Nuvigil 50; 150 & 250 mg Tablets.

NUVIGIL is indicated:

• to improve wakefulness in adult patients with excessive daytime sleepiness associated with narcolepsy.

Posology:

NUVIGIL (armodafinil) is for oral administration. NUVIGIL should be used only in patients who have had a complete evaluation of their excessive sleepiness, and in whom a diagnosis of the underlying disorder of narcolepsy has been made in accordance with International Classification of Sleep Disorders (ICSD) or Diagnostic and Statistical Manual (DSM) diagnostic criteria. Such an evaluation usually consists of a complete history and physical examination, and it may be supplemented with testing in a laboratory setting.

NUVIGIL may be taken with or without food, however administration with food may delay the onset of action and prolong the effect of the medicine (see section 5.2). To avoid a delayed onset of action NUVIGIL should be taken on an empty stomach.

Treatment with NUVIGIL should be initiated and supervised by medical practitioners with appropriate experience in the treatment of narcolepsy and who have access to sleep laboratory diagnostic facilities.

Narcolepsy:

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

Dosing in special populations:

The dose of NUVIGIL should be reduced in patients with severe (Child-Pugh class C) hepatic impairment, with or without cirrhosis (see section 5.2). There is a lack of data on dosing instruction for NUVIGIL (armodafinil) specific to the degree of liver impairment. There is inadequate information to determine safety and efficacy of dosing of NUVIGIL (armodafinil) in patients with mild, moderate or severe renal impairment (see section 5.2). There is insufficient information to recommend a safe and effective dose in severe renal impairment (CrCl less than 20 ml/min). In elderly patients, elimination of armodafinil and its metabolites may be reduced as a consequence of aging. Therefore reduction of NUVIGIL doses and patients close monitoring should be considered (see section 5.2, Special Populations).

When changing treatment from modafinil, systemic exposure to NUVIGIL (armodafinil) at steady state was approximately 40 % and 70 % higher than modafinil as assessed by C max and AUC 0-u03c4, respectively. Therefore, although dose adjustment may allow for comparable C max or AUC 0-u03c4, equivalent exposure (as assessed by both parameters) cannot be achieved due to the nature of the observed differences in the overall profiles of armodafinil and modafinil.

• Hypersensitivity to modafinil, armodafinil or any other ingredient listed in section 6.1.
• Patients who are pregnant or may become pregnant.
• Uncontrolled moderate to severe hypertension and in patients with cardiac dysrhythmias.

Armodafinil is a single enantiomer of racemic modafinil. The two enantiomers of modafinil have different pharmacokinetics. The half-life of armodafinil, the (R)-enantiomer, is approximately three times that of the (S)-enantiomer in adult humans. The implications of the pharmacokinetic differences between the medicines on the duration of clinical action remain unelucidated. No evidence of interconversion of the (R)- and (S)-enantiomers of modafinil have been observed in vitro or in vivo. Thus, armodafinil and modafinil are not bioequivalent, and therefore are not directly substitutable, (see section 4.2).

Serious rash, including Stevens-Johnson Syndrome: Serious rash requiring hospitalisation and discontinuation of treatment has been reported in adults in association with the use of NUVIGIL (armodafinil) and modafinil [the racemic mixture of (S)- and (R)-enantiomers]. NUVIGIL has not been studied in paediatric patients in any setting and is not approved for use in paediatric patients. In clinical trials of modafinil (the racemate), the incidence of rash resulting in discontinuation was approximately 0,8 % (13 per 1 585) in paediatric patients (age <17 years); these rashes included 1 case of possible Stevens-Johnson Syndrome (SJS) and 1 case of apparent multi-organ hypersensitivity reaction. 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 paediatric patients who received placebo. No serious skin rashes have been reported in adult clinical trials (0 per 4 264) of modafinil. Cases of serious or life-threatening rash, including SJS, Toxic Epidermal Necrolysis (TEN), and Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) have been reported in adults in worldwide post-marketing experience. The reporting rate of TEN and SJS associated with modafinil use, which is generally accepted to be an underestimate due to underreporting, exceeds the background incidence rate. Estimates of the background incidence rate for these serious skin reactions in the general population range between 1 to 2 cases per million-person years. Cases of serious rash similar to those observed with modafinil including skin and mouth blistering have been reported in adults in post-marketing experience with NUVIGIL. One fatal case of DRESS occurred in close temporal association (3 weeks) with the initiation of NUVIGIL treatment. There are no factors that are known to predict the risk of occurrence or the severity of rash associated with NUVIGIL or modafinil. Nearly all cases of serious rash associated with these medicines occurred within 1 to 5 weeks after treatment initiation. However, isolated cases have been reported after prolonged treatment (e.g. 3 months). Accordingly, duration of therapy cannot be relied upon as a means to predict the potential risk heralded by the first appearance of a rash. Although benign rashes also occur with NUVIGIL, it is not possible to reliably predict which rashes will prove to be serious. Accordingly, NUVIGIL should be discontinued at the first sign of rash, unless the rash is clearly not medicine related. Discontinuation of treatment may not prevent a rash from becoming life-threatening or permanently disabling or disfiguring.

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

Multi-organ hypersensitivity reactions: 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. A similar risk of multi-organ hypersensitivity reactions with NUVIGIL cannot be ruled out. Although there have been a limited number of reports, multi-organ hypersensitivity reactions may result in hospitalisation or be life-threatening. There are no factors that are known to predict the risk of occurrence or the severity of multi-organ hypersensitivity reactions. Signs and symptoms of this disorder were diverse; however, patients typically, although not exclusively, presented with fever and rash associated with other organ system involvement. Other associated manifestations included myocarditis, hepatitis, liver function test abnormalities, haematological abnormalities (e.g., eosinophilia, leukopenia, thrombocytopenia), pruritus, and asthenia. Because multi-organ hypersensitivity is variable in its expression, other organ system symptoms and signs, not noted here, may occur. If a multi-organ hypersensitivity reaction is suspected, NUVIGIL should be discontinued. Although there are no case reports to indicate cross-sensitivity with other medicines that produce this syndrome, the experience with medicines associated with multi-organ hypersensitivity would indicate this to be a possibility.

Persistent sleepiness: Patients with abnormal levels of sleepiness who take NUVIGIL should be advised that their level of wakefulness may not return to normal. Patients with excessive sleepiness, including those taking NUVIGIL, 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 narcolepsy controlled trials of NUVIGIL, anxiety, agitation, nervousness, and irritability were reasons for treatment discontinuation more often in patients on NUVIGIL compared to placebo (NUVIGIL 1,2 % and placebo 0,3 %). Depression was also a reason for treatment discontinuation more often in patients on NUVIGIL compared to placebo (NUVIGIL 0,6 % and placebo 0,2 %). Cases of suicide ideation were observed in clinical trials. Caution should be exercised when NUVIGIL is given to patients with a history of psychosis, depression, or mania. If psychiatric symptoms develop in association with NUVIGIL administration, NUVIGIL should be discontinued. Psychiatric adverse experiences have been reported in patients treated with modafinil. Modafinil and armodafinil (NUVIGIL) are very closely related. Therefore, the incidence and type of psychiatric symptoms associated with NUVIGIL are expected to be similar to the incidence and type of these events with modafinil. Post-marketing adverse events associated with the use of modafinil have included mania, delusions, hallucinations, suicidal ideation and aggression, some resulting in hospitalisation. Post-marketing adverse reactions associated with the use of NUVIGIL have included suicidal ideation, aggression, and also cases of mania, delusions and hallucinations, some resulting in hospitalisation. Many, but not all, patients had a prior psychiatric history. One healthy male volunteer developed ideas of reference, paranoid delusions, and auditory hallucinations in association with multiple daily 600 mg doses of modafinil and sleep deprivation. There was no evidence of psychosis 36 hours after medicine discontinuation.

Cardiovascular system: NUVIGIL has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable angina pectoris, and such patients should be treated with caution. In clinical studies of modafinil, cardiovascular adverse events, including chest pain, palpitations, dyspnoea and transient ischaemic T-wave changes on ECG were observed in three subjects in association with mitral valve prolapse or left ventricular hypertrophy. It is recommended that NUVIGIL 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 central nervous system (CNS) stimulants. Findings suggestive of mitral valve prolapse syndrome include, but are not limited to, ischaemic ECG changes, chest pain, or dysrhythmia. If new onset of any of these symptoms occurs, consider cardiac evaluation. Blood pressure monitoring in short-term (u22643 months) controlled trials of narcolepsy showed small average increases in mean systolic and diastolic blood pressure in patients receiving NUVIGIL 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 NUVIGIL requiring new or increased use of antihypertensive medicines (2,9 %) compared to patients on placebo (1,8 %). There was a consistent, average increase in pulse rate over placebo in 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 NUVIGIL. Caution should be exercised when prescribing NUVIGIL to patients with known cardiovascular disease.

In vitro data demonstrated that NUVIGIL weakly induces CYP1A2 and possibly CYP3A activities in a concentration-related manner and that CYP2C19 activity is reversibly inhibited by NUVIGIL. In vivo, CYP2B6 was induced by NUVIGIL. Other CYP activities did not appear to be affected by NUVIGIL. An in vitro study demonstrated that NUVIGIL is a substrate of P-glycoprotein.

Potential interactions with medicines that inhibit, induce, or are metabolised by cytochrome P450 isoenzymes and other hepatic enzymes: The existence of multiple pathways for NUVIGIL metabolism, as well as the fact that a non-CYP-related pathway is the most rapid in metabolising NUVIGIL, suggest that there is a low probability of substantive effects on the overall pharmacokinetic profile of NUVIGIL due to CYP inhibition by concomitant medicines. However, due to the partial involvement of CYP3A enzymes in the metabolic elimination of NUVIGIL, co-administration of potent inducers of CYP3A4/5 (e.g., carbamazepine, oxcarbazepine, phenobarbitone, phenytoin, rifabutin, rifampicin and St. Johnu2019s wort) or inhibitors of CYP3A4/5 (e.g.: protease inhibitors [e.g. ritonavir, indinavir, nelfinavir, saquinavir], clarithromycin, erythromycin, chloramphenicol, ketoconazole, itraconazole, nefazodone, diltiazem and verapamil) could alter the plasma concentrations of NUVIGIL.

The potential of NUVIGIL to alter the metabolism of other medicines by enzyme induction or inhibition: Medicines metabolised by CYP3A4/5: In vitro data demonstrated that the NUVIGIL (armodafinil) metabolite modafinil sulfone, is a weak inducer of CYP3A activity. In a clinical study, concomitant administration of NUVIGIL 250 mg resulted in a reduction in systemic exposure to midazolam by 32 % after a single oral dose (5 mg) and 17 % after a single intravenous dose (2 mg). Therefore, the blood levels and effectiveness of medicines that are substrates for CYP3A enzymes (e.g., steroidal contraceptives, ciclosporin, midazolam, and triazolam) may be reduced after initiation of concomitant treatment with NUVIGIL, and dose adjustment may be required.

In a clinical study the concomitant administration of NUVIGIL 250 mg with carbamazepine (400 mg/day) resulted in a reduction in the mean systemic exposure of carbamazepine by approximately 25 %. Carbamazepine dose adjustment may be required when co-administered with NUVIGIL, particularly when starting or stopping co-administration of the two medicines.

In a separate clinical study, concomitant administration of NUVIGIL 250 mg with quetiapine (300 mg to 600 mg daily doses) resulted in a reduction in the mean systemic exposure of quetiapine by approximately 29 %. No dose adjustment is required.

The blood levels of ciclosporin may be reduced when used with NUVIGIL. Monitoring of circulating ciclosporin concentrations and appropriate dosage adjustment for ciclosporin should be considered when these medicines are used concomitantly.

Medicines metabolised by CYP1A2: In vitro data demonstrated that NUVIGIL and its metabolite modafinil sulfone are weak inducers of CYP1A2 in a concentration-related manner. However, in a clinical study using caffeine as a probe substrate, no significant effect on CYP1A2 activity was observed.

Medicines metabolised by CYP2C19: In vitro data demonstrated that NUVIGIL, and more so its metabolite modafinil sulfone, are reversible inhibitors of CYP2C19 activity. In a clinical study, concomitant administration of NUVIGIL 400 mg resulted in a 40 % increase in exposure to omeprazole after a single oral dose (40 mg), as a result of moderate inhibition of CYP2C19 activity. Therefore, dose reduction may be required for some medicines that are substrates for CYP2C19 (e.g., phenytoin, diazepam, propranolol, omeprazole, esomeprazole and clomipramine) when used concomitantly with NUVIGIL.

Medicines metabolised by CYP2B6: In vitro data demonstrated that racemic modafinil is a weak inducer of CYP2B6 activity in a concentration-related manner.

Interactions with CNS active medicines: Concomitant administration of NUVIGIL with quetiapine reduced the systemic exposure of quetiapine. Data specific to NUVIGIL medicine interaction potential with other CNS active medicines are not available. However, the following available interaction information on modafinil should be applicable to NUVIGIL. Concomitant administration of modafinil with methylphenidate or dextroamphetamine produced no significant alterations on the pharmacokinetic profile of modafinil or either stimulant, even though the absorption of modafinil was delayed for approximately one hour. Concomitant modafinil or clomipramine did not alter the pharmacokinetic profile of either medicine; however, one incident of increased levels of clomipramine and its active metabolite desmethylclomipramine was reported in a patient with narcolepsy during treatment with modafinil. Data specific to NUVIGIL or modafinil medicine interaction potential with monoamine oxidase (MAO) inhibitors are not available. Therefore, caution should be used when concomitantly administering MAO inhibitors and NUVIGIL.

Women of childbearing potential/Contraception in males and females: Sexually active women of child-bearing potential must be on an effective contraceptive program before and while taking NUVIGIL and for two months after discontinuation of therapy (see section 4.5). As NUVIGIL may reduce the effectiveness of oral contraception alternative additional methods of contraception are required (see sections 4.4 and 4.5).

Pregnancy: NUVIGIL is contraindicated during pregnancy (see section 4.3). NUVIGIL taken during pregnancy has been associated with serious foetal abnormalities such as cardiac lesions and microcephaly. In addition intrauterine growth restriction and spontaneous abortion has been reported in association with NUVIGIL and modafinil in humans. A woman should not commence NUVIGIL until two reliable pregnancy tests have shown negative results one week apart. Patients should be cautioned regarding the potential increased risk of pregnancy when using steroidal contraceptives with NUVIGIL and for two months after discontinuation of therapy (see section 4.5). Modafinil and/or its metabolites cross the placenta in rats, but placental transfer of armodafinil per se has not been studied. In studies of armodafinil [(R)-modafinil] and modafinil [a mixture of (R)- and (S)-modafinil] conducted in rats (armodafinil, modafinil) and rabbits (modafinil), developmental toxicity was observed at clinically relevant plasma exposures. Oral administration of armodafinil to pregnant rats and rabbits throughout organogenesis resulted in increased incidences of foetal structural alterations and foetal toxicity at the highest dose. The highest no-effect dose for embryo foetal developmental toxicity in rats was associated with a plasma armodafinil exposure (AUC) less than that in humans at the maximum recommended human dose (MRHD) of NUVIGIL (250 mg/day).

Breastfeeding: It is not known whether armodafinil or its metabolites are excreted in human milk. The effects of armodafinil on infants who have been breastfed have not been studied. Breastfeeding is not recommended during administration of NUVIGIL. Modafinil and/or its metabolites including modafinil sulfone and modafinil acid have been found in the milk of lactating rats. Infant growth retardation has been reported in association with NUVIGIL use during breastfeeding.

Fertility: The effect of NUVIGIL on fertility is unknown.

Patients taking NUVIGIL should be advised that their level of wakefulness may not return to normal. Patients should be frequently reassessed for their degree of sleepiness and, if appropriate, advised to avoid driving or any other potentially dangerous activity. Undesirable effects such as blurred vision or dizziness might also affect ability to drive (see section 4.8). Family and caregivers should be aware that taking this medicine may not return the recipient to full wakefulness especially in relation to driving and the use of heavy machinery.

a. Summary of the safety profile: NUVIGIL has been evaluated for safety in over 1 100 patients. In the controlled clinical trials, the most commonly observed adverse events (u22655 %) associated with the use of NUVIGIL occurring more frequently than in the placebo-treated patients were headache, nausea, dizziness, and insomnia. The adverse event profile was similar across the studies. In the controlled clinical trials, 44 of the 645 patients (7 %) who received NUVIGIL discontinued due to an adverse experience compared to 16 of the 445 (4 %) of patients that received placebo. The most frequent reason for discontinuation was headache (1 %).

Incidence in Controlled Trials: The following table (Table 1) presents the adverse experiences that occurred at a rate of 1 % or more and were more frequent in patients treated with NUVIGIL than in placebo group patients. The prescriber should be aware that the figures provided below cannot be used to predict the frequency of adverse experiences in the course of usual medical practice, where patient characteristics and other factors may differ from those occurring during clinical studies.

b. Tabulated list of adverse reactions: Table 1: Incidence 1 % or greater of treatment-emergent adverse experiences in parallel-group, placebo-controlled clinical trials* with NUVIGIL (150 mg and 250 mg)

1 : SYSTEM ORGAN CLASS MeDRA preferred term NUVIGIL (percent, N=645) PLACEBO (percent, N=445) Cardiac disorders: Palpitations 2 1 Gastrointestinal disorders: Nausea 7 3 Diarrhoea 4 2 Dry mouth 4 1 Dyspepsia 2 0 Upper abdominal pain 2 1 Constipation 1 0 Vomiting 1 0 Loose stools 1 0 General disorders and administration site conditions: Fatigue 2 1 Thirst 1 0 Influenza - like illness 1 0 Pain 1 0 Pyrexia 1 0 Immune system disorders: Seasonal allergy 1 0 Investigations: Increased gamma glutamyltransferase 1 0 Increased heart rate 1 0 Metabolism and nutrition disorders: Anorexia 1 0 Decreased appetite 1 0 Nervous system disorders: Headache 17 9 Dizziness 5 2 Disturbance in attention 1 0 Tremor 1 0 Migraine 1 0 Paraesthesia 1 0 Psychiatric disorders: Insomnia 5 1 Anxiety 4 1 Depression 2 0 Agitation 1 0 Nervousness 1 0 Depressed mood 1 0 Renal and urinary disorders: Polyuria 1 0 Respiratory, thoracic and mediastinal disorders: Dyspnoea 1 0 Skin and subcutaneous tissue disorders: Rash 2 0 Contact dermatitis 1 0 Hyperhidrosis 1 0

*Included are only those events for which NUVIGIL incidence is greater than that of placebo. Events for which the NUVIGIL incidence was at least 1 % but equal to or less than placebo are not listed in the table. The events included the following: flatulence, chest pain, bronchitis, nasopharyngitis, sinusitis, upper respiratory tract infection, alanine aminotransferase increased, aspartate aminotransferase increased, arthralgia, back pain, oropharyngeal pain, cough and hypertension.

Dose dependency of adverse events: In clinical trials which compared doses of 150 mg/day and 250 mg/day of NUVIGIL and placebo, the only adverse events that appeared to be dose-related were headache, rash, depression, dry mouth, insomnia, and nausea. See Table 2 for additional information.

Table 2: Incidence of dose-dependent, treatment-emergent adverse experiences by dose and by treatment in parallel-group, placebo-controlled clinical trials* with NUVIGIL (150 mg and 250 mg): SOC MedDRA preferred term NUVIGIL 250 mg (%) N=198 NUVIGIL 150 mg (%) N=447 NUVIGIL Combined (%) N=645 Placebo (%) N=445 Gastrointestinal disorders: Nausea 9 6 7 3 Dry Mouth 7 2 4 u02c2 1

Nervous system disorders: Headache 23 14 17 9 Psychiatric disorders: Insomnia 6 4 5 1 Depression 3 1 2 u02c2 1 Skin and subcutaneous tissue disorders: Rash 4 1 2 u02c2 1

Vital Sign Changes: Blood pressure monitoring in controlled trials showed small average increases in mean systolic and diastolic blood pressure in patients receiving NUVIGIL as compared to placebo (1,2 to 4,3 mmHg in the various experimental groups). There was also a greater proportion of patients on NUVIGIL requiring new or increased use of antihypertensive medicines (2,9 %) compared to patients on placebo (1,8 %). There was a consistent, average increase in pulse rate over placebo. This increase varied from 0,9 to 3,5 BPM.

Symptoms of NUVIGIL overdose are likely to be central nervous system symptoms such as insomnia, restlessness, disorientation, confusion, agitation, anxiety, excitation and hallucination; digestive changes such as nausea and diarrhoea; and cardiovascular changes such as tachycardia, bradycardia, hypertension and chest pain and dyspnoea. No specific antidote exists for the toxic effects of a NUVIGIL overdose. Treatment should be symptomatic and supportive including cardiovascular monitoring. There are no data to suggest the utility of dialysis or urinary acidification or alkalinisation in enhancing medicine elimination.