Nuvigil®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Nuvigil® (Nuvigil®)

Composition:

Active substance: armodafinil;

One tablet contains armodafinil 50 mg, or 150 mg, or 250 mg;

Excipients: lactose monohydrate, microcrystalline cellulose, pregelatinized starch, povidone K29/32, sodium croscarmellose, magnesium stearate.

Pharmaceutical form. Tablets.

Main physico-chemical properties.

50 mg tablets: round, white to almost white tablets with an embossing on one side and "205" on the other side;

150 mg tablets: oval, white to almost white tablets with an embossing on one side and "215" on the other side;

250 mg tablets: oval, white to almost white tablets with an embossing on one side and "225" on the other side.

Pharmacotherapeutic group. Agents acting on the nervous system. Psychoanaleptics. Psychostimulants, agents used in attention deficit hyperactivity disorder, and nootropic agents. Central-acting sympathomimetics. Armodafinil.

ATC code N06BA13.

Pharmacological Properties

Pharmacodynamics

Armodafinil is the (R)-enantiomer of modafinil, which is a 1:1 mixture of (R)- and (S)-enantiomers.

The mechanism by which armodafinil promotes wakefulness is unknown. Armodafinil has pharmacological properties similar to modafinil, based on animal studies and in vitro investigations. The (R)- and (S)-enantiomers exhibit comparable pharmacological effects in animals.

The action of armodafinil and modafinil in promoting wakefulness is similar to that of sympathomimetic agents, including amphetamine and methylphenidate, although their pharmacological profile differs from that of these sympathomimetic amines.

Armodafinil is an indirect dopamine receptor agonist. Both armodafinil and modafinil bind to the dopamine transporter and inhibit dopamine reuptake in vitro. For modafinil, this activity has been associated in vivo with increased extracellular dopamine levels in certain brain regions of animals. In genetically modified mice lacking the dopamine transporter (DAT), modafinil did not induce wakefulness, indicating that this effect is DAT-dependent. However, the wakefulness-promoting effect of modafinil, unlike that of amphetamine, was not abolished by the dopamine receptor antagonist haloperidol in rats. Furthermore, the dopamine synthesis inhibitor alpha-methyl-p-tyrosine blocks the effect of amphetamine but does not block the locomotor activity induced by modafinil.

In addition to wakefulness-promoting and increased locomotor activity effects in animals, modafinil may produce psychoactive and euphoric effects, as well as changes in mood, sensation, thinking, and emotions, typical of other CNS stimulants in humans. Modafinil has reinforcing properties, as demonstrated by self-administration in monkeys previously trained to self-administer cocaine; modafinil was partially recognized as stimulant-like.

Clinical Studies

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

For each clinical study, statistical significance was defined as p ≤ 0.05.

Obstructive Sleep Apnea/Hypopnea Syndrome (OSAHS)

The efficacy of Nuvigil® in maintaining wakefulness in patients with excessive sleepiness due to OSAHS was established in 12-week, multicenter, placebo-controlled, double-blind, parallel-group studies involving outpatients meeting criteria of the International Classification of Sleep Disorders (ICSD) for OSAHS (which also met criteria of the American Psychiatric Association DSM-IV-TR).

In the first study, a total of 395 patients with OSAHS were randomized to receive Nuvigil® 150 mg/day, Nuvigil® 250 mg/day, or placebo. Patients receiving Nuvigil® showed statistically significant improvement in the ability to maintain wakefulness compared to placebo-treated patients, as measured by the Maintenance of Wakefulness Test (MWT) at the final visit.

In the second study, 263 patients with OSAHS were randomized to receive Nuvigil® 150 mg/day or placebo. Patients receiving Nuvigil® demonstrated statistically significant improvement in the ability to maintain wakefulness compared to placebo-treated patients, as assessed by MWT scores.

In all studies, Nuvigil® did not affect nighttime sleep, as evaluated by polysomnography.

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, double-blind, parallel-group study involving outpatients meeting criteria for narcolepsy according to the International Classification of Sleep Disorders. A total of 196 patients were randomized to receive Nuvigil® 150 mg/day, 250 mg/day, or placebo. Patients receiving Nuvigil® showed statistically significant improvement in the ability to maintain wakefulness compared to placebo-treated patients, as measured by MWT scores.

Nuvigil® did not affect nighttime sleep, as evaluated by polysomnography.

Shift Work Sleep Disorder (SWSD)

The efficacy of Nuvigil® in improving wakefulness in patients with excessive sleepiness associated with SWSD was demonstrated in a 12-week, multicenter, placebo-controlled, double-blind, parallel-group clinical study. A total of 254 patients with SWSD were randomized to receive Nuvigil® 150 mg/day or placebo. Nuvigil® did not affect daytime sleep, as evaluated by polysomnography.

Pharmacokinetics

After single and multiple oral doses, armodafinil exhibits linear, time-independent kinetics. Systemic exposure increases proportionally over the dose range of 50 to 400 mg. No time-dependent changes in kinetics were observed after 12 weeks of treatment. Steady-state levels of armodafinil are achieved after 7 days of administration. At steady state, systemic exposure to armodafinil is 1.8 times higher than after a single dose. Concentration-time profiles for the (R)-enantiomer after a single 50 mg dose of Nuvigil® or 100 mg of Modavigil® [modafinil, a 1:1 mixture of (R)- and (S)-enantiomers] were nearly identical. However, Cmax and AUC0–∞ of armodafinil at steady state were approximately 37% and 70% higher, respectively, after 200 mg of Nuvigil® compared to corresponding values for modafinil after 200 mg of modafinil, due to the faster clearance of the (S)-enantiomer (half-life of approximately 4 hours) compared to the (R)-enantiomer.

Absorption

Nuvigil® is rapidly absorbed after oral administration. Absolute oral bioavailability could not be determined due to the water insolubility of armodafinil, which precludes intravenous administration.

Effect of Food. The effect of food on the oral bioavailability of Nuvigil® is considered minimal; however, time to peak concentration (Tmax) may be delayed by approximately 2–4 hours after food intake. Since prolonged Tmax is also associated with later elevated plasma concentrations, food intake may potentially influence the onset and duration of the pharmacological effect of Nuvigil®.

Distribution

Nuvigil® has an apparent volume of distribution of approximately 42 L. Data on plasma protein binding of armodafinil are unavailable. However, modafinil is moderately bound to plasma proteins (approximately 60%), primarily to albumin. The potential for interaction between Nuvigil® and drugs that are highly protein-bound is considered minimal.

Metabolism

In vitro and in vivo data indicate that armodafinil undergoes hydrolytic deamination, S-oxidation, and aromatic ring hydroxylation, followed by glucuronide conjugation of the hydroxylated compounds.

Amide hydrolysis is the primary metabolic pathway, with sulfoxidation via cytochrome P450 (CYP)3A4/5 being the secondary pathway. Other oxidative products are formed too slowly in vitro to identify the responsible enzymes. Only two metabolites reach significant plasma concentrations: (R)-modafinil acid and modafinil sulfone.

Data on distribution, metabolism, and excretion of Nuvigil® are lacking. However, modafinil is primarily eliminated via hepatic metabolism, with less than 10% of the parent compound excreted in urine. Within 11 days after dosing, 81% of the administered radioactivity was recovered, predominantly in urine (80% vs. 1% in feces).

Excretion

After oral administration of Nuvigil®, armodafinil shows apparent monoexponential decline in peak plasma concentrations. The apparent terminal t1/2 is approximately 15 hours. The oral clearance of Nuvigil® is approximately 33 mL/min.

Special Patient Populations

Pediatric

The pharmacokinetics of armodafinil have not been studied in children.

Age

In a clinical study, systemic exposure to armodafinil was approximately 15% higher in elderly patients (age ≥ 65 years, N=24), corresponding to approximately 12% lower oral clearance (CL/F), compared to younger subjects (age 18–45 years, N=25). Systemic exposure to armodafinil acid (metabolite) was approximately 61% and 73% higher for Cmax and AUC0–∞, respectively, compared to younger subjects. Systemic exposure to the sulfone metabolite was approximately 20% lower in elderly patients compared to younger patients. Subgroup analysis of elderly subjects showed that subjects aged ≥ 75 years and 65–74 years had approximately 21% and 9% lower oral clearance, respectively, compared to younger subjects. Mean blood concentration was approximately 10% higher in subjects aged 65–74 years (N=17) and 27% higher in subjects aged ≥ 75 years (N=7) compared to younger subjects. These changes are not considered clinically significant in elderly patients; however, since some older patients have higher mean plasma concentrations of armodafinil, lower doses should be considered for them.

Gender

Population pharmacokinetic analysis does not indicate a significant effect of gender on armodafinil pharmacokinetics.

Race

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

Renal Impairment

In a single-dose study of 200 mg modafinil, severe chronic renal impairment (creatinine clearance ≤ 20 mL/min) did not significantly affect modafinil pharmacokinetics, but exposure to modafinil acid (metabolite) increased 9-fold. There are insufficient data to determine the safety and efficacy of Nuvigil® (armodafinil) in patients with mild, moderate, or severe renal impairment.

Hepatic Impairment

Oral clearance of modafinil was reduced by approximately 60% in patients with hepatic cirrhosis (Child-Pugh class B or C), and steady-state concentrations were twice as high as in healthy subjects. Therefore, the dose of Nuvigil® should be reduced in patients with severe hepatic impairment (see sections "Dosage and Administration" and "Special Warnings and Precautions"). There are insufficient data on the use of Nuvigil® (armodafinil) according to the degree of hepatic impairment.

Preclinical Studies

Genotoxicity

Armodafinil tested negative in in vitro bacterial reverse mutation assay and in vitro chromosomal aberration assay in human lymphocytes. Modafinil tested negative in a series of in vitro assays (e.g., bacterial reverse mutation assay, mouse lymphoma TK assay, chromosomal aberration assay in human lymphocytes, BALB/3T3 mouse embryonic cell transformation assay) and in vivo assays (micronucleus test in mouse bone marrow cells). These studies indicate that armodafinil has low genotoxic potential.

Clinical characteristics.

Indications.

• To maintain wakefulness in patients with excessive sleepiness associated with obstructive sleep apnea/hypopnea syndrome (as an adjunct to continuous positive airway pressure (CPAP) therapy);
• for the treatment of excessive sleepiness associated with moderate to severe chronic sleep-wake schedule disorder (due to circadian rhythm disruption) in shift work disorder when non-pharmacological interventions are unsuccessful or inappropriate;
• to maintain wakefulness in patients with excessive daytime sleepiness associated with narcolepsy.

Contraindications.

• Hypersensitivity to modafinil, armodafinil, or any other component of the medicinal product;
• the medicinal product is contraindicated in pregnant women, women planning pregnancy, and women who may become pregnant (who are not using effective contraception; see section "Special precautions for use. Embryo-fetal toxicity").

Interaction with other medicinal products and other forms of interaction.

In vitro results indicate that armodafinil weakly induces CYP1A2 activity and may induce CYP3A activity in a concentration-dependent manner, and reversibly inhibits CYP2C19 activity. In vivo, armodafinil induces CYP2B6. Armodafinil does not affect other CYP enzymes. In vitro studies have shown that armodafinil is a substrate of P-glycoprotein.

Potential interactions with medicinal products that inhibit or induce cytochrome P450 isoenzymes or are metabolized by cytochrome P450 isoenzymes and other hepatic enzymes

The existence of multiple metabolic pathways for armodafinil, along with the fact that the non-CYP metabolic pathway is the primary route of armodafinil metabolism, suggests a low likelihood of significant impact on the overall pharmacokinetic profile of Nuvigil® due to CYP inhibition when co-administered with other medicinal products.

However, due to the partial involvement of CYP3A enzymes in the metabolic elimination of armodafinil, concomitant use of strong CYP3A4/5 inducers (e.g., carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifampin, and St. John’s wort) or CYP3A4/5 inhibitors (e.g., protease inhibitors: ritonavir, indinavir, nelfinavir, saquinavir; clarithromycin, erythromycin, chloramphenicol, ketoconazole, itraconazole, nefazodone, diltiazem, and verapamil) may alter plasma concentrations of armodafinil.

Potential of Nuvigil® to alter the metabolism of other medicinal products via enzyme induction or inhibition

Medicinal products metabolized by CYP3A4/5

In vitro data indicate that modafinil sulfone, a metabolite of armodafinil, is a weak inducer of CYP3A activity. In a clinical study, concomitant administration of Nuvigil® 250 mg resulted in a 32% reduction in systemic exposure to midazolam after a single 5 mg oral dose and a 17% reduction after a single 2 mg intravenous dose. Therefore, blood levels and efficacy of medicinal products that are substrates of CYP3A enzymes (e.g., steroid contraceptives, cyclosporine, midazolam, and triazolam) may decrease following initiation of concomitant Nuvigil® therapy, and dose adjustment may be required.

In a clinical study, concomitant administration of Nuvigil® 250 mg with carbamazepine 400 mg/day resulted in approximately a 25% reduction in mean systemic exposure to carbamazepine. Dose adjustment of carbamazepine may be necessary when co-administered with Nuvigil®, particularly at the initiation or discontinuation of concomitant therapy.

In a separate clinical study, concomitant administration of Nuvigil® 250 mg with quetiapine at a daily dose of 300–600 mg resulted in approximately a 29% reduction in mean systemic exposure to quetiapine. Dose adjustment is not required.

Blood levels of cyclosporine may decrease when administered with Nuvigil®. When these medicinal products are used concomitantly, cyclosporine blood concentrations should be monitored and appropriate dose adjustments made.

Medicinal products metabolized by CYP1A2

In vitro results indicate that armodafinil and its metabolite modafinil sulfone are concentration-dependent weak inducers of CYP1A2. However, in a clinical study using caffeine as a marker substrate, no significant effect on CYP1A2 activity was observed.

Medicinal products metabolized by CYP2C19

In vitro data show that armodafinil and, to a greater extent, its metabolite modafinil sulfone are reversible inhibitors of CYP2C19 activity. In a clinical study, concomitant administration of Nuvigil® 400 mg increased exposure to omeprazole by 40% after a single 40 mg oral dose, due to moderate inhibition of CYP2C19 activity. Therefore, dose reduction of certain medicinal products that are CYP2C19 substrates (e.g., phenytoin, diazepam, propranolol, omeprazole, esomeprazole, and clomipramine) may be necessary when co-administered with Nuvigil®.

Medicinal products metabolized by CYP2B6

In vitro data indicate that racemic modafinil is a concentration-dependent weak inducer of CYP2B6 activity.

Interaction with central nervous system (CNS)-active medicinal products

Concomitant administration of Nuvigil® with quetiapine reduced systemic exposure to quetiapine.

Data on specific interactions between Nuvigil® and other CNS-active medicinal products are lacking. However, information on modafinil may be extrapolated to Nuvigil®.

Concomitant administration of modafinil with methylphenidate or dextroamphetamine did not cause significant changes in the pharmacokinetic profiles of modafinil or either stimulant, although absorption of modafinil was prolonged by approximately one hour.

Concomitant administration of modafinil with clomipramine did not alter the pharmacokinetic profile of either agent. However, in one patient with narcolepsy receiving modafinil, increased levels of clomipramine and its active metabolite desmethylclomipramine were observed.

Data on interactions between Nuvigil® or modafinil and monoamine oxidase inhibitors (MAOIs) are lacking. Therefore, caution should be exercised when co-administering MAOIs with Nuvigil®.

Interaction with P-glycoprotein

One in vitro study showed that armodafinil is a substrate, but not an inhibitor, of P-glycoprotein. The clinical impact of P-glycoprotein inhibition on armodafinil bioavailability is unknown.

Interaction with other medicinal products

Data on interactions between Nuvigil® and other medicinal products are lacking. However, information on modafinil may be extrapolated to Nuvigil®.

Concomitant administration of modafinil and warfarin did not cause significant changes in the pharmacokinetic profiles of (R)- and (S)-warfarin. However, since only a single dose of warfarin was used in this study, interactions cannot be excluded. Therefore, when Nuvigil® is co-administered with warfarin, more frequent monitoring of prothrombin time/INR should be considered.

Special precautions for use.

Armodafinil is the enantiomer of racemic modafinil. The two enantiomers of modafinil exhibit different pharmacokinetics. In adults, the half-life of armodafinil, the (R)-enantiomer, is approximately three times longer than that of the (S)-enantiomer. The clinical significance of this pharmacokinetic difference regarding the duration of clinical effect remains unknown. In vitro or in vivo, no evidence has been found of interconversion between the (R)- and (S)-enantiomers of modafinil.

Therefore, armodafinil and modafinil are not bioequivalent and are not interchangeable (see section "Dosage and administration").

Severe skin rash, including Stevens–Johnson syndrome

Severe skin rash requiring hospitalization and discontinuation of treatment has been reported in adults receiving Nuvigil® (armodafinil) and modafinil—the racemic mixture of (S)- and (R)-enantiomers.

The use of Nuvigil® in pediatric patients has not been studied for any indication, and the drug is not approved for use in children for any indication.

In clinical trials of modafinil, the incidence of rash leading to discontinuation was approximately 0.8% (13 out of 1585 patients) in children (aged <17 years); this rash included one case of possible Stevens–Johnson syndrome and one case of probable multiorgan hypersensitivity reaction. Several cases were associated with fever and other abnormalities (e.g., vomiting, leukopenia). The median time to onset of rash leading to discontinuation was 13 days. Among 380 pediatric patients receiving placebo, no such cases were observed. In modafinil clinical trials in adults, no cases of severe rash were reported (0 out of 4264 patients). According to worldwide postmarketing experience, rare cases of severe or life-threatening skin rash associated with modafinil and armodafinil have been reported in both adults and children, including Stevens–Johnson syndrome, toxic epidermal necrolysis, and drug rash with eosinophilia and systemic symptoms (DRESS). During the postmarketing use of armodafinil, cases of Stevens–Johnson syndrome and other severe rashes have been reported in adults and one child, similar to those observed with modafinil, including skin and oral blisters. One case of Stevens–Johnson syndrome in a child has been reported during postmarketing use of armodafinil. One fatal case of DRESS was reported, occurring in close temporal association (within 3 weeks) with the initiation of armodafinil treatment.

Predictive factors for the risk or severity of rash associated with armodafinil or modafinil are unknown. Nearly all cases of severe rash associated with these agents occurred within 1–5 weeks after treatment initiation. However, isolated cases have also been reported after prolonged treatment (e.g., 3 months). Therefore, the duration of treatment cannot predict the potential risk indicated by the initial appearance of rash.

Although benign rashes may also occur with Nuvigil®, it is not possible to predict which rashes will become severe. Therefore, Nuvigil® should be discontinued at the first sign of rash, unless the rash is clearly unrelated to the drug. Discontinuation of treatment may not prevent progression to life-threatening or permanently disabling or disfiguring rash.

Angioedema and anaphylactoid reactions

Angioedema and hypersensitivity reactions (with rash, dysphagia, and bronchospasm) have been observed during treatment with Nuvigil®. Patients should be advised to discontinue treatment and immediately notify their physician if they experience any signs or symptoms of angioedema or anaphylaxis (such as swelling of the face, eyes, lips, tongue, or throat; difficulty swallowing or breathing; hoarseness).

Multiorgan hypersensitivity reactions

Multiorgan hypersensitivity reactions, including at least one fatal case, have been reported during postmarketing surveillance following initiation of modafinil (median time to onset: 13 days; range: 4–33 days). Similarly, one fatal case of DRESS has been reported during the postmarketing use of armodafinil. An analogous risk of multiorgan hypersensitivity reactions with armodafinil cannot be excluded.

Although the number of reported cases has been limited, multiorgan hypersensitivity reactions may lead to hospitalization or be life-threatening. Predictive factors for the risk or severity of multiorgan hypersensitivity reactions are unknown. Signs and symptoms of this disorder have varied, but patients usually, though not exclusively, presented with fever and rash associated with involvement of other organ systems. Other associated manifestations included myocarditis, hepatitis, abnormalities in liver function tests, hematologic abnormalities (e.g., eosinophilia, leukopenia, thrombocytopenia), pruritus, and asthenia. Because multiorgan hypersensitivity may present with diverse manifestations, other, unmentioned symptoms involving other organ systems are possible.

Nuvigil® should be discontinued if a multiorgan hypersensitivity reaction is suspected. Although there are no reports of cross-allergy with other drugs causing this syndrome, experience with other drugs associated with multiorgan hypersensitivity reactions suggests such a possibility.

Persistent somnolence

Patients with abnormal sleepiness taking Nuvigil® should be informed that their level of alertness may not return to normal. In patients with excessive sleepiness, including those taking Nuvigil®, the degree of sleepiness should be frequently assessed, and patients should be advised, when appropriate, to refrain from driving and other potentially hazardous activities. Physicians authorized to prescribe such medications should also be aware that patients may not recognize their own excessive sleepiness unless directly questioned about sleepiness during specific activities.

Psychiatric symptoms

In premarketing controlled trials of Nuvigil® for narcolepsy, obstructive sleep apnea/hypopnea syndrome (OSAHS), and shift work sleep disorder (SWSD), anxiety, agitation, nervousness, and irritability led to treatment discontinuation more frequently in patients receiving Nuvigil® compared to placebo (Nuvigil®: 1.2%; placebo: 0.3%). Depression was also a more frequent reason for discontinuation in patients receiving Nuvigil® compared to placebo (Nuvigil®: 0.6%; placebo: 0.2%). Suicidal ideation has been reported in clinical trials.

Caution should be exercised when prescribing Nuvigil® to patients with a history of psychosis, depression, or mania. If psychiatric symptoms occur during treatment with Nuvigil®, consideration should be given to discontinuing the drug.

Psychiatric adverse reactions have been reported in patients receiving modafinil. Modafinil and armodafinil (Nuvigil®) are closely related compounds. Therefore, the frequency and type of psychiatric symptoms associated with Nuvigil® are expected to be similar to those associated with modafinil. Postmarketing adverse reactions associated with modafinil include mania, delusional thinking, hallucinations, suicidal ideation, and aggression, some of which led to hospitalization. Postmarketing adverse reactions associated with armodafinil include suicidal ideation, aggression, and cases of mania, sometimes resulting in hospitalization. Many, but not all, of these patients had a history of psychiatric disorders. In one healthy male volunteer, ideas of reference, paranoid delusions, and auditory hallucinations developed after multiple daily doses of 600 mg modafinil associated with sleep deprivation. Psychotic symptoms resolved within 36 hours after discontinuation of the drug.

Cardiovascular system

The use of Nuvigil® in patients with recent myocardial infarction or unstable angina has not been adequately studied; therefore, such patients should be treated with caution.

In modafinil clinical trials, cardiovascular adverse reactions including chest pain, palpitations, dyspnea, and transient ischemic changes in T-waves on ECG were observed, with three subjects having mitral valve prolapse or left ventricular hypertrophy. Nuvigil® tablets are not recommended for patients with a history of left ventricular hypertrophy or mitral valve prolapse who experienced mitral valve prolapse syndrome during prior use of CNS stimulants. Ischemic ECG changes, chest pain, or arrhythmia may indicate mitral valve prolapse. Cardiological evaluation should be considered in new episodes of any of these symptoms.

Blood pressure monitoring in short-term (≤3 months) premarketing controlled trials of the drug in OSAHS, SWSD, and narcolepsy showed a slight increase in mean systolic and diastolic blood pressure in patients receiving Nuvigil® compared to placebo (ranging from 1.2 to 4.3 mm Hg across different study groups). A slightly higher proportion of patients receiving Nuvigil® required initiation or dose increase of antihypertensive medications (2.9%) compared to placebo (1.8%). In premarketing controlled trials, a small but consistent mean increase in pulse rate was observed compared to placebo, ranging from 0.9 to 3.5 beats per minute. Monitoring of heart rate and blood pressure may be appropriate for patients receiving Nuvigil®. Caution should be exercised when prescribing Nuvigil® to patients with known cardiovascular disease.

Embryofetal toxicity

According to postmarketing reports, armodafinil may have a negative effect on the fetus and is contraindicated in pregnant women or women who may become pregnant (see sections "Contraindications," "Use in pregnancy or breastfeeding"). Women of reproductive potential should have a negative pregnancy test within one week prior to starting armodafinil treatment. Postmarketing reports indicate that armodafinil use during pregnancy has been associated with cases of serious congenital anomalies (e.g., congenital heart defects, microcephaly).

Pregnant women should be informed of the potential risk to the fetus. Women of reproductive potential should be advised to use effective contraception during armodafinil therapy and for one month after discontinuation of armodafinil.

Patients (women) using contraception

Sexually active women of reproductive potential should initiate contraceptive measures before starting Nuvigil®. The effectiveness of steroid contraceptives (including oral contraceptives, implants, injectable agents, and hormone-releasing intrauterine devices) may be reduced during Nuvigil® treatment and for two months after discontinuation (see section "Interaction with other medicinal products and other forms of interaction"). During Nuvigil® treatment and for two months after discontinuation, patients using steroid contraceptives are advised to use alternative or additional contraceptive methods.

Fetal development delay and impaired growth in infants

Reports of intrauterine growth retardation and impaired growth in infants have been associated with armodafinil and modafinil use. Infants whose mothers take these medications during pregnancy or breastfeeding may be affected.

Potential for abuse and dependence

Although the abuse potential of armodafinil has not been specifically studied, it is likely similar to that of modafinil.

In humans, modafinil may produce psychoactive and euphoric effects, mood changes, altered perception, cognition, and sensations typical of other CNS stimulants. Modafinil has reinforcing properties, as evidenced by self-administration in monkeys previously trained to self-administer cocaine. In some studies, modafinil has also been considered partially stimulant-like. Physicians should closely monitor patients, especially those with a history of drug or stimulant abuse (e.g., methylphenidate, amphetamine, or cocaine). Patients should be monitored for signs of misuse or abuse (e.g., dose escalation or drug-seeking behavior).

The abuse potential of modafinil (200, 400, and 800 mg) was evaluated relative to methylphenidate (45 and 90 mg) in an inpatient study involving individuals with a history of drug abuse. Results of this clinical study showed that modafinil may produce psychoactive and euphoric effects similar to other known CNS stimulants (methylphenidate).

Effect on laboratory test results

Parameters of clinical chemistry, hematology, and urinalysis were monitored in studies. Mean plasma levels of gamma-glutamyl transferase (GGT) and alkaline phosphatase (ALP) increased after Nuvigil® administration compared to placebo. In several subjects, GGT and ALP levels exceeded normal limits. No differences were observed in alanine aminotransferase (ALT), aspartate aminotransferase (AST), total protein, albumin, or total bilirubin levels, although rare isolated elevations of AST and/or ALT were reported. One case of mild pancytopenia, which resolved after discontinuation of the drug, was observed after 35 days of treatment. A slight mean reduction in serum uric acid levels from baseline was observed compared to placebo. The clinical significance of these findings is unknown.

Use in hepatic impairment

The dose of Nuvigil® should be reduced in patients with severe hepatic impairment with or without cirrhosis (see section "Dosage and administration"). There are insufficient data on the use of different doses of Nuvigil® (armodafinil) according to the degree of hepatic impairment.

Use in renal impairment

There are insufficient data to determine the safety and efficacy of Nuvigil® (armodafinil) in patients with mild, moderate, or severe renal impairment (see section "Dosage and administration").

Use in elderly patients

Elimination of armodafinil and its metabolites may be reduced in elderly patients. Therefore, consideration should be given to using lower doses and careful monitoring of these patients (see section "Dosage and administration").

Excipients

This medicinal product contains lactose. Nuvigil® tablets in strengths of 50 mg, 150 mg, and 250 mg contain 35.9 mg, 107.7 mg, and 179.5 mg of lactose monohydrate, respectively. Patients with galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should consult their physician before taking this medicinal product.

Use during pregnancy or breastfeeding.

Pregnancy

According to postmarketing reports and animal studies, armodafinil may have a negative effect on the fetus and is contraindicated in pregnant women or women who may become pregnant (see sections "Contraindications," "Special precautions for use"). Based on data from a pregnancy registry, the frequency of serious congenital malformations (e.g., cardiac anomalies, microcephaly) with armodafinil/modafinil use is approximately 17.3% compared to 3% in the general population. Reports of intrauterine growth retardation and spontaneous abortions have been associated with armodafinil and modafinil use.

Patients should be warned about the possible increased risk of pregnancy when using steroid contraceptives (including oral contraceptives, implants, injectable agents, and hormone-releasing intrauterine devices) with Nuvigil® and for two months after treatment ends (see section "Interaction with other medicinal products and other forms of interaction").

Breastfeeding

It is unknown whether armodafinil or its metabolites are excreted in human milk. Breastfeeding is not recommended during Nuvigil® treatment.

Ability to affect reaction speed when driving or operating machinery.

Although Nuvigil® does not cause functional disturbances, any medicinal product affecting the CNS may alter judgment, thinking, or motor skills. Patients should be advised to refrain from driving or operating machinery until they are confident that Nuvigil® treatment does not adversely affect their ability to perform such activities.

Dosage and Administration

Nuvigil® should be prescribed to patients only after careful assessment of their excessive sleepiness and establishment of a diagnosis of the underlying disorder of narcolepsy, obstructive sleep apnea/hypopnea syndrome (OSAHS), or shift work sleep disorder (SWSD) according to the diagnostic criteria of the International Classification of Sleep Disorders (ICSD) or the Diagnostic and Statistical Manual of Mental Disorders (DSM). This assessment typically includes a comprehensive medical history and physical examination and may be supplemented by laboratory testing. Some patients may have more than one sleep disorder contributing to excessive sleepiness (e.g., OSAHS and SWSD occurring simultaneously in the same patient).

Nuvigil® may be taken with or without food. However, administration with food may delay the onset of its effect and prolong its duration (see section "Pharmacokinetics. Absorption. Effect of food").

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

Treatment with Nuvigil® should be initiated and supervised by a physician experienced in the management of sleep disorders, with access to sleep laboratory diagnostic facilities.

Narcolepsy

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

Obstructive Sleep Apnea/Hypopnea Syndrome (OSAHS)

In OSAHS, Nuvigil® is not indicated for the treatment of the underlying condition. If continuous positive airway pressure (CPAP) therapy is appropriate for the patient, maximal efforts should be made to ensure adequate CPAP use before initiating Nuvigil® for excessive sleepiness. When Nuvigil® is used as an adjunct to CPAP therapy, patients should be encouraged to continue CPAP therapy, and adherence to CPAP should be periodically assessed. In clinical trials of Nuvigil®, a slight trend toward reduced CPAP use over time was observed (mean decrease of 18 minutes in patients receiving Nuvigil® compared to a decrease of 6 minutes in placebo patients, with a mean baseline use of 6.9 hours per night).

The recommended dose of Nuvigil® for patients with OSAHS is 150 mg or 250 mg once daily in the morning. In patients with OSAHS, doses up to 250 mg/day administered as a single dose were well tolerated, but there are no clear data demonstrating additional benefit compared to the 150 mg/day dose.

Chronic sleep disturbance (due to circadian rhythm disorder) associated with shift work (SWSD)

The recommended dose of Nuvigil® for patients with SWSD is 150 mg once daily approximately 1 hour before the start of the work shift.

Dosing in specific patient populations

The dose of Nuvigil® should be reduced in patients with severe hepatic impairment, with or without cirrhosis. Currently, there is insufficient data to provide dosing recommendations for Nuvigil® (armodafinil) based on the degree of hepatic impairment.

There is currently insufficient information to determine the safety and efficacy of Nuvigil® (armodafinil) in patients with mild, moderate, or severe renal impairment.

In elderly patients, elimination of armodafinil and its metabolites may be reduced due to age-related factors. Therefore, lower doses should be considered for such patients, with careful monitoring of their clinical status.

Pediatric patients

There is insufficient data on the efficacy and safety of the use of this medication in children. Severe rashes have been observed in pediatric patients treated with modafinil. Armodafinil is not approved for use in children for any indication.

Overdose

There have been no reports of overdose with Nuvigil® in clinical trials. Symptoms of Nuvigil® overdose are likely similar to those of modafinil overdose. Symptoms observed in modafinil clinical trials included excitation or agitation, insomnia, and mild to moderate increases in hemodynamic parameters.

Based on post-marketing experience with modafinil, there have been no reports of fatal overdose with modafinil alone (doses up to 12 g). However, fatal outcomes have occurred with overdose involving multiple drugs, including modafinil. The most frequently reported symptoms associated with modafinil overdose, alone or in combination with other drugs, include insomnia, central nervous system symptoms such as restlessness, disorientation, confusion, excitement, and hallucinations; gastrointestinal symptoms such as nausea and diarrhea; and cardiovascular symptoms such as tachycardia, bradycardia, hypertension, and chest pain. The most frequently reported symptoms associated with armodafinil overdose, alone or in combination with other drugs, include anxiety, insomnia, and dyspnea.

There is no specific antidote for Nuvigil®. In the event of overdose, symptomatic treatment should be primarily employed, including cardiovascular monitoring. There are no data on the benefit of dialysis, urinary acidification, or alkalinization to enhance drug elimination.

Adverse reactions.

OSA, SWD and narcolepsy

The safety of Nuvigil® was evaluated in a study involving over 1100 patients with excessive sleepiness associated with OSA, SWD and narcolepsy.

In pre-approval controlled clinical studies, the most common adverse reactions (≥ 5 %) observed in patients treated with Nuvigil® and occurring more frequently than in patients treated with placebo were headache, nausea, dizziness, and insomnia. The adverse reaction profile was similar across all studies.

In pre-approval controlled clinical studies, 44 out of 645 patients (7 %) receiving Nuvigil® discontinued treatment due to adverse reactions, compared with 16 out of 445 (4 %) patients receiving placebo. The most common reason for discontinuation was headache (1 %).

Frequency in controlled studies

The table below (Table 1) lists adverse reactions observed at a frequency of 1 % or higher and which were more common in patients treated with Nuvigil® compared to patients treated with placebo in pre-approval controlled clinical studies.

The prescriber should be aware that the figures listed below cannot be used to predict the frequency of adverse reactions in routine medical practice, where patient characteristics and other factors may differ from those during clinical trials. Likewise, the frequency listed cannot be directly compared with rates from other clinical studies involving different treatments, users, or investigators. However, familiarity with this information provides prescribers with a basis for assessing the relative impact of pharmacological and non-pharmacological factors on the frequency of adverse reactions in the studied patient group.

Table 1

Treatment-emergent adverse reactions occurring at a frequency of 1 % or higher in placebo-controlled clinical studies* with
Nuvigil® (150 mg and 250 mg) in OSA, SWD and narcolepsy in parallel-group studies1

System organ class	Nuvigil® (%, N = 645)	Placebo (%, N = 445)
Cardiac disorders Palpitations	2	1
Gastrointestinal disorders Nausea Diarrhea Dry mouth Dyspepsia Upper abdominal pain Constipation Vomiting Loose stools	7 4 4 2 2 1 1 1	3 2 1 0 1 0 0 0
General disorders and administration site conditions Fatigue Thirst Influenza-like illness Pain Pyrexia	2 1 1 1 1	1 0 0 0 0
Immune system disorders Seasonal allergy	1	0
Investigations Increased gamma-glutamyltransferase Increased heart rate	1 1	0 0
Metabolism and nutrition disorders Anorexia Decreased appetite	1 1	0 0
Nervous system disorders Headache Dizziness Attention disorders Tremor Migraine Paraesthesia	17 5 1 1 1 1	9 2 0 0 0 0
Psychiatric disorders Insomnia Anxiety Depression Agitation Nervousness Depressed mood	5 4 2 1 1 1	1 1 0 0 0 0
Renal and urinary disorders Polyuria	1	0
Respiratory, thoracic and mediastinal disorders Dyspnoea	1	0
Skin and subcutaneous tissue disorders Rash Contact dermatitis Increased sweating	2 1 1	0 0 0

* Four double-blind, placebo-controlled clinical studies on the use of the drug in IH, SWPD, and narcolepsy; frequencies rounded to the nearest whole number. Only adverse reactions are included for which the frequency during Nuvigil® administration was higher than with placebo.

1 The table does not list adverse reactions that occurred at a frequency of at least 1% with Nuvigil®, but were equal to or lower than with placebo. These reactions included: abdominal distension, chest pain, bronchitis, nasopharyngitis, sinusitis, upper respiratory tract infections, increased alanine aminotransferase levels, increased aspartate aminotransferase levels, arthralgia, back pain, oropharyngeal pain, cough, and hypertension.

Dose-dependence of adverse reactions

In pre-registration, controlled clinical studies comparing doses of 150 mg/day and 250 mg/day of Nuvigil® with placebo, only the following adverse reactions showed a dose-dependent relationship: headache, rash, depression, dry mouth, insomnia, and nausea. Additional information is provided in Table 2.

Table 2

Frequency of dose-dependent, treatment-related adverse reactions observed in placebo-controlled clinical studies* of Nuvigil® (150 mg and 250 mg) in IH, SWPD, and narcolepsy in parallel groups

System organ class	Nuvigil® 250 mg (%) N = 198	Nuvigil® 150 mg (%) N = 447	Nuvigil® combination (%) N = 645	Placebo (%) N = 445
Gastrointestinal disorders
Nausea	9	6	7	3
Dry mouth	7	2	4	˂ 1
Nervous system disorders
Headache	23	14	17	9
Psychiatric disorders
Insomnia	6	4	5	1
Depression	3	1	2	˂ 1
Skin and subcutaneous tissue disorders
Rash	4	1	2	˂ 1

* Four double-blind, placebo-controlled studies in OHS, OSAS, and narcolepsy.

Changes in vital signs

Monitoring of blood pressure in pre-registration controlled studies of the drug's use in OSAS, OHS, and narcolepsy showed a slight increase in mean systolic and diastolic blood pressure in patients treated with Nuvigil® compared to patients receiving placebo (from 1.2 to 4.3 mm Hg across different study groups). A slightly higher proportion of patients treated with Nuvigil® also required initiation of antihypertensive therapy or an increase in antihypertensive dosage (2.9%) compared to patients receiving placebo (1.8%). In pre-registration controlled studies, a small but consistent mean increase in pulse rate was observed compared to placebo-treated patients. This increase ranged from 0.9 to 3.5 beats per minute.

Post-marketing experience

Below are the adverse reactions reported during post-marketing use of Nuvigil®.

Adverse reactions are categorized by frequency as follows: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10,000, < 1/1000); very rare (< 1/10,000); not known (cannot be estimated from available data).

Cardiac disorders. Common: palpitations; very rare: supraventricular arrhythmia, myocardial infarction.

General disorders. Common: fatigue, influenza-like symptoms, pain, pyrexia, thirst; rare: abnormal sensations, irritability.

Immune system disorders. Common: seasonal allergy; very rare: drug hypersensitivity, anaphylaxis.

Nervous system disorders. Very common: headache; common: dizziness, attention disturbances, migraine, paraesthesia; very rare: seizures.

Psychiatric disorders. Common: anxiety, depression, agitation, depressed mood, insomnia, nervousness; very rare: hallucinations, anger, aggression, drug dependence, psychotic disorder, suicidal thoughts, suicide attempt; not known: mania.

Respiratory, thoracic and mediastinal disorders. Very rare: throat tightness, laryngeal edema.

Gastrointestinal disorders. Not known: oral ulcers (including blisters and mucosal ulcers of the oral cavity).

Skin and subcutaneous tissue disorders. Common: rash, contact dermatitis, increased sweating; very rare: Stevens-Johnson syndrome, alopecia; not known: drug reaction with eosinophilia and systemic symptoms (DRESS).

Reporting suspected adverse reactions. Reporting of suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua

Shelf life. 3 years.

Storage conditions. Store below 25 °C. Do not refrigerate or freeze. Keep out of reach of children.

Packaging. 7 tablets in a blister; 1 blister per carton (for 150 mg and 250 mg tablets); 10 tablets in a blister; 3 blisters per carton (for 50 mg, 150 mg, and 250 mg tablets).

Prescription status. Prescription only.

Manufacturer. PLIVA Hrvatska d.o.o.

Manufacturer's address and place of business. Prilaz baruna Filipovića 25, 10000 Zagreb, Croatia.