Instructions for Nuvigil tablets 150 mg blister No. 7
Composition
active ingredient: armodafinil;
1 tablet contains 50 mg or 150 mg or 250 mg of armodafinil;
Excipients: lactose monohydrate, microcrystalline cellulose, pregelatinized starch, povidone K29/32, croscarmellose sodium, magnesium stearate.
Dosage form
Pills.
Basic physicochemical properties.
50 mg tablets: round, white to off-white tablets debossed on one side and “205” on the other side;
150 mg tablets: oval, white to off-white tablets debossed on one side and “215” on the other side;
250 mg tablets: oval, white to off-white tablets debossed on one side and “225” on the other side.
Pharmacotherapeutic group
Drugs acting on the nervous system. Psychoanaleptics. Psychostimulants, drugs used for attention deficit hyperactivity disorder, and nootropics. Centrally acting sympathomimetics. Armodafinil.
ATX code N06B A13.
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 contributes to the maintenance of a state of alertness is unknown. Armodafinil has pharmacological properties similar to modafinil, based on animal and in vitro studies. The (R)- and (S)-enantiomers have the same pharmacological effects in animals.
The wakefulness-promoting effects of armodafinil and modafinil are similar to those 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 in vitro and inhibit dopamine reuptake. For modafinil, this activity has been associated in vivo with increases in extracellular dopamine levels in several brain regions of animals. In genetically engineered mice lacking the dopamine transporter (DAT), modafinil did not induce a state of alertness, suggesting that this effect is DAT-dependent. However, the arousal-promoting effect of modafinil, unlike that of amphetamine, was not reversed in rats by the dopamine receptor antagonist haloperidol. In addition, the dopamine synthesis inhibitor alpha-methyl-p-tyrosine blocks the effects of amphetamine but does not block the locomotor activity induced by modafinil.
In addition to its effects of alertness and increased locomotor activity in animals, modafinil can produce psychoactive and euphoric effects, changes in mood, sensations, thinking, and emotions, typical of other CNS stimulants in humans. Modafinil has reinforcing properties, as demonstrated by self-administration of the drug in monkeys previously trained to self-administer cocaine; modafinil has been partially characterized as stimulant-like.
Pharmacokinetics.
After single and multiple oral doses, armodafinil exhibits linear, time-independent kinetics. The increase in systemic exposure is dose-proportional over the dose range of 50 to 400 mg. After 12 weeks of dosing, no time-dependent change in kinetics was observed. Steady-state armodafinil was apparent after 7 days of dosing. At steady state, systemic exposure to armodafinil was 1.8 times greater than that after a single dose. The concentration-time profiles for the (R)-enantiomer following a single dose of 50 mg Nuvigil® or 100 mg Modavigil® [modafinil, a 1:1 mixture of (R)- and (S)-enantiomers] were virtually identical. However, Cmax and AUC0-∞ of armodafinil at steady state were 37% and 70% higher, respectively, after administration of 200 mg Nuvigil® compared to the corresponding values for modafinil after administration of 200 mg 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 insolubility of armodafinil in water, which makes intravenous administration impossible.
The impact of food
The effect of food on the oral bioavailability of Nuvigil® is considered minimal; however, the time to peak concentration (Tmax) may be delayed by approximately 2 to 4 hours following ingestion of food. Since the prolongation of Tmax is also associated with later increased plasma concentrations, food intake has the potential to affect the onset and duration of pharmacological action of Nuvigil®.
Distribution
Nuvigil® has an apparent volume of distribution of approximately 42 L. There are no data on the binding of armodafinil to plasma proteins. However, modafinil is moderately bound to plasma proteins (approximately 60%), primarily to albumin. The potential for interactions between Nuvigil® and drugs that are extensively bound to proteins is considered minimal.
Metabolism
Amide hydrolysis is the single most important metabolic pathway, with sulfone formation via cytochrome P450 (CYP)3A4/5 being the second most important. Other in vitro oxidation products are formed too slowly to identify the enzymes responsible for them. Only two metabolites reach significant plasma concentrations [(R)-modafinil acid and modafinil sulfone].
Data on the distribution, metabolism and excretion of Nuvigil® are not available. However, modafinil is eliminated primarily by hepatic metabolism, with less than 10% of the parent compound excreted in the urine. 81% of the parent radioactivity was recovered 11 days post-dose, predominantly in the urine (80% vs. 1% in the feces).
Breeding
Following oral administration of Nuvigil®, armodafinil exhibits an 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 groups
Children
The pharmacokinetics of armodafinil in children have not been studied.
Age
In a clinical study, systemic exposure to armodafinil was approximately 15% higher in elderly subjects (aged ≥ 65 years, N=24), corresponding to an approximately 12% lower oral clearance (CL/F), compared to younger subjects (aged 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 subjects compared to younger subjects. Subgroup analysis of elderly subjects showed that elderly subjects ≥ 75 years and 65–74 years had lower oral clearance by approximately 21% and 9%, respectively, compared to younger subjects. Mean blood levels were 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 younger subjects. These changes are not considered clinically relevant in elderly patients; however, since some older patients have higher mean blood concentrations of armodafinil, lower doses should be considered.
Sex
Population pharmacokinetic analysis does not indicate an effect of gender on the pharmacokinetics of armodafinil.
Racial affiliation
The effect of race on the pharmacokinetics of armodafinil has not been studied.
Kidney dysfunction
In a single-dose study of 200 mg modafinil, severe chronic renal failure (creatinine clearance ≤ 20 mL/min) did not significantly affect the pharmacokinetics of modafinil, 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.
Liver dysfunction
The oral clearance of modafinil was reduced by approximately 60% in patients with cirrhosis (Child-Pugh class B or C), and steady-state concentrations were twice those in normal subjects. Accordingly, the dose of Nuvigil® should be reduced in patients with severe hepatic impairment (see sections 4.2 and 4.4). There is insufficient data on the use of Nuvigil® (armodafinil) in patients with severe hepatic impairment.
Clinical trials
The efficacy of Nuvigil® in improving alertness has been established in the following disorders: obstructive sleep apnea/hypopnea syndrome (OSAS), narcolepsy, and chronic sleep disturbance (due to sleep-wake cycle disorder) associated with shift work (CSWD).
For each clinical study, a p value of ≤ 0.05 was considered to be statistically significant.
Obstructive sleep apnea/hypopnea syndrome (OSAS)
The efficacy of Nuvigil® in maintaining alertness in patients with excessive sleepiness due to OSAHS was established in a 12-week, multicenter, placebo-controlled, double-blind, parallel-group study of outpatients who met the International Classification of Sleep Disorders (ICSD) criteria for OSAHS (who also met the American Psychiatric Association criteria).
DSM IV-TR).
In the first study, 3021, a total of 395 patients with OSAS were randomized to receive Nuvigil® 150 mg/day, Nuvigil® 250 mg/day, or placebo. Patients receiving Nuvigil® showed a statistically significant improvement in the ability to maintain a state of alertness compared to patients receiving placebo, as measured by the TST (Test of Alertness) at the last visit.
In the second study, 3,025,263 patients with OSAS were randomized to receive Nuvigil® 150 mg/day or placebo. Patients taking Nuvigil® showed a statistically significant improvement in the ability to maintain a state of alertness compared to patients taking placebo, as measured by the TBI.
In all studies, Nuvigil® had no effect on nocturnal sleep, as assessed by polysomnography.
The efficacy of Nuvigil® in improving alertness in patients with excessive sleepiness associated with narcolepsy was established in a 12-week, multicenter, placebo-controlled, double-blind, parallel-group study in outpatients who met the criteria for the International Classification of Sleep Disorders in Narcolepsy. A total of 196 patients were randomized to receive Nuvigil® 150 mg/day or 250 mg/day, or placebo. Patients receiving Nuvigil® demonstrated a statistically significant improvement in the ability to maintain alertness compared to patients receiving placebo, as measured by the TBI.
Nuvigil® did not affect nighttime sleep as assessed by polysomnography.
Chronic sleep disturbance (due to sleep-wake cycle disorder) in shift work (CSWD)
The efficacy of Nuvigil® in improving alertness in patients with excessive sleepiness associated with HPSPR was demonstrated in a 12-week, multicenter, placebo-controlled, double-blind, parallel-group clinical trial. A total of 254 HPSPR patients were randomized to receive Nuvigil® 150 mg/day or placebo. Nuvigil® had no effect on daytime sleepiness as assessed by polysomnography.
Indication
– To maintain alertness in patients with excessive sleepiness in obstructive sleep apnea/sleep 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 disturbance (due to sleep-wake cycle disorder) in shift work when non-pharmacological interventions are unsuccessful or inappropriate;
– to maintain a state of alertness in patients with excessive daytime sleepiness associated with narcolepsy.
Contraindication
– Hypersensitivity to modafinil, armodafinil or any other components of the drug;
– the drug is contraindicated in pregnant women, women planning pregnancy, and women who may become pregnant (who are not using effective contraception, see the section “Special precautions for use. Embryofetal toxicity”).
Interaction with other medicinal products and other types of interactions
In vitro results have shown that armodafinil weakly induces CYP1A2 and possibly 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 drugs that inhibit or induce cytochrome P450 isoenzymes or are metabolized by cytochrome P450 isoenzymes and other hepatic enzymes
The existence of multiple pathways for the metabolism of armodafinil, as well as the fact that the non-CYP pathway is the most rapid in the metabolism of armodafinil, suggests that there is a low likelihood of a significant effect on the overall pharmacokinetic profile of Nuvigil® due to CYP inhibition when co-administered with other drugs.
However, due to the partial involvement of CYP3A enzymes in the metabolic elimination of armodafinil, concomitant administration of potent 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 armodafinil plasma concentrations.
Potential for Nuvigil® to alter the metabolism of other drugs by enzyme induction or inhibition
Drugs metabolized by CYP3A4/5
In vitro data have shown that the armodafinil metabolite modafinil sulfone is a weak inducer of CYP3A activity. In a clinical study, co-administration of Nuvigil® 250 mg resulted in a 32% decrease in systemic exposure to midazolam after a single 5 mg oral dose and a 17% decrease after a single 2 mg intravenous dose. Accordingly, the blood levels and efficacy of drugs that are substrates of CYP3A enzymes (e.g., steroidal contraceptives, cyclosporine, midazolam, and triazolam) may be reduced after initiation of co-administration of Nuvigil®, and therefore dose adjustment may be required.
In a clinical study, co-administration of Nuvigil® 250 mg with carbamazepine 400 mg/day resulted in a decrease in mean systemic exposure to carbamazepine of approximately 25%. Dose adjustment of carbamazepine may be required when co-administered with Nuvigil®, especially when initiating or discontinuing concomitant use of these drugs.
In a separate clinical study, co-administration of Nuvigil® 250 mg with quetiapine 300-600 mg daily resulted in a decrease in mean systemic exposure to quetiapine of approximately 29%. No dose adjustment is required.
When taken with Nuvigil®, cyclosporine blood levels may decrease. When these drugs are taken simultaneously, cyclosporine blood levels should be monitored and the cyclosporine dose adjusted accordingly.
In vitro results have shown that armodafinil and its metabolite modafinil sulfone are weak inducers of CYP1A2 in a concentration-dependent manner. However, a clinical study using caffeine as a marker substrate showed no significant effect on CYP1A2 activity.
Drugs metabolized by CYP2C19
In vitro data have shown that armodafinil and, to a greater extent, its metabolite modafinil sulfone, are reversible inhibitors of CYP2C19 activity. In a clinical study, co-administration of Nuvigil® 400 mg resulted in a 40% increase in omeprazole exposure after a single 40 mg oral dose, resulting in a modest inhibition of CYP2C19 activity. Therefore, a dose reduction of some medicinal products that are substrates of CYP2C19 (e.g. phenytoin, diazepam, propranolol, omeprazole, esomeprazole and clomipramine) may be required when co-administered with Nuvigil®.
Drugs metabolized by CYP2B6
In vitro data have shown that racemic modafinil is a weak, concentration-dependent inducer of CYP2B6 activity.
Interaction with CNS-active drugs
Co-administration of Nuvigil® with quetiapine reduced systemic exposure to quetiapine.
There are no data on specific interactions of Nuvigil® with other CNS-active drugs. However, the information on modafinil can be extrapolated to Nuvigil®.
Coadministration of modafinil and methylphenidate or dextroamphetamine did not significantly alter the pharmacokinetic profile of modafinil or either of these stimulants, although the absorption of modafinil was delayed by approximately one hour.
Coadministration of modafinil with clomipramine did not alter the pharmacokinetic profile of either drug. However, one patient with narcolepsy showed increased levels of clomipramine and its active metabolite desmethylclomipramine during modafinil treatment.
There are no data on the interaction of Nuvigil® or modafinil with monoamine oxidase inhibitors (MAOIs). Therefore, caution should be exercised when MAOIs and Nuvigil® are used concomitantly.
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 the bioavailability of armodafinil is unknown.
Interaction with other drugs
There are no data on the interaction of Nuvigil® with other drugs. However, the information on modafinil can be extrapolated to Nuvigil®.
Co-administration of modafinil and warfarin did not significantly alter the pharmacokinetic profiles of (R)- and (S)-warfarin. However, since only a single dose of warfarin was used in this study, an interaction cannot be ruled out. Therefore, more frequent monitoring of prothrombin time/INR should be considered when Nuvigil® is co-administered with warfarin.
Application features
Armodafinil is the enantiomer of racemic modafinil. The two enantiomers of modafinil have different pharmacokinetics. In adults, the half-life of armodafinil, the (R)-enantiomer, is approximately three times longer than the half-life of the (S)-enantiomer. The significance of this pharmacokinetic difference between the two agents for the duration of clinical action remains unknown. There is no evidence of interconversion between the (R)- and (S)-enantiomers of modafinil in vitro or in vivo.
Therefore, armodafinil and modafinil are not bioequivalent and therefore not interchangeable (see section “Method of administration and dosage”).
Severe rash, including Stevens-Johnson syndrome
Severe rash requiring hospitalization and discontinuation of treatment has been reported in adults in association with the use of Nuvigil® (armodafinil) and modafinil, a racemic mixture of (S)- and (R)-enantiomers.
In clinical trials of modafinil, the incidence of rash leading to discontinuation was approximately 0.8% (13 patients per 1585) in children (< 17 years of age); these rashes included 1 case of possible Stevens-Johnson syndrome and 1 case of probable multiorgan hypersensitivity reaction. Several cases were associated with fever and other disorders (e.g., vomiting, leukopenia). The median time to rash leading to discontinuation was 13 days. There were no such cases in the 380 pediatric patients receiving placebo. There were also no cases of severe rash in clinical trials of modafinil in adults (0 per 4264 patients). In worldwide post-marketing experience, rare cases of severe or life-threatening rash, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug rash with eosinophilia and systemic symptoms (DRESS), have been reported in adults and children. During post-marketing use of armodafinil, Stevens-Johnson syndrome and other severe rashes have been reported in adults and one child, similar to those seen with modafinil, including blistering of the skin and mouth. During post-marketing use of armodafinil, one case of Stevens-Johnson syndrome in a child has been reported. One fatal case of DRESS has been reported, which occurred in close temporal association (2 weeks) with the initiation of armodafinil treatment.
Factors that predict the risk or severity of rash associated with armodafinil or modafinil are unknown. Almost all cases of severe rash associated with these agents have occurred within 1 to 5 weeks of initiating treatment. However, isolated cases have also been reported after prolonged treatment (e.g., 3 months). Thus, the duration of treatment cannot predict the potential risk as indicated by the first appearance of rash.
Although benign rashes may occur with Nuvigil®, it is not possible to predict which rashes will be severe. Accordingly, Nuvigil® should be discontinued at the first sign of a rash, unless the rash is not related to the drug. Discontinuation of treatment may not prevent the rash from becoming life-threatening or causing permanent disability or disfigurement.
Angioedema and anaphylactoid reactions
Angioedema and hypersensitivity (with rash, dysphagia, and bronchospasm) have been reported with Nuvigil®. Patients should be advised to discontinue treatment and immediately report to their physician any signs or symptoms suggestive of angioedema or anaphylaxis (such as swelling of the face, eyes, lips, tongue, or larynx; difficulty swallowing or breathing; hoarseness).
Multiorgan hypersensitivity reactions
Multiorgan hypersensitivity reactions, including at least one fatal case, have been reported in post-marketing surveillance after initiation of modafinil (median time to onset 13 days; range 4–33). Similarly, one fatal case of DRESS has been reported during the post-marketing period with armodafinil. A similar risk of multiorgan hypersensitivity reactions with armodafinil cannot be excluded.
Although the number of reports has been limited, it is safe to say that multiorgan hypersensitivity reactions can be hospital-related or life-threatening. Predictors of the risk or severity of multiorgan hypersensitivity reactions are unknown. The signs and symptoms of this disorder have been variable, but patients typically, although not exclusively, present with fever and rash associated with involvement of other organ systems. Other associated manifestations have included myocarditis, hepatitis, liver function test abnormalities, hematologic abnormalities (e.g., eosinophilia, leukopenia, thrombocytopenia), pruritus, and asthenia. Because multiorgan hypersensitivity has a diverse presentation, other organ system symptoms not described here are possible.
If multiorgan hypersensitivity reactions are suspected, Nuvigil® should be discontinued. Although there are no reports of cross-allergy with other drugs that cause this syndrome, experience with drugs associated with multiorgan hypersensitivity reactions suggests that this is a possibility.
Constant drowsiness
Patients with abnormal drowsiness who are taking Nuvigil® should be advised that their level of alertness may not return to normal. Patients with excessive drowsiness, including those taking Nuvigil®, should be frequently assessed for the extent of their drowsiness and, if appropriate, advised to refrain from driving or engaging in other potentially hazardous activities. Prescribing physicians should also be aware that patients may not acknowledge excessive drowsiness when directly asked about drowsiness during certain activities.
In pre-marketing controlled trials of Nuvigil® in narcolepsy, OSAGS, and HPSPR, anxiety, agitation, nervousness, and irritability were the reasons for discontinuation of treatment more frequently in patients taking Nuvigil® compared to patients taking placebo (Nuvigil® – 1.2% and placebo – 0.3%). Depression was also the reason for discontinuation of treatment more frequently in patients taking Nuvigil® compared to patients taking placebo (Nuvigil® – 0.6% and placebo – 0.2%). Cases of suicidal ideation were reported in clinical trials.
Caution should be exercised when prescribing Nuvigil® to patients with a history of psychosis, depression, or mania. If psychiatric symptoms develop during the use of Nuvigil®, discontinuation of Nuvigil® should be considered.
Psychiatric adverse reactions have been reported in patients receiving modafinil. Modafinil and armodafinil (Nuvigil®) are closely related compounds. Accordingly, the frequency and type of psychiatric symptoms associated with Nuvigil® are expected to be similar to the frequency and type of these events associated with modafinil. Postmarketing adverse reactions associated with modafinil included mania, delusions, hallucinations, suicidal ideation, and aggression, some of which led to hospitalization. Postmarketing adverse reactions associated with armodafinil included suicidal ideation, aggression, and mania, some of which led to hospitalization. Many, but not all, of these patients had a history of psychiatric disorders. One healthy male volunteer developed ideation, paranoid delusions, and auditory hallucinations after multiple daily doses of 600 mg of modafinil, associated with sleep deprivation. The signs of psychosis resolved 36 hours after discontinuation of the drug.
Cardiovascular system
Nuvigil® has not been adequately studied in patients with a recent history of myocardial infarction or unstable angina, and should be treated with caution in such patients.
In clinical trials of modafinil, cardiovascular adverse reactions were observed, including chest pain, palpitations, dyspnea, and transient ischemic T-wave changes on the ECG, which in three subjects were associated with mitral valve prolapse or left ventricular hypertrophy. Nuvigil® tablets are not recommended for use in patients with a history of left ventricular hypertrophy or in patients with mitral valve prolapse who have experienced mitral valve prolapse syndrome with prior CNS stimulant therapy. Mitral valve prolapse is indicated by, but is not limited to, ischemic ECG changes, chest pain, or arrhythmia. Cardiac evaluation should be considered for new episodes of any of these symptoms.
Blood pressure monitoring in short-term (≤ 3 months) pre-marketing controlled trials of the drug in OSAGS, HPSPR and narcolepsy showed a small increase in mean systolic and diastolic blood pressure in patients taking Nuvigil® compared to patients taking placebo (from 1.2 to 4.3 mm Hg in different experimental groups). Also, a slightly higher proportion of patients taking Nuvigil® required the appointment of antihypertensive drugs or an increase in the dosage of antihypertensive drugs (2.9%) compared to patients taking placebo (1.8%). In pre-marketing controlled trials, a small but consistent mean increase in pulse rate was observed compared to patients taking placebo. This increase ranged from 0.9 to 3.5 beats per minute. Monitoring of heart rate and blood pressure may be appropriate for patients taking Nuvigil®. Caution should be exercised when prescribing Nuvigil® to patients with known cardiovascular disease.
Embryofetal toxicity
According to post-marketing reports, armodafinil may have adverse effects on the fetus and is contraindicated for use in pregnant women or women who may become pregnant (see sections 4.3, 4.4, and 4.8). Women of childbearing potential must have a negative pregnancy test within one week prior to initiating treatment with armodafinil. In post-marketing reports, use of armodafinil 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 childbearing potential should be advised to use effective contraception during treatment with armodafinil and for one month after stopping treatment with armodafinil.
Sexually active women of childbearing potential should be advised to use contraception before starting Nuvigil®. The effectiveness of steroid contraceptives (including birth control pills, implants, injectables, and hormone-releasing intrauterine devices) may be reduced during Nuvigil® treatment and for two months after discontinuation of treatment (see section 4.5). During treatment with Nuvigil® and for two months after discontinuation of Nuvigil®, patients taking steroid contraceptives are advised to use alternative methods of contraception or to use additional methods of contraception.
Fetal growth retardation during pregnancy and infancy
Intrauterine growth retardation and infant growth retardation have been reported with the use of armodafinil and modafinil. Infants may be exposed to armodafinil or modafinil during pregnancy or while breastfeeding.
Genotoxicity
Armodafinil was negative in the in vitro bacterial reverse mutation assay and the in vitro human lymphocyte chromosome aberration assay. Modafinil was negative in a series of in vitro (e.g., bacterial reverse mutation assay, murine lymphoma TK (thymidine kinase) assay, human lymphocyte chromosome aberration assay, BALB/3T3 mouse embryonic cell transformation assay) and in vivo (mouse bone marrow micronucleus assay) assays. These studies indicate that armodafinil has a low genotoxic potential.
Potential for abuse and dependence
Although the abuse potential of armodafinil has not been specifically studied, it is likely to be similar to that of modafinil.
In humans, modafinil can produce psychoactive and euphoric effects, changes in mood, perception, thinking and sensations, typical of other CNS stimulants. Modafinil has reinforcing properties, as evidenced by its self-administration by monkeys previously trained to self-administer cocaine. In some studies, modafinil has also been considered to be partly a stimulant-like substance. Physicians should closely monitor patients, especially those with a history of drug and/or stimulant abuse (e.g., methylphenidate, amphetamine or cocaine). Patients should be observed 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 in individuals with a history of drug abuse. The results of this clinical study showed that modafinil can produce psychoactive and euphoric effects similar to other known CNS stimulants (methylphenidate).
Impact on laboratory test results
Clinical chemistry, hematology, and urinalysis parameters were monitored in the studies. Mean plasma gamma-glutamyltransferase (GGT) and alkaline phosphatase (ALP) levels increased with Nuvigil® compared with placebo. Several subjects had GGT and ALP levels above the normal range. There were no differences in alanine aminotransferase (ALT), aspartate aminotransferase (AST), total protein, albumin, or total bilirubin, although there were rare cases of isolated increases in AST and/or ALT. One case of mild pancytopenia occurred after 35 days of treatment, which resolved after discontinuation of the drug. In clinical studies, a small mean decrease from baseline in serum uric acid was observed compared with placebo. The clinical significance of these findings is unknown.
Excipients
This medicinal product contains lactose. Nuvigil® tablets in dosages 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 doctor before taking this medicinal product.
Liver dysfunction
The dose of Nuvigil® should be reduced in patients with severe hepatic impairment with or without cirrhosis (see Dosage and Administration). There are insufficient data on the use of different doses of Nuvigil® (armodafinil) according to the degree of hepatic impairment.
Kidney dysfunction
There are insufficient data to determine the safety and efficacy of Nuvigil® (armodafinil) in patients with mild, moderate, or severe renal impairment (see Dosage and Administration).
Use in elderly patients
The elimination of armodafinil and its metabolites may be reduced in elderly patients. Therefore, lower doses should be considered and careful monitoring should be performed in this patient population (see section 4.2).
Use during pregnancy or breastfeeding
According to post-marketing reports and animal studies, armodafinil may cause fetal harm and is contraindicated in pregnant women or women of childbearing potential (see Contraindications, Precautions). Based on preliminary pregnancy registry data, the incidence of major congenital malformations (e.g. cardiac anomalies, microcephaly) with armodafinil/modafinil is approximately 17.3% compared to 3% in the general population. Intrauterine growth retardation and spontaneous abortion have been reported with armodafinil and modafinil.
Patients should be warned about the possible increased risk of pregnancy when using steroid contraceptives (including birth control pills, implants, injectables, and hormone-releasing intrauterine devices) and Nuvigil®, as well as for two months after stopping treatment (see section “Interaction with and
