Neoresotyl

Neoresotyl is indicated to improve wakefulness in adult patients with excessive sleepiness associated with obstructive sleep apnea (OSA), narcolepsy, or shift work disorder (SWD).

Limitations Of Use

In OSA, Neoresotyl is indicated to treat excessive sleepiness and not as treatment for the underlying obstruction. If continuous positive airway pressure (CPAP) is the treatment of choice for a patient, a maximal effort to treat with CPAP for an adequate period of time should be made prior to initiating Neoresotyl for excessive sleepiness.

Dosage In Obstructive Sleep Apnea (OSA) And Narcolepsy

The recommended dosage of Neoresotyl for patients with OSA or narcolepsy is 150 mg to 250 mg taken orally once a day as a single dose in the morning.

In patients with OSA, doses up to 250 mg/day, given as a single dose, have been well tolerated, but there is no consistent evidence that these doses confer additional benefit beyond that of the 150 mg/day dose.

Dosage In Shift Work Disorder (SWD)

The recommended dosage of Neoresotyl for patients with SWD is 150 mg taken orally once a day as a single dose approximately 1 hour prior to the start of their work shift.

Dosage Modification In Patients With Severe Hepatic Impairment

In patients with severe hepatic impairment, the dosage of Neoresotyl should be reduced.

Use In Geriatric Patients

Consideration should be given to the use of lower doses and close monitoring in geriatric patients.

Neoresotyl is contraindicated in patients with known hypersensitivity to modafinil or armodafinil or its inactive ingredients.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Serious Dermatologic Reactions, including Stevens-Johnson Syndrome And Toxic Epidermal Necrosis

Serious rash requiring hospitalization and discontinuation of treatment has been reported in association with the use of Neoresotyl (armodafinil) or modafinil (the racemic mixture of S- and R-enantiomers).

Neoresotyl has not been studied in pediatric patients in any setting and is not approved for use in pediatric patients for any indication.

In clinical trials of modafinil, the incidence of rash resulting in discontinuation was approximately 0.8% (13 per 1,585) in pediatric patients (age < 17 years); these rashes included 1 case of possible Stevens-Johnson syndrome (SJS) and 1 case of apparent multi-organ hypersensitivity reaction/ Drug Rash with Eosinophilia and Systemic Symptoms (DRESS). Several of the cases were associated with fever and other abnormalities (e.g., vomiting, leukopenia). The median time to rash that resulted in discontinuation was 13 days. No such cases were observed among 380 pediatric patients who received placebo.

Skin and mouth sores, blistering, and ulceration have been reported with modafinil and Neoresotyl in the postmarketing setting. Recurrence of signs and symptoms of serious dermatologic reactions following rechallenge has been reported in some cases.

Rare cases of serious or life-threatening rash, including SJS and toxic epidermal necrolysis (TEN), have been reported in adults and children in worldwide post-marketing experience with modafinil and Neoresotyl.

There are no factors, including duration of therapy, that are known to predict the risk of occurrence or the severity of rash associated with modafinil or Neoresotyl. In cases where the time to onset was reported, serious rash occurred 1 day to 2 months after initiation of treatment, but isolated cases of serious dermatologic reactions have been reported with symptoms beginning after prolonged treatment (e.g., 3 months).

Although benign rashes also occur with Neoresotyl, it is not possible to reliably predict which rashes will prove to be serious. Accordingly, Neoresotyl should be discontinued at the first sign of rash, skin or mouth sores, or blistering or ulceration, unless the rash is clearly not drug-related. Discontinuation of treatment may not prevent a rash from becoming life-threatening or permanently disabling or disfiguring.

Drug Reaction With Eosinophilia And System Symptoms (DRESS)/Multiorgan Hypersensitivity

DRESS, also known as multi-organ hypersensitivity, has been reported with Neoresotyl. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection. Eosinophilia is often present. This disorder is variable in its expression, and other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present even though rash is not evident.

One fatal case of DRESS that occurred in close temporal association (3 weeks) with the initiation of Neoresotyl treatment has been reported in the postmarketing setting. In addition, multi-organ hypersensitivity reactions, including at least one fatality in post-marketing experience, have occurred in close temporal association (median time to detection 13 days; range 4-33) to the initiation of modafinil. Although there have been a limited number of reports, multi-organ hypersensitivity reactions may result in hospitalization or be life-threatening.

If a multi-organ hypersensitivity reaction is suspected, Neoresotyl should be discontinued. Although there are no case reports to indicate cross-sensitivity with other drugs that produce this syndrome, the experience with drugs associated with multi-organ hypersensitivity would indicate this to be a possibility.

Angioedema And Anaphylaxis Reactions

Angioedema and hypersensitivity (with rash, dysphagia, and bronchospasm), were observed with Neoresotyl. Patients should be advised to discontinue therapy and immediately report to their physician any signs or symptoms suggesting angioedema or anaphylaxis (e.g., swelling of face, eyes, lips, tongue or larynx; difficulty in swallowing or breathing; hoarseness).

Persistent Sleepiness

Patients with abnormal levels of sleepiness who take Neoresotyl should be advised that their level of wakefulness may not return to normal. Patients with excessive sleepiness, including those taking Neoresotyl, should be frequently reassessed for their degree of sleepiness and, if appropriate, advised to avoid driving or any other potentially dangerous activity. Prescribers should also be aware that patients may not acknowledge sleepiness or drowsiness until directly questioned about drowsiness or sleepiness during specific activities.

Psychiatric Symptoms

In pre-approval narcolepsy, OSA and SWD controlled trials of Neoresotyl, anxiety, agitation, nervousness, and irritability were reasons for treatment discontinuation more often in patients on Neoresotyl compared to placebo (Neoresotyl 1.2% and placebo 0.3%). Depression was also a reason for treatment discontinuation more often in patients on Neoresotyl compared to placebo (Neoresotyl 0.6% and placebo 0.2%). Cases of suicidal ideation were observed in clinical trials.

Caution should be exercised when Neoresotyl is given to patients with a history of psychosis, depression, or mania. If psychiatric symptoms develop in association with Neoresotyl administration, consider discontinuing Neoresotyl.

Psychiatric adverse reactions have been reported in patients treated with modafinil. Modafinil and Neoresotyl (armodafinil) are very closely related. Therefore, the incidence and type of psychiatric symptoms associated with Neoresotyl are expected to be similar to the incidence and type of these events with modafinil.

Post-marketing adverse reactions associated with the use of Neoresotyl, some of which have resulted in hospitalization, have included mania, delusions, hallucinations, suicidal ideation, and aggression. Many, but not all, patients who developed psychiatric adverse reactions had a prior psychiatric history. In these cases, reported Neoresotyl total daily doses ranged from 50 mg to 450 mg, which includes doses below and above the recommended dosages.

Effects On Ability To Drive And Use Machinery

Although Neoresotyl has not been shown to produce functional impairment, any drug affecting the central nervous system (CNS) may alter judgment, thinking or motor skills. Patients should be cautioned about operating an automobile or other hazardous machinery until it is reasonably certain that Neoresotyl therapy will not adversely affect their ability to engage in such activities.

Cardiovascular Events

In clinical studies of modafinil, cardiovascular adverse reactions, including chest pain, palpitations, dyspnea and transient ischemic T-wave changes on ECG were observed in three subjects in association with mitral valve prolapse or left ventricular hypertrophy. It is recommended that Neoresotyl tablets not be used in patients with a history of left ventricular hypertrophy or in patients with mitral valve prolapse who have experienced the mitral valve prolapse syndrome when previously receiving CNS stimulants. Findings suggestive of mitral valve prolapse syndrome include but are not limited to ischemic ECG changes, chest pain, or arrhythmia. If new onset of any of these findings occurs, consider cardiac evaluation.

Blood pressure monitoring in short term ( ≤ 3 months) pre-approval controlled trials of OSA, SWD, and narcolepsy showed small average increases in mean systolic and diastolic blood pressure in patients receiving Neoresotyl as compared to placebo (1.2 to 4.3 mmHg in the various experimental groups). There was also a slightly greater proportion of patients on Neoresotyl requiring new or increased use of antihypertensive medications (2.9%) compared to patients on placebo (1.8%). There was a small, but consistent, average increase in pulse rate over placebo in pre-approval controlled trials. This increase varied from 0.9 to 3.5 BPM. Increased monitoring of heart rate and blood pressure may be appropriate in patients on Neoresotyl. Caution should be exercised when prescribing Neoresotyl to patients with known cardiovascular disease.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Serious Dermatologic Reactions

Advise patients and caregivers about the risk of potentially fatal serious skin reactions. Educate patients about the signs and symptoms that may signal a serious skin reaction. Instruct patients to discontinue Neoresotyl and consult with their healthcare provider immediately if a skin reaction such as rash, mouth sores, blisters, or peeling skin occurs during treatment with Neoresotyl.

DRESS/Multi-organ Hypersensitivity

Instruct patients that a fever associated with signs of other organ system involvement (e.g., rash, lymphadenopathy, hepatic dysfunction) may be drug-related and should be reported to their healthcare provider immediately.

Angioedema And Anaphylactic Reactions

Advise patients of life-threatening symptoms suggesting anaphylaxis or angioedema (such as hives, difficulty in swallowing or breathing, hoarseness, or swelling of the face, eyes, lips, or tongue) that can occur with Neoresotyl. Instruct them to discontinue Neoresotyl and immediately report these symptoms to their healthcare provider.

Wakefulness

Advise patients that treatment with Neoresotyl will not eliminate their abnormal tendency to fall asleep. Advise patients that they should not alter their previous behavior with regard to potentially dangerous activities (e.g., driving, operating machinery) or other activities requiring appropriate levels of wakefulness, until and unless treatment with Neoresotyl has been shown to produce levels of wakefulness that permit such activities. Advise patients that Neoresotyl is not a replacement for sleep.

Continuing Previously Prescribed Treatments

Inform patients that it may be critical that they continue to take their previously prescribed treatments (e.g., patients with OSA receiving CPAP should continue to do so).

Psychiatric Symptoms

Advise patients to stop taking Neoresotyl and contact their physician right away if they experience, depression, anxiety, or signs of psychosis or mania.

Pregnancy

Advise women that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Neoresotyl during pregnancy.

Females Of Reproductive Potential

Caution females regarding the potential increased risk of pregnancy when using hormonal contraceptives (including depot or implantable contraceptives) with Neoresotyl and advise females who are using a hormonal method of contraception to use an additional barrier method or an alternative non-hormonal method of contraception during treatment with Neoresotyl and for one month after discontinuation of Neoresotyl.

Concomitant Medication

Advise patients to inform their physician if they are taking, or plan to take, any prescription or over-the-counter drugs, because of the potential for interactions between Neoresotyl and other drugs.

Alcohol

Advise patients that the use of Neoresotyl in combination with alcohol has not been studied. Advise patients that it is prudent to avoid alcohol while taking Neoresotyl.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

In a mouse carcinogenicity study, armodafinil (R-modafinil) was administered at oral doses of up to300 mg/kg/day in males and 100 mg/kg/day in females for approximately two years, no tumorigenic effects were observed.

In a rat carcinogenicity study modafinil (a mixture of R-and S-modafinil) was administered at oral doses of up to 60 mg/kg/day for two years; no tumorigenic effects were observed.

At the highest doses studied in mouse and rat, the plasma armodafinil exposures (AUC) were less than that in humans at the MRHD of Neoresotyl (250 mg/day).

Mutagenesis

Armodafinil was negative in an in vitro bacterial reverse mutation assay and in an in vitro chromosomal aberration assay in human lymphocytes.

Modafinil was negative in a series of in vitro (i.e., bacterial reverse mutation, mouse lymphoma tk, chromosomal aberration in human lymphocytes, cell transformation in BALB/3T3 mouse embryo cells) or in vivo (mouse bone marrow micronucleus) assays.

Impairment Of Fertility

A fertility and early embryonic development (to implantation) study was not conducted with armodafinil alone.

Oral administration of modafinil (doses of up to 480 mg/kg/day) to male and female rats prior to and throughout mating, and continuing in females through day 7 of gestation produced an increase in the time to mate at the highest dose; no effects were observed on other fertility or reproductive parameters. The no-effect dose of 240 mg/kg/day was associated with a plasma armodafinil AUC less than that in humans at the MRHD of Neoresotyl.

Use In Specific Populations

Pregnancy

Pregnancy Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Neoresotyl during pregnancy. Healthcare providers are encouraged to register pregnant patients, or pregnant women may enroll themselves in the registry by calling 1-866-404-4106.

Risk Summary

Limited available data on armodafinil use in pregnant women are insufficient to inform a drug associated risk of adverse pregnancy outcomes. Intrauterine growth restriction and spontaneous abortion have been reported in association with armodafinil and modafinil. Although the pharmacology of armodafinil is not identical to that of the sympathomimetic amines, armodafinil shares some pharmacologic properties with this class. Some sympathomimetics have been associated with intrauterine growth restriction and spontaneous abortions.

In animal reproduction studies of armodafinil (R-modafinil) and modafinil (a mixture of R-and S-modafinil) conducted in pregnant rats (armodafinil, modafinil) and rabbits (modafinil) during organogenesis, evidence of developmental toxicity (increased embryofetal and offspring mortality, decreased fetal growth) was observed at clinically relevant plasma exposures.

All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Animal Data

Oral administration of armodafinil (60, 200, or 600 mg/kg/day) to pregnant rats throughout organogenesis resulted in decreased fetal body weight and increased incidences of fetal variations indicative of growth delay at the highest dose, which was also maternally toxic. The highest no-effect dose for embryofetal developmental toxicity in rat (200 mg/kg/day) was associated with a plasma armodafinil exposure (AUC) less than that in humans at the maximum recommended human dose (MRHD) of Neoresotyl (250 mg/day).

Modafinil (50, 100, or 200 mg/kg/day) administered orally to pregnant rats throughout organogenesis produced an increase in resorptions and an increased incidence of fetal variations at the highest dose tested. The higher no-effect dose for embryofetal developmental toxicity (100 mg/kg/day) was associated with a plasma armodafinil AUC less than that in humans at the MRHD of Neoresotyl. However, in a subsequent rat study of up to 480 mg/kg/day of modafinil, no adverse effects on embryofetal development were observed.

In a study in which modafinil (45, 90, or 180 mg/kg/day) was orally administered to pregnant rabbits during organogenesis, embryofetal death was increased at the highest dose. The highest no-effect dose for developmental toxicity (100 mg/kg/day) was associated with a plasma armodafinil AUC less than that in humans at the MRHD of Neoresotyl.

Modafinil administration to rats throughout gestation and lactation at oral doses of up to 200 mg/kg/day resulted in decreased viability in the offspring at doses greater than 20 mg/kg/day, a dose resulting in a plasma armodafinil AUC less than that in humans at the MRHD of Neoresotyl. No effects on postnatal developmental and neurobehavioral parameters were observed in surviving offspring.

Lactation

Risk Summary

There are no data on the presence of armodafinil or its metabolites in human milk, the effects on the breastfed infant, or the effect of this drug on milk production. Modafinil was present in rat milk when animals were dosed during the lactation period. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for armodafinil and any potential adverse effects on the breastfed child from armodafinil or from the underlying maternal condition.

Females And Males Of Reproductive Potential

The effectiveness of hormonal contraceptives may be reduced when used with Neoresotyl and for one month after discontinuation of therapy. Advise women who are using a hormonal method of contraception to use an additional barrier method or an alternative non-hormonal method of contraception during treatment with Neoresotyl and for one month after discontinuation of Neoresotyl treatment.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established. Serious rash has been seen in pediatric patients receiving modafinil.

Geriatric Use

In elderly patients, elimination of armodafinil and its metabolites may be reduced as a consequence of aging. Therefore, consideration should be given to the use of lower doses and close monitoring in this population.

Hepatic Impairment

The dosage of Neoresotyl should be reduced in patients with severe hepatic impairment.

The following serious adverse reactions are described below and elsewhere in the labeling:

• Serious Dermatologic Reactions
• Drug Reaction with Eosinophilia and System Symptoms (DRESS)/Multiorgan Hypersensitivity
• Angioedema and Anaphylaxis Reactions
• Persistent Sleepiness
• Psychiatric Symptoms
• Effects on Ability to Drive and Use Machinery
• Cardiovascular Events

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Neoresotyl has been evaluated for safety in over 1,100 patients with excessive sleepiness associated with OSA, SWD, and narcolepsy.

Most Common Adverse Reactions

In the placebo-controlled clinical trials, the most common adverse reactions ( ≥ 5%) associated with the use of Neoresotyl more frequently than in placebo-treated patients were headache, nausea, dizziness, and insomnia. The adverse reaction profile was similar across the studies.

Table 1 presents the adverse reactions that occurred at a rate of 1% or more and were more frequent in Neoresotyl-treated patients than in placebo-treated patients in the placebo-controlled clinical trials.

Table 1: Adverse Reactions in Pooled Placebo-Controlled Clinical Trials* in OSA, Narcolepsy, and SWD with Neoresotyl (150 mg and 250 mg)

Dose-Dependent Adverse Reactions

In the placebo-controlled clinical trials which compared doses of 150 mg/day and 250 mg/day of Neoresotyl and placebo, the following adverse reactions were dose-related: headache, rash, depression, dry mouth, insomnia, and nausea. See Table 2 for additional information.

Table 2: Dose-Dependent Adverse Reactions in Pooled Placebo-Controlled Clinical Trials in OSA, Narcolepsy and SWD

Adverse Reactions Resulting In Discontinuation Of Treatment

In placebo-controlled clinical trials, 44 of the 645 patients (7%) who received Neoresotyl discontinued due to an adverse reaction compared to 16 of the 445 (4%) of patients that received placebo. The most frequent reason for discontinuation was headache (1%).

Laboratory Abnormalities

Clinical chemistry, hematology, and urinalysis parameters were monitored in the studies. Mean plasma levels of gamma glutamyltransferase (GGT) and alkaline phosphatase (AP) were found to be higher following administration of Neoresotyl, but not placebo. Few patients, however, had GGT or AP elevations outside of the normal range. No differences were apparent in alanine aminotransferase (ALT), aspartate aminotransferase (AST), total protein, albumin, or total bilirubin, although there were rare cases of isolated elevations of AST and/or ALT. A single case of mild pancytopenia was observed after 35 days of treatment and resolved with drug discontinuation. A small mean decrease from baseline in serum uric acid compared to placebo was seen in clinical trials. The clinical significance of this finding is unknown.

Postmarketing Experience

The following adverse reactions have been identified during post approval use of Neoresotyl. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Gastrointestinal Disorders: Mouth Sores (including mouth blistering and ulceration)

Fatal overdoses involving modafinil alone or involving Neoresotyl or modafinil in combination with other drugs have been reported in the postmarketing setting. Symptoms most often accompanying Neoresotyl or modafinil overdose, alone or in combination with other drugs, have included anxiety, dyspnea, insomnia; central nervous system symptoms such as restlessness, disorientation, confusion, excitation and hallucination; digestive changes such as nausea and diarrhea; and cardiovascular changes such as tachycardia, bradycardia, hypertension, and chest pain.

No specific antidote exists for the toxic effects of a Neoresotyl overdose. Such overdoses should be managed with primarily supportive care, including cardiovascular monitoring.

Armodafinil exhibits linear time-independent kinetics following single and multiple oral dose administration. Increase in systemic exposure is proportional over the dose range of 50 to 400 mg. No time-dependent change in kinetics was observed through 12 weeks of dosing. Apparent steady state for armodafinil was reached within 7 days of dosing. At steady state, the systemic exposure for armodafinil is 1.8 times the exposure observed after a single dose. The concentration-time profiles of the R-enantiomer following administration of a single-dose of 50 mg Neoresotyl or 100 mg PROVIGIL (modafinil, a 1:1 mixture of R-and S-enantiomers) are nearly superimposable. However, the Cmax and AUC0-∞, of armodafinil at steady-state were approximately 37% and 70% higher, respectively, following administration of 200 mg Neoresotyl than the corresponding values of modafinil following administration of 200 mg PROVIGIL due to the more rapid clearance of the S-enantiomer (elimination half-life approximately 4 hours) as compared to the R-enantiomer.

Absorption

Neoresotyl is readily absorbed after oral administration. The absolute oral bioavailability was not determined due to the aqueous insolubility of armodafinil, which precluded intravenous administration. Peak plasma concentrations are attained at approximately 2 hours in the fasted state. Food effect on the overall bioavailability of Neoresotyl is considered minimal; however, time to reach peak concentration (tmax) may be delayed by approximately 2-4 hours in the fed state. Since the delay in tmax is also associated with elevated plasma concentrations later in time, food can potentially affect the onset and time course of pharmacologic action for Neoresotyl.

Distribution

Neoresotyl has an apparent volume of distribution of approximately 42 L. Data specific to armodafinil protein binding are not available. However, modafinil is moderately bound to plasma protein (approximately 60%), mainly to albumin. The potential for interactions of Neoresotyl with highly protein-bound drugs is considered to be minimal.

Elimination

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

Metabolism

In vitro and in vivo data show that armodafinil undergoes hydrolytic deamidation, S-oxidation, and aromatic ring hydroxylation, with subsequent glucuronide conjugation of the hydroxylated products. Amide hydrolysis is the single most prominent metabolic pathway, with sulfone formation by cytochrome P450 (CYP) 3A4/5 being next in importance. The other oxidative products are formed too slowly in vitro to enable identification of the enzyme(s) responsible. Only two metabolites reach appreciable concentrations in plasma (i.e., R-modafinil acid and modafinil sulfone).

Excretion

Data specific to Neoresotyl disposition are not available. However, modafinil is mainly eliminated via metabolism, predominantly in the liver, with less than 10% of the parent compound excreted in the urine. A total of 81% of the administered radioactivity was recovered in 11 days post-dose, predominantly in the urine (80% vs. 1.0% in the feces).