to the dopamine transporter and inhibit dopamine reuptake. For modafinil, this in vivo activity was associated with an increase in extracellular dopamine levels in some areas of the animal brain. In genetically modified mice that lacked a dopamine transporter (DAT), modafinil did not cause a wakeful state, indicating that this action is dependent on DAT. Nevertheless, the effect of maintaining wakefulness caused by modafinil, unlike the effect of amphetamine in rats, was not leveled out by the dopamine receptor antagonist haloperidol. In addition, the dopamine synthesis inhibitor alpha-methyl-n-gyrosine blocks the action of amphetamine, but does not block the locomotor activity caused by modafinil.

In addition to the effect of wakefulness and increased locomotor activity in animals, modafinil can have a psychoactive effect and cause a state of euphoria, changes in mood, feelings, thinking and emotions, characteristic of other CNS stimulants in humans. Modafinil has reinforcing properties, which demonstrates the independent administration of the drug by monkeys, who were previously taught to take cocaine on their own; modafinil is partially defined as a stimulant.

Pharmacokinetics After single and multiple oral administration, armodafinil exhibits time-independent linear kinetics. The increase in systemic exposure is proportional in the dose range from 50 to 400 mg. After 12 weeks of drug administration, no time-dependent kinetic changes were observed. The apparent equilibrium state of armodafinil was achieved after 7 days of using the drug. At equilibrium, the systemic exposure of armodafinil is 1.8 times higher than exposure after taking a single dose.

The concentration – time profiles for the (R) enantiomer after taking a single dose of 50 mg of Nuvigil or 100 mg of modafinil, a 1: 1 mixture of (R) and (S) enantiomers almost coincided. Still C_max and AUC_0-∞ armodafinil in equilibrium were higher by 37 and 70%, respectively. after taking 200 mg of Nuvigil compared with the corresponding values ​​for modafinil after applying 200 mg of modafinil due to the faster clearance of the (S) -enantiomer (T_½ ≈4 h) compared with the (R) enantiomer.

Suction. Nuvigil is rapidly absorbed after oral administration. Absolute oral bioavailability could not be determined due to the inability to dissolve armodafinil in water, which makes it impossible to administer iv.

The effect of food. The effect of food on the oral bioavailability of Nuvigil is considered minimal, however, after a meal, the time to reach C_max (Tmax) can be delayed by ≈2–4 hours. Since Tmax is also associated with later elevated plasma concentrations, food intake can potentially affect the onset and duration of the pharmacological action of Nuvigil.

Distribution. The apparent volume of distribution of Nuvigil ≈42 l. There are no data on the binding of armodafinil to plasma proteins.Nevertheless, modafinil binds moderately to plasma proteins (≈60%), mainly to albumin. The interaction potential of Nuvigil with drugs that actively bind to blood proteins is considered minimal.

Metabolism. In vitro and in vivo data demonstrate that armodafinil undergoes hydrolytic deamination, S-oxidation and hydroxylation of the aromatic ring, followed by conjugation of the hydroxylated compounds with glucuronic acid.

Amide hydrolysis is the single most important route of metabolism, and the second most important is the formation of sulfone using cytochrome P450 (CYP) 3A4 / 5. Other oxidation products are formed in vitro extremely slowly to determine the enzymes responsible for their formation. Only two metabolites achieve significant plasma concentrations of ((R) -modafinilic acid and modafinil sulfone).

No data are available on the distribution, metabolism, and excretion of Nuvigil. Nevertheless, modafinil is predominantly eliminated by metabolism in the liver and 10% of the starting compound is excreted in the urine. 11 days after the dose, in general, 81% of the initial radioactivity was determined in the urine (compared with 1.0% in feces).

Following oral administration of Nuvigil, armodafinil shows an apparent monoexponential decrease in C_max in blood plasma. Obvious Finite T_½ ≈15 hours. Nuvigil oral clearance is ≈33 ml / min.

Special patient groups.

Children. The pharmacokinetics of armodafinil in children has not been investigated.

Age. In a clinical study, the systemic exposure of armodafinil was ≈15% higher in elderly patients (aged 65 years, N = 24). which corresponded to a decrease in oral clearance (CL / F) of about 12% compared with younger subjects (aged 18–45 years, N = 25). The systemic exposure of armodafinilic acid (metabolite) was higher by ≈61 and ≈73% for C_max and AUC_0-∞ accordingly, compared with younger subjects. The systemic exposure of the sulfone metabolite was ≈20% lower in elderly patients compared to younger patients. The analysis of subgroups of elderly subjects demonstrated that in elderly subjects aged 75 years and 65–74 years, the level of oral clearance was observed, which was lower by ≈21 and ≈9%, respectively, compared with younger subjects. The average blood concentration was ≈10% higher in subjects aged 65–74 years (N = 17) and 27% in subjects aged 75 years (N = 7) compared with younger subjects. These changes are not considered clinically significant for elderly patients, however, since some elderly patients have a higher average concentration of armodafinil in the blood, they should consider the possibility of using lower doses.

Floor. A population analysis of pharmacokinetics does not indicate the effect of gender on the pharmacokinetics of armodafinil.

Racial affiliation. The effect of race on the pharmacokinetics of armodafinil has not been studied.

Impaired renal function. In a single dose study of 200 mg of modafinil, severe chronic renal failure (creatinine clearance ≤20 ml / min) did not significantly affect the pharmacokinetics of modafinil, nevertheless, the exposure of modafinilic acid (metabolite) increased by 9 times. There is insufficient data to determine the safety and effectiveness of Nuvigil (armodafinil) in patients with mild, moderate and severe renal impairment.

Impaired liver function. Oral clearance of modafinil was ≈60% lower in patients with liver cirrhosis (Child-Pugh class B or C), and the equilibrium concentration was twice as high as in ordinary patients. Accordingly, the dose of Nuvigil should be reduced in patients with severe hepatic impairment (seeAPPLICATION, SPECIAL INSTRUCTIONS), regarding the use of Nuvigil (armodafinil), depending on the degree of liver damage, there is insufficient data.

Clinical researches. The effectiveness of Nuvigil to improve wakefulness was established in the following disorders: obstructive sleep apnea / sleep hypopnea syndrome (SOAHS), narcolepsy and chronic sleep disturbance (due to disruption of the sleep-wake cycle) during shift work (HNSPR).

For each clinical study, p0.05 was considered a parameter of statistical significance.

Obstructive sleep apnea / sleep hypopnea syndrome (SOAGS). The effectiveness of Nuvigil to maintain wakefulness in patients with excessive drowsiness due to SOAGS was established in 12-week, multicenter, placebo-controlled, double-blind studies in parallel groups of outpatients who met the ICSD criteria for SOAGS (also meeting the criteria of the American Psychiatric Association DSM IV-TR).

In the first study of 3021, a total of 395 patients with SOAGS were randomized to receive Nuvigil at a dose of 150 mg / day, Nuvigil at a dose of 250 mg / day or the corresponding placebo. Patients taking Nuvigil showed a statistically significant improvement in their ability to maintain wakefulness compared with placebo-treated patients according to the wakefulness test (WBC) indicators on their last visit.

In the second study of 3025, a total of 263 patients with SOAGS were randomized to receive Nuvigil at a dose of 150 mg / day or placebo. Patients taking Nuvigil showed a statistically significant improvement in their ability to maintain a wakeful state compared with placebo-treated patients according to TPB.

In all studies, Nuvigil did not affect night sleep, which was evaluated using polysomnography.

Narcolepsy The effectiveness of Nuvigil in improving wakefulness in patients with excessive drowsiness associated with narcolepsy was established in a 12-week, multicenter, placebo-controlled, double-blind study in parallel groups of outpatients who met the criteria for the International Classification of Narcolepsy Disorders. A total of 196 patients were randomized to receive Nuvigil at a dose of 150 mg / day or 250 mg / day or an appropriate placebo. Patients taking Nuvigil showed a statistically significant improvement in their ability to maintain wakefulness compared with placebo-treated patients according to TPB.

Nuvigil did not affect night sleep, which was evaluated using polysomnography.

KhNPR. The effectiveness of Nuvigil to improve wakefulness in patients with excessive drowsiness associated with HNSPR was demonstrated in a 12-week, multicenter, placebo-controlled, double-blind, parallel-group study. A total of 254 patients with HNSPR were randomized to receive Nuvigil at a dose of 150 mg / day or placebo. Nuvigil did not affect daytime sleep, which was evaluated using polysomnography.

Indications

• Maintaining wakefulness in patients with coagulation as an adjunct to therapy by creating a constant positive airway pressure (CPAP-therapy); treatment of excessive drowsiness associated with chronic respiratory infections, when the use of nonpharmacological interventions is unsuccessful or impractical; maintenance of wakefulness in patients with excessive daytime sleepiness associated with narcolepsy.

Application

Nuvigil should be prescribed to patients only after a careful assessment of their excessive drowsiness and the main diagnosis of narcolepsy, coag or chronic kidney disease in accordance with the icsd diagnostic criteria or the diagnostic and statistical guidelines for psychiatric diseases (dsm). this assessment usually includes a complete medical history and medical examination and may be supplemented by laboratory data. in some patients, more than one sleep disorder can be observed, causing excessive drowsiness (for example, the combined presence of coags and chronic sleep syndrome in one patient).

Nuvigil can be taken with food or on an empty stomach. Nevertheless, the use of the drug with food can delay the onset of its action. and also prolong the effect (see Pharmacokinetics. Absorption. Effect of food).

To avoid delayed onset of action, Nuvigil should be taken on an empty stomach.

Nuvigil treatment should be initiated and monitored by a physician with relevant experience in treating sleep disorders who has access to the diagnostic tools of the sleep research laboratory.

Narcolepsy The recommended dose of Nuvigil for patients with narcolepsy is 150 mg or 250 mg once daily in the morning.

SOAGS. With SOAGS, Nuvigil is not indicated for the treatment of the underlying disease. If CPAP therapy is suitable for the patient, maximum efforts should be made to conduct it for an adequate period of time before the start of the use of the drug Nuvigil with excessive drowsiness. When using Nuvigil in addition to CPAP therapy, the patient should be encouraged to use CPAP therapy and periodically check compliance with its regimen. Studies on the use of Nuvigil revealed a weak tendency to shorten the period of use of CPAP therapy (average shortening by 18 min in patients taking Nuvigil, compared with a decrease of 6 min in patients taking placebo, with an average duration of initial CPAP therapy = 6, 9 hours per night).

The recommended dose of Nuvigil for patients with SOAGS is 150 mg or 250 mg once daily in the morning. In patients with SOAGS, a single dose of up to 250 mg / day was well tolerated, but there is no clear evidence that these doses have an additional positive effect compared to a dose of 150 mg / day.

KhNPR. The recommended dose of Nuvigil for patients with HNSR is 150 mg / day about 1 hour before the start of the work shift.

Separate categories of patients. The dose of Nuvigil should be reduced in patients with severe hepatic impairment with or without cirrhosis. Currently, there is insufficient data regarding the dosage recommendations of Nuvigil (armodafinil), depending on the degree of impaired liver function.

Currently, there is insufficient information to determine the safety and effectiveness of doses of the drug Nuvigil (armodafinil) in patients with mild, moderate or severe impaired renal function.

In elderly patients, the excretion of armodafinil and its metabolites can be reduced due to age-related factors. Accordingly, in such patients, the use of low doses should be considered.

Contraindications

Hypersensitivity to modafinil, armodafinil or any component of the drug; pregnancy.

Side effects

Soags, khnspr and narcolepsy. the safety of nuvigil was assessed in a study of 1100 patients with excessive drowsiness associated with coag, khnsp and narcolepsy.

In re-registration controlled clinical trials, the most frequent adverse reactions (≥5%) in patients taking Nuvigil, who were more likely than patients taking placebo, were headache, nausea, dizziness, and insomnia. The adverse reaction profile was similar in all studies.

In pre-registered controlled clinical trials, 44 of 645 patients (7%) who took Nuvigil stopped taking the drug due to adverse reactions compared with 16 of 445 (4%) patients who took placebo. The most common reason for stopping the drug was a headache (1%).

Frequency in controlled studies.

Table 1 below shows the adverse reactions observed with a frequency of ≥1%, which were more often observed in patients taking Nuvigil compared with patients taking placebo in pre-registration controlled clinical trials.

The person prescribing the drug should be aware that the data below cannot be used to predict the incidence of adverse reactions during normal medical practice, as patient characteristics and other factors may differ from those during clinical trials. Likewise, it is not possible to compare the reduced incidence of side effects with data from other clinical trials involving other treatments, patients or researchers. Nevertheless, familiarization with this frequency gives prescribing persons a basis for assessing the relative contribution of pharmacological and nonpharmacological factors to the frequency of adverse reactions in the study group of patients.

Table 1. Treatment-related adverse reactions occurring with a frequency of ≥1% during placebo-controlled clinical trials * the use of Nuvigil (150 and 250 mg) with SOAGS, HNSPR and narcolepsy in parallel groups¹

Organ systems and adverse reactions	Nuvigil (%, N = 645)	Placebo (%, N = 445)
From the heart Palpitation	2	1
From the digestive tract Nausea Diarrhea Dry mouth Dyspepsia Pain in the upper abdomen Constipation Vomiting Loose stool	7 4 4 2 2 1 1 1	3 2 1 1 0
General disorders and reactions at the injection site Fatigability Thirst Flu-like symptoms Pain Pyrexia	2 1 1 1 1	1 0 0
From the immune system Seasonal allergy	1
Laboratory and clinical research methods Level up gamma glutamyl transferase Heart rate increase	1 1	0
On the part of metabolism and nutrition Anorexia Decreased appetite	1 1	0
From the nervous system Headache Dizziness Attention Disorders Tremor Migraine Paresthesia	17 5 1 1 1 1	9 2 0 0
From the psyche Insomnia Anxiety Depression Agitation Nervousness Depressed mood	5 4 2 1 1 1	1 1 0 0
From the kidneys and urinary system Polyuria	1
From the respiratory system, chest and mediastinal organs Dyspnoea	1
On the part of the skin and subcutaneous tissue Rash Contact dermatitis Increased sweating	2 1 1	0

* Four double-blind, placebo-controlled clinical trials of the use of the drug for SOAHS, HNSR and narcolepsy: the frequency is rounded to the nearest whole number. Only adverse reactions are included, the frequency of which with Nuvigil is higher than with placebo.

¹Adverse reactions are not presented in the table, the frequency of which with Nuvigil was ≥1% and at the same time was equal to or lower than with placebo. These reactions included the following: bloating, chest pain, bronchitis, nasopharyngitis, sinusitis, upper respiratory tract infections. increased levels of AlAT, AsAT, arthralgia, back pain, oropharyngeal pain, cough and hypertension.

Dose dependence of adverse reactions. In pre-registered controlled clinical trials, the doses of 150 mg / day and 250 mg / day of Nuvigil and placebo were compared, the following adverse reactions were demonstrated as dose-response: headache, rash, depression, dry mouth, insomnia and nausea.

Additional information is given in table 2.

Table 2. The frequency of dose-related adverse reactions associated with treatment, depending on the dose and type of treatment during placebo-controlled clinical trials * the use of Nuvigil (150 and 250 mg) with SOAGS, HNSR and narcolepsy in parallel groups

Organ systems and adverse reactions	Nuvigil 250 mg (%) N = 198	Nuvigil 150 mg (%) N = 447	Nuvigil combination (%) N = 645	Placebo (%) N = 445
From the digestive tract
Nausea	9	6	7	3
Dry mouth	7	2	4	1
From the nervous system
Headache	23	14	17	9
From the psyche
Insomnia	6	4	5	1
Depression	3	1	2	1
On the part of the skin and subcutaneous tissue
Rash	4	1	2	1

* Four double-blind, placebo-controlled clinical trials of the use of the drug in SOAHS, HNSR and narcolepsy.

Changes in the basic vital signs of the body. Monitoring of blood pressure in pre-registration controlled studies of the use of the drug with SOAG, HNSR and narcolepsy showed a slight average increase in the average systolic and diastolic blood pressure in patients taking Nuvigil, compared with patients taking placebo (from 1.2 to 4.3 mm Hg. in different experimental groups). Also, a negligible majority of patients taking Nuvigil needed antihypertensive drugs or an increase in their dose (2.9%) compared with patients taking placebo (1.8%). In pre-registration controlled studies, a small, nevertheless stable, average increase in heart rate was found compared with patients taking placebo. This increase ranged from 0.9 to 3.5 beats / min.

Post-marketing application experience. The following are adverse reactions recorded during the post-marketing experience with Nuvigil.

The frequency of adverse reactions is divided into the following categories: often (from ≥1 / 100 to 1/10), infrequently (≥1 / 1000 to 1/100), rarely (from ≥1 / 10,000 to 1/1000), very rarely (1/10 000).

From the side of the heart: very rarely - supraventricular arrhythmia, myocardial infarction.

General disorders: rarely - abnormal sensations, irritability.

On the part of the immune