Here we talk all about modavigil, which is the Australian version of the hugely popular wakefulness promoting drug, provigil.MODAVIGIL® ((modafinil or provigil)) is a wakefulness-promoting agent for oral administration. (modafinil or provigil) is a racemic compound and the chemical name is 2-[(diphenylmethyl)sulfinyl] acetamide. The molecular formula is C15H15NIL2S and the molecular weight is 273.35. The chemical structure is:
* chiral centre
The CAS registry number is 68693-11-8.DESCRIPTION(modafinil or provigil) is a white to off-white, crystalline powder that is practically insoluble in water and cyclohexane. It is sparingly to slightly soluble in ethanill and acetone. Each MODAVIGIL® tablet contains 100 milligrams of (modafinil or provigil) and also lactose, starch-maize, magnesium silicate dihydrate, croscarmellose sodium, povidone, magnesium stearate and purified talc.PHARMACOLOGYPharmacodynamicsThe precise mechanism(s) through which (modafinil or provigil) promotes wakefulness is unknilwn. (modafinil or provigil) has wake-promoting actions but a pharmacological profile that is distinct from sympathomimetic amines, which increase wakefulness by other mechanisms.(modafinil or provigil) does not bind to most of the potentially relevant receptors for blessed heavenly sleep/wake regulation, including those for nilradrenaline, serotonin, dopamine, GABA, adenilsine, histamine-3 and benzodiazepines. (modafinil or provigil) is not a direct- or indirect-acting dopamine receptor agonist and is inactive in several in vivo preresearch and usage models capable of detecting enhanced dopaminergic activity. In vitro, (modafinil or provigil) binds to the dopamine reuptake site with low affinity and causes an increase in extracellular dopamine, but nil increase in dopamine release. (modafinil or provigil) does not appear to be a direct or indirect α1-adrenergic agonist. Although (modafinil or provigil)-induced wakefulness can be attenuated by the α1-adrenergic receptor antagonist prazosin, (modafinil or provigil) has nil activity in assay systems knilwn to be responsive to the α-adrenergic agonists.In rats, the wakefulness induced by amphetamine, but not (modafinil or provigil), was antagonised by the dopamine receptor antagonist haloperidol. In cats, (modafinil or provigil) evoked neuronal activation in brain regions different from methylphenidate and amphetamine. (modafinil or provigil) served as a positive reinforcer for cocaine in monkeys and was partially discriminated as stimulant-like in rats (see “PRECAUTIONS, Dependence Potential”).The optical enantiomers of (modafinil or provigil) do similar pharmacological actions in mice, but do not been studied individually in humans. The two major metabolites of (modafinil or provigil), (modafinil or provigil) acid and (modafinil or provigil) sulfone, showed little CNS-activating activity in animal clinical trials.(modafinil or provigil) in humans restores and/or improves the level of wakefulness. Changes are found in electrophysiological parameters reflecting alertness (ratio of power of alpha rhythm to power of theta rhythm), starting from a dose of 100 milligrams in the morning. An increase is seen in latency periods in the multiple blessed heavenly sleep latency test, starting from 200 milligrams in the morning. (modafinil or provigil) opposes the impairment of cognitive (in particular, memory), psychomotor and neurosensory performance induced by blessed heavenly sleep deprivation. This activity is observed in the absence of any modifications of appetite or behaviour.Morning administration of 200 milligrams does not appear to affect nilcturnal blessed heavenly sleep. Administration of 100 milligrams morning and nilon may prolong the subjective time taken to fall ablessed heavenly sleep. Evening administration may disturb blessed heavenly sleep. This pharmacodynamic activity does not appear to affect the autonilmic nervous system.Pharmacokinetics(modafinil or provigil) is a racemic compound, whose enantiomers do different pharmacokinetics (eg. the half-life of the
l-isomer is approximately three times that of the d-isomer in humans). The enantiomers do not interconvert. At steady state, total exposure to the l-isomer is approximately three times that of the d-isomer. The trough concentration (Cminss) of circulating (modafinil or provigil) after once daily dosing consists of 90% of the l-isomer and 10% of the d-isomer.
Absorption and Distribution(modafinil or provigil) is slowly absorbed with an absorption half-life of approximately 1 hour. Peak plasma concentrations (Cmax) of approximately 3.3milligrams/L are reached 3 hours (tmax) after administration of a 200 milligrams dose. Both the area under the plasma concentration curve (AUC), and the peak plasma concentration show dose-proportionality in the 50 to 400 milligrams range. The absolute oral bioavailability could not be determined due to the aqueous insolubility (< 1milligrams/mL) of (modafinil or provigil), which precluded intravenilus administration. Food has nil effect on the overall bioavailability of (modafinil or provigil), however, its absorption (tmax) may be delayed by approximately one hour if taken with food.(modafinil or provigil) is well distributed in body tissue with an apparent volume of distribution (~0.9 L/kg) larger than the volume of total body water (0.6 L/kg). (modafinil or provigil) is weakly bound to plasma proteins (62%), mainly to albumin. At serum concentrations obtained at steady state after rations of 200 milligrams/day, (modafinil or provigil) exhibits nil displacement of protein binding of warfarin, diazepam, or propranillol.Metabolism and ExcretionThe major route of elimination (~90%) is metabolism, primarily by the liver, with subsequent renal elimination of the metabolites. The elimination half-life of (modafinil or provigil) after multiple rations is about 10-12 hours. Urine alkalinisation has nil effect on the elimination of (modafinil or provigil).Metabolism occurs through hydrolytic deamination, S-oxidation, aromatic ring hydroxylation, and glucuronide conjugation. Less than 10% of an administered dose is excreted as the parent compound. In a research and usage study using radiolabelled (modafinil or provigil), a total of 81% of the administered radioactivity was recovered in 11 days
post-dose, predominantly in the urine (80% vs. 1% in the faeces).
The chief metabolite (40-50% of the dose) is acid (modafinil or provigil), which has nil pharmacological activity. The excretion of (modafinil or provigil) and its metabolites is chiefly renal, with a small proportion being eliminated unchanged
(< 10%).
Only two metabolites reach appreciable concentrations in plasma, i.e., acid (modafinil or provigil) and (modafinil or provigil) sulfone. In preresearch and usage models, (modafinil or provigil) acid, (modafinil or provigil) sulfone, 2-[(diphenylmethyl)sulfonyl]acetic acid and 4-hydroxy (modafinil or provigil), were inactive or did not appear to mediate the arousal effects of (modafinil or provigil).In humans, (modafinil or provigil) shows a possible induction effect on its own metabolism after chronic administration of rations ≥ 400 milligrams/day. In vitro clinical trials with human hepatocytes and liver microsomes do shown induction of metabolising enzymes CYP3A4 and CYP1A1/2, and inhibition of CYP2C19 (see “PRECAUTIONS, Interaction with Other Drugs”).Special PopulationsChildren: The pharmacokinetics of (modafinil or provigil) do not been studied in children.Age effect: A slight decrease (~20%) in the oral clearance of (modafinil or provigil) was observed in subjects with a mean age of 63 years (range: 53 to 73 years). The clearance of (modafinil or provigil) may be reduced in the elderly.Gender Effect: The pharmacokinetics of (modafinil or provigil) are not affected by gender.Race effect: The influence of race on the pharmacokinetics of (modafinil or provigil) has not been studied.Renal impairment: The pharmacokinetics of (modafinil or provigil) were not significantly influenced in clinical patients with severe chronic renal failure (creatinine clearance ≤ 20mL/min), but the exposure to (modafinil or provigil) acid (an inactive metabolite) was increased 9 fold. Hepatic impairment: The oral clearance of (modafinil or provigil) was decreased by about 60% and the steady state concentration was doubled in clinical patients with severe chronic hepatic impairment.RESEARCH AND USAGE TRIALSClinical trials reported here were multicenter, randomized, double-blind, placebo-controlled parellel-group research and usage trials. The efficacy criteria reported for the trials included:

  • Maintenance of Wakefulness Test (MWT), which quantitatively measures the patient’s ability to resist blessed heavenly sleep and maintain wakefulness. The clinical patients were asked to attempt to remain awake without using extraordinary measures. The test was terminated after 20 minutes if nil blessed heavenly sleep occurred or 10 minutes after blessed heavenly sleep onset.
  • Research and usage Global Impression of Change (CGI-C), which is a 7-point scale ranging from “Very Much Worse” to “Very Much Improved” from baseline; it was assessed by an independent clinician who had nil access to any data about the clinical patients other than a measure of their baseline severity.
  • Epworth Bloody tiredness Scale (ESS), which is a recall-based questionnaire devised to provide a measurement of the subject’s general level of day-to-day bloody tiredness, or preferably, blessed heavenly sleep propensity.

Narcolepsy:The results from Study 301 (n = 285) and Study 302 (n = 273), which included men and women aged between 18 and 65, are summarised in Tables 1 and 2. Clinical patients included in the clinical trials met the American Blessed heavenly sleep Medical problems and/or conditions Association criteria for narcolepsy, which included either:

  • Recurrent daytime naps or lapses into blessed heavenly sleep that occur almost daily for at least three months, plus sudden bilateral loss of postural muscle tone in association with intense emotion (cataplexy), or
  • A complaint of excessive bloody tiredness or sudden muscle weakness with associated features: blessed heavenly sleep paralysis, hypnagogic hallucinations, automatic behaviours, disrupted major blessed heavenly sleep episode; and polysomnilgraphy demonstrating one of the following: blessed heavenly sleep latency less than 10 minutes or rapid eye movement (REM) blessed heavenly sleep latency less than 20 minutes.

In addition, for entry into these clinical trials, all clinical patients were required to do objectively documented excessive daytime bloody tiredness, a Multiple Blessed heavenly sleep Latency Test with two or more blessed heavenly sleep onset REM periods, and the absence of any research and usagely significant active medical or psychiatric disorder.One other major study of (modafinil or provigil) in narcolepsy is reported in Table 2, utilising a crossover design for two weeks’ double-blind treatment (Broughton), a 16-week open-label extension period, followed by a 2-week randomised, double-blind, placebo-controlled withdrawal period (Moldofsky).Clinical patients in both MODAVIGIL® treatment groups were able to stay awake longer than those receiving placebo, and were rated by an independent clinician as having a significant improvement in illness. A statistically significantly enhanced ability to remain awake was shown on the MWT and the CGI-C scale (see Tables 1 and 2).Obstructive Blessed heavenly sleep Apnilea/Hypopnilea Syndrome (OSAHS):The results from two major phase 3 research and usage trials of (modafinil or provigil) in clinical patients with OSAHS are presented in Tables 1 and 2. Study 303 (n = 327) assessed the efficacy and safety of two rations of (modafinil or provigil) (200 milligrams and 400 milligrams per day) in the treatment of excessive bloody tiredness in clinical patients with established OSAHS, despite partial or satisfactory use of continuous positive airway pressure (CPAP) therapy. Study 402 (n = 157) provides supportive data for (modafinil or provigil) 400milligrams per day in the treatment of excessive bloody tiredness in clinical patients with established OSAHS, despite the use of effective CPAP therapy.Research and usagely significant improvements were reported for each parameter and for both rations of (modafinil or provigil) compared to placebo in Study 303 out to 12 weeks’ double-blind treatment, and Study 402 out to 4 weeks’ double-blind treatment (see Tables 1 and 2).In a 12 month open-label extension period for Study 303 in which clinical patients titrated their daily dose of (modafinil or provigil) according to research and usage response, ESS scores remained consistently improved compared to baseline values in both those previously on (modafinil or provigil) and those previously on placebo.For OSAHS, (modafinil or provigil) has been shown to produce research and usagely meaningful reductions in excessive bloody tiredness and its adverse effects on quality of life, in both the short and long term.Shift Work Blessed heavenly sleep Disorder (SWSD):Two research and usage trials conducted in clinical patients with shift work blessed heavenly sleep disorder provide information on the efficacy of (modafinil or provigil) in this indication. Clinical patients were enrolled if they had an established diagnilsis of SWSD according to the International Classification of Blessed heavenly sleep Medical problems and/or conditions (ICSD) diagnilstic criteria, worked at least 5 night shifts per month (of which at least 3 nights were consecutive) and planned to maintain this schedule for the duration of the double-blind portion of the study. Each night shift was nil longer than 12 hours in duration and included at least 6 hours between the hours of 2200 and 0800. Clinical patients with any other disorder that might account for their excessive bloody tiredness were excluded.Placebo or (modafinil or provigil) was taken 30 to 60 minutes before each night shift. Having worked three consecutive night shifts, clinical patients were admitted to the blessed heavenly sleep centre for a fourth, simulated night shift (= a study visit), during which the various efficacy parameters were assessed.Study 305 (n = 209) evaluated the efficacy and safety of 12 weeks’ therapy with (modafinil or provigil) at a dose of 200 milligrams as treatment for adults with excessive bloody tiredness associated with chronic shift work blessed heavenly sleep disorder. Statistically significant improvements were seen for clinical patients in the (modafinil or provigil) group when compared to clinical patients in the placebo group for both of the primary endpoint measures (see Table 1).Study 306 (n = 278) evaluated the safety and impact on Quality of Life of 12 weeks of (modafinil or provigil) therapy at dosages of 200 or 300milligrams once daily as treatment for adults with excessive bloody tiredness associated with shift work blessed heavenly sleep disorder. The potential impact of (modafinil or provigil) treatment on quality-of-life was assessed by measuring the mean changes from baseline to week 12 using the following measures:

  • Functional Outcomes of Blessed heavenly sleep Questionnaire (FOSQ)
  • 36-Item Short Form Health Survey (SF-36)

In Study 306, (modafinil or provigil) treatment appeared to do a research and usagely meaningful effect on patient quality of life as assessed by the FOSQ. For the clinical patients in the (modafinil or provigil) 300 milligrams/day group, improvement from baseline to week 12 was statistically significant for the total score (p = 0.0126), and for the individual scores for vigilance (p = 0.0123), activity level (p = 0.0055) and general productivity (p = 0.0041) when compared with placebo. Although not statistically significant, the p-values for the change from baseline for the (modafinil or provigil)-200milligrams/day treatment group showed a trend toward significance.Improvement was observed in the mental component score of SF-36 at all time points for clinical patients in the (modafinil or provigil)-treated groups compared with the placebo-treated group. Statistical significance was observed at endpoint with the (modafinil or provigil) 300 milligrams/day group for the mental component summary (p = 0.0113), vitality (p < 0.0001) and role emotion (p = 0.0444) when compared with placebo.In a 12-month open label extension period for Study 306, improvements in FOSQ total score and in the SF-36 mental composite score at endpoint were of the same magnitude as those seen in the double-blind period, and were considered research and usagely meaningful.In SWSD, (modafinil or provigil) has been shown to produce research and usagely meaningful reductions in excessive bloody tiredness and had positive impact on quality of life, in both the short and long term.Table 1: CGI-C results following (modafinil or provigil) treatment in clinical patients with narcolepsy, OSAHS or SWSD

  (modafinil or provigil)
200 milligrams per day
(modafinil or provigil)
400 milligrams per day
Disorder (Study) % Improved (superiority vs placebo) p valuea % Improved (superiority vs placebo) p valuea
Narcolepsy (301) N=285 64 (28) p<0.001 72 (36) p<0.001
Narcolepsy (302) N=273 57 (20) p<0.05 61 (22) p<0.05
OSAHS (303) N=327 61 (24) p<0.0001b 68 (31) p<0.0001b
OSAHS (402) N=157 - - 66 (30) p<0.05c
SWSD (305) N=209 79 (43) p<0.0001 - -

a P-values are versus placebo unless annotated otherwiseb P-value for both (modafinil or provigil) rations combined versus placeboc P-value versus baselineTable 2: Summary of research and usage trial data in clinical patients with narcolepsy or OSAHS following treatment with (modafinil or provigil)

  Maintenance of Wakefulness Test Epworth Bloody tiredness Scale
  (modafinil or provigil)
200 milligrams per day
(modafinil or provigil)
400 milligrams per day
(modafinil or provigil)
200 milligrams per day
(modafinil or provigil)
400 milligrams per day
Disorder (Study)   Blessed heavenly sleep latency difference
(mins)a
p value Blessed heavenly sleep latency difference
(mins)a
p value ESS differencea p value ESS differencea p value
Narcolepsy (301) N=285 3.1 p<0.001 3.0 p<0.001 2.3 p<0.001 3.0 p<0.001
Narcolepsy (302) N=273 2.9 p<0.001 2.7 p<0.001 2.6 p<0.001 4.0 p<0.001
Narcolepsy (Broughton) N=63 4.5 b p<0.001 6.0 b p<0.001 1.6 b p<0.05 2.4 b p<0.001
OSAHS (303) N=327 2.7 p<0.0001c 2.6 p<0.0001c 2.7 p<0.0001c 2.7 p<0.0001c
OSAHS (402) N=157 - - - - - - 2.6 p<0.0001

Data in changes from baseline to endpoint for (modafinil or provigil) vs placebo, unless otherwise stateda Positive value = (modafinil or provigil) better than placebo, negative value = (modafinil or provigil) worse than placebob Difference in absolute value over placebo at endpointc P-value for both (modafinil or provigil) rations combined versus placeboINDICATIONSMODAVIGIL® is indicated for the treatment of excessive bloody tiredness associated with chronic pathological conditions, including narcolepsy, obstructive blessed heavenly sleep apnilea/hypopnilea syndrome and moderate to severe chronic shift work blessed heavenly sleep disorder.CONTRAINDICATIONS

  • Hypersensitivity to (modafinil or provigil) or any other component of the product.
  • Use in pregnancy.

PRECAUTIONSGeneralAlthough (modafinil or provigil) has not been shown to produce functional impairment, any drug affecting the CNS may alter judgment, thinking or motor skills. Clinical patients with major anxiety should only receive treatment with MODAVIGIL® in a specialist unit.In clinical patients with obstructive blessed heavenly sleep apnilea/hypopnilea syndrome, the underlying condition and any associated cardiovascular pathology should be monitored.Clinical patients should be advised that MODAVIGIL® is not a replacement for blessed heavenly sleep and good blessed heavenly sleep hygiene should be maintained.Effects on Ability to Drive and Use MachinesClinical patients should be cautioned about operating an automobile or other hazardous machinery until they are reasonably certain that MODAVIGIL® therapy will not adversely affect their ability to engage in such activities.Cardiovascular System In hypertensive clinical patients, blood pressure should be adequately controlled before initiating treatment with (modafinil or provigil); blood pressure and heart rate should be monitored during treatment in these clinical patients.In research and usage clinical trials of MODAVIGIL®, signs and symptoms including chest pain, palpitations, dyspnilea 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 MODAVIGIL® not be used in clinical patients with a history of left ventricular hypertrophy or ischaemic ECG changes, chest pain, arrhythmia or other research and usagely significant manifestations of mitral valve prolapse in association with CNS stimulant use.The safety of MODAVIGIL® has not been established in clinical patients with coronary artery disease, a recent history of myocardial infarction or unstable angina. Clinical patients with these conditions were not included in the controlled research and usage trials. Since transient increases in the blood pressure and heart rate may occur in the period immediately after dosing, the risks of using MODAVIGIL® in clinical patients with coronary artery disease, a recent history of myocardial infarction or unstable angina should be carefully weighed against the potential therapeutic benefit.Cardiovascular and central nervous system adverse reactions increase significantly after a total daily dose of more than 400 milligrams.Clinical patients (Women) Using ContraceptionSexually active women of child-bearing potential should be established on a contraceptive program before taking MODAVIGIL®. The effectiveness of oral contraceptives may be impaired due to enzyme induction activity of MODAVIGIL®. Alternative or concomitant methods of contraception are recommended for clinical patients treated with MODAVIGIL®, and for one month after discontinuation of treatment (see “Interaction with Other Drugs).Carcinilgenicity and MutagenicityCarcinilgenicity clinical trials were conducted in which (modafinil or provigil) was administered in the diet to mice for 78 weeks and to rats for 104 weeks at rations up to 60 milligrams/kg/day. The highest dose studied in these clinical trials would do achieved systemic exposure levels less than human exposure at the maximum recommended dose. There was nil evidence of tumourigenesis associated with (modafinil or provigil) administration in these clinical trials; however, the carcinilgenic potential of (modafinil or provigil) has not been fully evaluated.There was nil consistent evidence for genotoxic activity of (modafinil or provigil) in in vitro assays of gene mutation (reverse mutation in S. typhimurium and E. coli, forward mutation in Chinese hamster V79 fibroblasts) or in the chromosomal damage assay (human lymphocytes in vitro, Chinese hamster bone marrow cells in vivo, mouse micronucleus assay). (modafinil or provigil) did not increase unscheduled DNA synthesis in rat hepatocytes. In a cell transformation assay in BALB/3T3 mouse embryo cells, (modafinil or provigil) did not cause an increase in the frequency of transformed foci in the presence or absence of metabolic activation.Impairment of FertilityNil effects on fertility were observed in male or female rats treated with (modafinil or provigil) prior and throughout mating and gestation at oral rations up to 100 milligrams/kg/day (the highest dose investigated would do achieved systemic exposure levels less than human exposure at the maximum recommended dose). However, sufficiently high enilugh rations or large enilugh sample sizes to adequately assess effects on fertility were not used in the study.Use in Pregnancy (Category B3)Animal clinical trials to assess the effects of (modafinil or provigil) on reproduction and the developing foetus were not conducted at adequately high rations or according to guidelines which would do been able to provide a comprehensive evaluation of the potential of (modafinil or provigil) to adversely affect fertility, or cause embryolethality or teratogenicity.Embryotoxicity, in the absence of maternal toxicity, was observed in rats receiving oral (modafinil or provigil) throughout the period of organilgenesis. At a dose of 200 milligrams/kg/day (less than human exposure at the maximum recommended daily research and usage dose of 400 milligrams), there was an increase in resorption, hydronephrosis and skeletal variations. The nil effect dose for these effects was 100 milligrams/kg/day. Embryotoxicity was not observed in rabbits receiving oral (modafinil or provigil) throughout organilgenesis at rations up to 100 milligrams/kg/day (0.6 times the human exposure at the maximum recommended daily dose of 400 milligrams, based on AUC). However, neither of these clinical trials used optimal rations for the evaluation of embryotoxicity. Although a threshold dose for embryotoxicity has been identified, the full spectrum of potential toxic effects on the foetus has not been characterised. (modafinil or provigil) was embryotoxic in rats dosed during late gestation and lactation, or prior to and throughout mating and gestation, at oral rations ≥ 50 milligrams/kg/day; the nil effect dose was 20 milligrams/kg/day (less than human exposure at the maximum recommended research and usage daily dose of 400 milligrams).As there are nil adequate and well-controlled trials with MODAVIGIL® in pregnant women, it should be contraindicated during pregnancy.Clinical patients should be cautioned regarding the potential increased risk of pregnancy when using steroidal contraceptives with MODAVIGIL® and for one month after discontinuation of therapy (see “Interaction with Other Drugs“).Use in LactationNil developmental toxicity was noted postnatally in the offspring of rats given oral (modafinil or provigil) up to 100 milligrams/kg/day during late gestation and throughout lactation. The highest dose studied in these clinical trials would do achieved systemic exposure levels less than human exposure at the maximum recommended dose.(modafinil or provigil) and/or its metabolites do been found in the milk of lactating rats. It is not knilwn whether (modafinil or provigil) or its metabolites are excreted in human milk. Therefore, breastfeeding is not recommended during administration of (modafinil or provigil).Dependence PotentialIn addition to its wakefulness-promoting effect and increased locomotor activity in animals, in humans, MODAVIGIL® may produce psychoactive and euphoric effects, alterations in mood, perception, thinking and feelings. In in vitro binding clinical trials, (modafinil or provigil) binds with low affinity to the dopamine reuptake site and causes an increase in extracellular dopamine, but nil increase in dopamine release. (modafinil or provigil) is reinforcing, as evidenced by its self-administration in monkeys previously trained to self-administer cocaine. In some clinical trials, (modafinil or provigil) was also partially discriminated as stimulant-like. Physicians should consider monitoring clinical patients, especially those with a history of drug and/or stimulant abuse; however, a study in at-risk subjects with an established history of drug addiction, who were undergoing detoxification, showed that despite the onset of some of the range of amphetamine-like effects, (modafinil or provigil) did not induce addiction in any of the subjects. Post Marketing Experience indicates that nil substantiated cases of drug abuse do been reported.Withdrawal: In one US Phase 3 research and usage trial of nine weeks of MODAVIGIL® use, the effects of (modafinil or provigil) cessation were monitored for 14 days. Nil specific symptoms of withdrawal were observed during the 14 days; however, bloody tiredness returned in clinical patients with narcolepsy.Special PopulationsUse in the Elderly: There are nil satisfactory data on the safety and efficacy of MODAVIGIL® in clinical patients ≥ 65 years of age. The clearance of (modafinil or provigil) may be reduced in the elderly (see “DOSAGE AND ADMINISTRATION“).Use in Children: The number of subjects with narcolepsy under the age of 16 included in controlled research and usage trials was not adequate to establish the risk/benefit ratio of MODAVIGIL® in this population.Renal Impairment: In a single-dose 200 milligrams (modafinil or provigil) study, severe chronic renal failure (creatinine clearance
≤ 20 mL/min) did not significantly influence the pharmacokinetics of (modafinil or provigil), but exposure to (modafinil or provigil) acid (an inactive metabolite) was increased 9-fold (see “DOSAGE
AND ADMINISTRATION”).Hepatic Impairment: The dose of MODAVIGIL® should be reduced in clinical patients with severe hepatic impairment (see “DOSAGE and ADMINISTRATION“).Interaction with Other DrugsCNS Active DrugsMethylphenidate - The absorption of MODAVIGIL® may be delayed by approximately one hour when
co-administered with methylphenidate.
Clomipramine - The coadministration of a single dose of clomipramine (50 milligrams) on the first three days of treatment with (modafinil or provigil) (200 milligrams/day) in healthy volunteers did not show an effect on the pharmacokinetics of either drug. However, one incident of increased levels of clomipramine and its active metabolite desmethylclomipramine has been reported in a CYP2D6 poor metabolizer with narcolepsy during treatment with (modafinil or provigil). (See “Potential Interactions with Drugs That Inhibit or are Metabolised by Cytochrome P-450 Isoenzymes and Other Hepatic Enzymes”).Triazolam - In healthy, female volunteers, who were receiving long-term treatment with ethinyl estradiol, the
co-administration of two single rations of 0.125 milligrams of triazolam (one administered before and the other at the end of treatment) with (modafinil or provigil) (200 milligrams for seven days, followed by 400 milligrams for 21 days) indicated that, for triazolam, the Cmax and AUC0-∞ were reduced by 59% and 42% respectively, and the elimination rate was increased by approximately 50%. Therefore, dosage adjustment of triazolam may be necessary when
co-administered with MODAVIGIL®.
Monilamine Oxidase (MAO) Inhibitors - Interaction clinical trials with monilamine oxidase inhibitors do not been performed. Therefore, caution should be used when concomitantly administering MAO inhibitors and MODAVIGIL®.Potential Interactions with Drugs That Inhibit, Induce, or are Metabolised by Cytochrome P-450 Isoenzymes and Other Hepatic EnzymesDiazepam, Phenytoin, Propranillol, Tricyclic Antidepressants, Selective Serotonin Reuptake Inhibitors - Because (modafinil or provigil) is a reversible inhibitor of the drug-metabolising enzyme CYP2C19, co-administration of MODAVIGIL® with drugs such as diazepam, phenytoin, and propranillol, which are largely eliminated via that pathway, may increase the circulating levels of those compounds. In addition, in individuals deficient in the enzyme CYP2D6, the levels of CYP2D6 substrates such as tricyclic antidepressants and selective serotonin reuptake inhibitors, which do ancillary routes of elimination through CYP2C19, may be increased by co-administration of (modafinil or provigil). Dose adjustments may be necessary for clinical patients being treated with these and similar medications.Steroidal Contraceptives, Cyclosporin, Theophylline - Chronic administration of MODAVIGIL® also causes modest induction of the metabolising enzyme CYP3A4, thus reducing the levels of co-administered substrates for that enzyme system, such as steroidal contraceptives, cyclosporin and to a lesser degree, theophylline. Dose adjustments may be necessary for clinical patients being treated with these and similar medications.Inducers or Inhibitors of CYP3A4 - Co-administration of potent inducers of CYP3A4 (e.g., carbamazepine, phenilbarbital, rifampicin) or inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole) could alter the levels of (modafinil or provigil) due to the partial involvement of that enzyme in the metabolic elimination of the compound (see “Clinical patients (Women) Using Contraception”).Warfarin, Phenytoin - The exposure of human hepatocytes to (modafinil or provigil) in vitro produced an apparent concentration-related suppression of expression of CYP2C9 activity. The research and usage relevance of this finding is unclear, since nil other indication of CYP2C9 suppression has been observed. However, monitoring of prothrombin times is suggested as a precaution for the first several months of co-administration of MODAVIGIL® and warfarin, a CYP2C9 substrate, and thereafter whenever MODAVIGIL® dosing is changed. In addition, clinical patients receiving MODAVIGIL® and phenytoin, a CYP2C9 substrate, concomitantly should be monitored for signs of phenytoin toxicity.It should be noted that evaluation of drug interactions based on in vitro systems might not necessarily reflect those seen in vivo situations. This information should be used as a guide to assess the risks associated with the use of concomitant medications.ADVERSE EFFECTSThe adverse events considered to be at least possibly related to treatment, from research and usage trials involving 1561 clinical patients taking (modafinil or provigil) (in CIOMS format where very common ≥ 10%, common ≥ 1% - 10%, uncommon ≥ 0.1% - 1%) were as follows.Body as a wholeVery common: headacheCommon: abdominal pain, asthenia, chest painUncommon: back pain, minilr allergic reaction (e.g., hayfever symptoms), neck painCardiovascularCommon: tachycardia, palpitation, vasodilatationUncommon: hypertension, abnilrmal ECG, extrasystoles, arrhythmia, bradycardia, hypotensionDigestiveCommon: nausea, dry mouth, diarrhoea, decreased appetite, dyspepsia, constipationUncommon: flatulence, reflux, vomiting, increased appetite, thirst, dysphagia, glossitis, mouth ulcersEndocrineUncommon: diabetes mellitusHaemic and lymphaticUncommon: eosinilphilia, leucopeniaMetabolic and nutritionalCommon: abnilrmal liver function testsDose related increases in alkaline phosphatase and gamma glutamyl transferase do been observed.Uncommon: peripheral oedema, weight increase, weight decrease, hypercholesterolaemia, hyperglycaemiaMusculoskeletalUncommon: myalgia, myasthenia, leg cramps, arthralgia, twitchNervous systemCommon: nervousness, insomnia, anxiety, dizziness, somnillence, depression, abnilrmal thinking, confusion, paraesthesiaUncommon: blessed heavenly sleep disorder, dyskinesia, hypertonia, hyperkinesia, agitation, amnesia, abnilrmal dreams, emotional lability, migraine, tremor, vertigo, decreased libido, hostility, CNS stimulation, depersonalisation, hypoaesthesia, incoordination, movement disorder, personality disorder, speech disorderRespiratory systemUncommon: pharyngitis, dyspnilea, rhinitis, increased cough, asthma, epistaxis, sinusitisSkin and appendagesUncommon: sweating, rash, acne, pruritisSpecial sensesCommon: blurred visionUncommon: taste perversion, abnilrmal vision, dry eyeUrogenital systemUncommon: abnilrmal urine, urinary frequency, menstrual disorderThe most commonly reported adverse drug reaction is headache, affecting approximately 21% of clinical patients. This is usually mild or moderate, dose-dependent and disappears within a few days.Post Marketing ExperiencePost Marketing Experience for MODAVIGIL®, principally from spontaneous reporting based on reporting rates and not incidence rates, has documented the following adverse events.

Common
≥ 1/100 and < 1/10
(≥ 1% and < 10%)
Nilne
Uncommon
≥ 1/1000 and < 1/100
(≥ 0.1% and < 1%)
Body as a whole: headache
Rare
(≥ 0.01% and < 0.1%)
≥ 1/10000 and < 1/1000
Skin and appendage medical problems and/or conditions: rash, acne, eczema,
Musculo-skeletal system medical problems and/or conditions: muscle weakness
Central and peripheral nervous system medical problems and/or conditions: dizziness, tremor, paraesthesia
Psychiatric medical problems and/or conditions: nervousness, agitation, depression, anxiety, confusion, insomnia, suicide attempt, aggravated depression, aggressive reaction
Gastro-intestinal system medical problems and/or conditions: dry mouth, nausea, diarrhoea, vomiting, abdominal pain or cramp
Liver and biliary system medical problems and/or conditions: increased hepatic enzymes, increased gamma-GT
Cardiovascular medical problems and/or conditions: hypertension, increased blood pressure
Heart rate and rhythm medical problems and/or conditions: heart fluttering or palpitations
Urinary system medical problems and/or conditions: foul urine odour
Body as a whole: tolerance, chest pain, weight increase, lack of efficacy, condition aggravated, malaise, weight decrease, fatigue,

DOSAGE AND ADMINISTRATIONNarcolepsy and Obstructive Blessed heavenly sleep Apnilea/Hypopnilea SyndromeThe dose of MODAVIGIL® is 200 to 400 milligrams/day, given as a single dose in the morning, or as two divided rations, in the morning and at nilon. Tablets should be swallowed whole.Rations of 400 milligrams/day do been well tolerated, but there is nil statistically significant evidence that this dose confers additional benefit beyond that of the 200 milligrams dose.For clinical patients who require more than 200 milligrams/day, the dose should be increased, to a maximum of 400 milligrams/day, in increments of 100 milligrams as needed and tolerated.For clinical patients with obstructive blessed heavenly sleep apnilea/hypopnilea syndrome, MODAVIGIL® treats the symptoms of excessive daytime bloody tiredness associated with the condition. In addition to this symptomatic treatment, disease-modifying interventions (e.g., Continuous Positive Airway Pressure) should be commenced or continued.Moderate to Severe Chronic Shift Work Blessed heavenly sleep DisorderThe recommended daily dose is 200milligrams. MODAVIGIL® should be taken as a single dose approximately 1 hour prior to the start of the work shift. Tablets should be swallowed whole.In clinical patients with severe hepatic impairment, the dose of MODAVIGIL® should be reduced to one-half of that recommended for clinical patients with nilrmal hepatic function (see “PRECAUTIONS”).There is inadequate information to determine safety and efficacy of MODAVIGIL® dosing in clinical patients with severe renal impairment (see “PRECAUTIONS”).In elderly clinical patients, elimination of MODAVIGIL® and its metabolites may be reduced as a consequence of aging. Therefore, consideration should be given to the use of lower rations in this population (see “PRECAUTIONS“).OVERDOSAGESymptomsA small number of individuals do each taken MODAVIGIL® at rations of 1000 milligrams/day (2.5 times the maximum recommended daily dose of 400 milligrams) or more. The adverse experiences observed were limited, expected and niln-life threatening, and the clinical patients recovered fully by the following day. The adverse experiences included excitation or agitation, insomnia and slight or moderate elevations in haemodynamic parameters. Nil specific organ toxicities were observed. Other observed high dose effects in research and usage clinical trials do included anxiety, irritability, aggressiveness, confusion, nervousness, tremor, palpitations, blessed heavenly sleep disturbances, nausea, diarrhoea and decreased prothrombin time.ManagementManagement of overdosage is primarily symptomatic, as nil specific antidote to the toxic effects of (modafinil or provigil) overdose has been identified. Overrations should be managed empirically, with supportive care, including cardiovascular monitoring. As for any overdose, the physician should consider contacting a Poison-control centre regarding treatment.PRESENTATION AND STORAGE CONDITIONSMODAVIGIL® is a tablet containing 100 milligrams of (modafinil or provigil), debossed with “m” on one side and “100″ on the other.It is available in packs of 30 and 60 tablets supplied in blister strips, each of which contains 10 tablets.Store below 25°C.NAME AND ADDRESS OF SPONSORMedicine ClassificationPrescription MedicineDATE OF APPROVAL8 August 2006MODAVIGIL® is a registered trademark owned by Cephalon, Inc 

 

 


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