Carcinogenicity studies were conducted in which modafinil (a mixture of R- and S-modafinil) was administered in the diet to mice for 78 weeks and to rats for 104 weeks at doses of 6, 30, and 60 mg/kg/day. The highest doses studied were associated with plasma modafinil exposures (AUC) less than that in humans at the recommended human dose (RHD) of modafinil (200 mg/day). There was no evidence of tumorigenesis associated with modafinil administration in these studies. However, the mouse study was inadequate because the high dose was not a maximum tolerated dose (MTD). In a mouse carcinogenicity study in which armodafinil (the R-enantiomer of modafinil) was administered at oral doses of up to 300 mg/kg/day in males and 100 mg/kg/day in females for approximately 2 years, no tumorigenic effects were observed. The highest doses studied, which were considered MTDs, were associated with plasma armodafinil exposures less than (females) or 2 times (males) that in humans at the RHD of modafinil.
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
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 modafinil AUC less than that in humans at the RHD of modafinil.
The effectiveness of modafinil in improving wakefulness in adult patients with excessive sleepiness associated with narcolepsy was established in two U.S. 9 week, multi-center, placebo‑controlled, parallel-group, double‑blind studies of outpatients who met the criteria for narcolepsy. A total of 558 patients were randomized to receive modafinil 200 or 400 mg/day, or placebo. The criteria for narcolepsy include either: 1) recurrent daytime naps or lapses into 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 2) a complaint of excessive sleepiness or sudden muscle weakness with associated features: sleep paralysis, hypnagogic hallucinations, automatic behaviors, disrupted major sleep episode; and polysomnography demonstrating one of the following: sleep latency less than 10 minutes or rapid eye movement (REM) sleep latency less than 20 minutes. For entry into these studies, all patients were required to have objectively documented excessive daytime sleepiness, via a Multiple Sleep Latency Test (MSLT) with two or more sleep onset REM periods and the absence of any other clinically significant active medical or psychiatric disorder. The MSLT, an objective polysomnographic assessment of the patient’s ability to fall asleep in an unstimulating environment, measured latency (in minutes) to sleep onset averaged over 4 test sessions at 2 hour intervals. For each test session, the subject was told to lie quietly and attempt to sleep. Each test session was terminated after 20 minutes if no sleep occurred or 15 minutes after sleep onset.
In both studies, the primary measures of effectiveness were: 1) sleep latency, as assessed by the Maintenance of Wakefulness Test (MWT); and 2) the change in the patient’s overall disease status, as measured by the Clinical Global Impression of Change (CGI-C). For a successful trial, both measures had to show statistically significant improvement.
The MWT measures latency (in minutes) to sleep onset averaged over 4 test sessions at 2 hour intervals following nocturnal polysomnography. For each test session, the subject was asked to attempt to remain awake without using extraordinary measures. Each test session was terminated after 20 minutes if no sleep occurred or 10 minutes after sleep onset. The CGI-C is a 7 point scale, centered at No Change , and ranging from Very Much Worse to Very Much Improved. Patients were rated by evaluators who had no access to any data about the patients other than a measure of their baseline severity. Evaluators were not given any specific guidance about the criteria they were to apply when rating patients.
Both studies demonstrated improvement in objective and subjective measures of excessive daytime sleepiness for both the 200 mg and 400 mg doses compared to placebo. Patients treated with modafinil showed a statistically significantly enhanced ability to remain awake on the MWT at each dose compared to placebo at final visit (Table 2). A statistically significantly greater number of patients treated with modafinil at each dose showed improvement in overall clinical condition as rated by the CGI-C scale at final visit (Table 3).
Nighttime sleep measured with polysomnography was not affected by the use of modafinil.
The effectiveness of modafinil in improving wakefulness in patients with excessive sleepiness associated with OSA was established in two multi-center, placebo-controlled clinical studies of patients who met the criteria for OSA. The criteria include either: 1) excessive sleepiness or insomnia, plus frequent episodes of impaired breathing during sleep, and associated features such as loud snoring, morning headaches and dry mouth upon awakening; or 2) excessive sleepiness or insomnia and polysomnography demonstrating one of the following: more than five obstructive apneas, each greater than 10 seconds in duration, per hour of sleep and one or more of the following: frequent arousals from sleep associated with the apneas, bradytachycardia, and arterial oxygen desaturation in association with the apneas. In addition, for entry into these studies, all patients were required to have excessive sleepiness as demonstrated by a score ≥10 on the Epworth Sleepiness Scale (ESS), despite treatment with continuous positive airway pressure (CPAP). Evidence that CPAP was effective in reducing episodes of apnea/hypopnea was required along with documentation of CPAP use.
In the first study, a 12 week trial, a total of 327 patients with OSA were randomized to receive modafinil 200 mg/day, modafinil 400 mg/day, or matching placebo. The majority of patients (80%) were fully compliant with CPAP, defined as CPAP use greater than 4 hours/night on > 70% of nights. The remainder were partially CPAP compliant, defined as CPAP use < 4 hours/night on >30% of nights. CPAP use continued throughout the study. The primary measures of effectiveness were 1) sleep latency, as assessed by the Maintenance of Wakefulness Test (MWT) and 2) the change in the patient’s overall disease status, as measured by the Clinical Global Impression of Change (CGI-C) at the final visit [see Clinical Studies ( 14.1) for a description of these measures].
Patients treated with modafinil showed a statistically significant improvement in the ability to remain awake compared to placebo-treated patients as measured by the MWT at final visit (Table 2). A statistically significant greater number of patients treated with modafinil showed improvement in overall clinical condition as rated by the CGI-C scale at final visit (Table 3). The 200 mg and 400 mg doses of modafinil produced statistically significant effects of similar magnitude on the MWT, and also on the CGI-C.
In the second study, a 4 week trial, 157 patients with OSA were randomized to receive modafinil 400 mg/day or placebo. Documentation of regular CPAP use (at least 4 hours/night on 70% of nights) was required for all patients. The primary measure of effectiveness was the change from baseline on the ESS at final visit. The baseline ESS scores for the modafinil and placebo groups were 14.2 and 14.4, respectively. At week 4, the ESS was reduced by 4.6 in the modafinil group and by 2 in the placebo group, a difference that was statistically significant.
Nighttime sleep measured with polysomnography was not affected by the use of modafinil.
The effectiveness of modafinil in improving wakefulness in patients with excessive sleepiness associated with SWD was demonstrated in a 12 week placebo-controlled clinical trial. A total of 209 patients with chronic SWD were randomized to receive modafinil 200 mg/day or placebo. All patients met the criteria for chronic SWD. The criteria include: 1) either, a) a primary complaint of excessive sleepiness or insomnia which is temporally associated with a work period (usually night work) that occurs during the habitual sleep phase, or b) polysomnography and the MSLT demonstrate loss of a normal sleep-wake pattern (i.e., disturbed chronobiological rhythmicity); and 2) no other medical or mental disorder accounts for the symptoms, and 3) the symptoms do not meet criteria for any other sleep disorder producing insomnia or excessive sleepiness (e.g., time zone change [jet lag] syndrome).
It should be noted that not all patients with a complaint of sleepiness who are also engaged in shift work meet the criteria for the diagnosis of SWD. In the clinical trial, only patients who were symptomatic for at least 3 months were enrolled.
Enrolled patients were also required to work a minimum of 5 night shifts per month, have excessive sleepiness at the time of their night shifts (MSLT score < 6 minutes), and have daytime insomnia documented by a daytime polysomnogram.
The primary measures of effectiveness were 1) sleep latency, as assessed by the MSLT performed during a simulated night shift at the final visit and 2) the change in the patient’s overall disease status, as measured by the CGI-C at the final visit [see Clinical Studies ( 14.1) for a description of these measures.].
Patients treated with modafinil showed a statistically significant prolongation in the time to sleep onset compared to placebo-treated patients, as measured by the nighttime MSLT at final visit (Table 2). A statistically significant greater number of patients treated with modafinil showed improvement in overall clinical condition as rated by the CGI-C scale at final visit (Table 3).
Daytime sleep measured with polysomnography was not affected by the use of modafinil.
|Modafinil 200 mg*||Modafinil 400 mg*||Placebo|
|Disorder||Measure||Baseline||Change from Baseline||Baseline||Change from Baseline||Baseline||Change from Baseline|
*Significantly different than placebo for all trials (p<0.01 for all trials but SWD, which was p<0.05)
|Disorder||Modafinil 200 mg*||Modafinil 400 mg*||Placebo|
*Significantly different than placebo for all trials (p<0.01)
Modafinil tablets, USP are available as follows:
Modafinil tablets USP, 100 mg are white to off white colored capsule shaped tablets debossed with ‘M’ on one side and 100 MG on other side.
30s count HDPE container in a carton NDC 42043-160-03
90s count HDPE container in a carton NDC 42043-160-90
100s count HDPE container in a carton NDC 42043-160-01
Modafinil tablets USP, 200 mg are white to off white colored capsule shaped tablets debossed with ‘M’ on one side and 200 MG on other side with a breakline between 200 and MG.
30s count HDPE container in a carton NDC 42043-161-03
90s count HDPE container in a carton NDC 42043-161-90
100s count HDPE container in a carton NDC 42043-161-01
Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature].
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Advise patients to stop taking modafinil tablets and to notify their physician right away if they develop a rash, hives, mouth sores, blisters, peeling skin, trouble swallowing or breathing, or a related allergic phenomenon.
Driving and Dangerous Activities
Advise patients not to 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 modafinil tablets has been shown to produce levels of wakefulness that permit such activities. Advise patients that modafinil tablets are 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).
Discontinuing Drug Due to Adverse Reactions
Advise patients to stop taking modafinil tablets and contact their physician right away if they experience chest pain, rash, depression, anxiety, or signs of psychosis or mania.
Advise patients to notify their physician if they become pregnant or intend to become pregnant during therapy. Caution patients regarding the potential increased risk of pregnancy when using steroidal contraceptives (including depot or implantable contraceptives) with modafinil tablets and for one month after discontinuation of therapy.
Advise patients to notify their physician if they are breastfeeding an infant.
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 modafinil tablets and other drugs.
Advise patients that the use of modafinil tablets in combination with alcohol has not been studied. Advise patients that it is prudent to avoid alcohol while taking modafinil tablets.
Modafinil (moe-DAFF-in-ill) Tablets, USP [C-IV]
Read this Medication Guide before you start taking modafinil tablets and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or treatment.
What is the most important information I should know about modafinil tablets?
Modafinil tablets may cause serious side effects including a serious rash or a serious allergic reaction that may affect parts of your body such as your liver or blood cells. Any of these may need to be treated in a hospital and may be life-threatening.
Stop taking modafinil tablets and call your doctor right away or get emergency help if you have any of these symptoms:
- skin rash, hives, sores in your mouth, or your skin blisters and peels
- swelling of your face, eyes, lips, tongue, or throat
- trouble swallowing or breathing
- fever, shortness of breath, swelling of the legs, yellowing of the skin or whites of the eyes, or dark urine.
If you have a severe rash with modafinil tablets, stopping the medicine may not keep the rash from becoming life-threatening or causing you to be permanently disabled or disfigured.
Modafinil tablets are not approved for use in children for any medical condition.
It is not known if modafinil tablets are safe or effective in children under 17 years of age.
What are modafinil tablets?
Modafinil tablets are a prescription medicine used to improve wakefulness in adults who are very sleepy due to one of the following diagnosed sleep disorders:
- obstructive sleep apnea (OSA). Modafinil tablets are used to treat excessive sleepiness, but not the obstruction or medical condition that is causing OSA. You should talk with your doctor about treatments for OSA before you start taking modafinil tablets and during treatment with modafinil tablets. Modafinil tablets do not take the place of treatments that your doctor has prescribed for OSA. It is important that you continue to use these treatments as prescribed by your doctor.
- shift work disorder (SWD)
Modafinil tablets will not cure these sleep disorders. Modafinil tablets may help the sleepiness caused by these conditions, but it may not stop all your sleepiness. Modafinil tablets do not take the place of getting enough sleep. Follow your doctor’s advice about good sleep habits and using other treatments.
Modafinil is a federally controlled substance (C-IV) because it can be abused or lead to dependence. Keep modafinil tablets in a safe place to prevent misuse and abuse. Selling or giving away modafinil tablets may harm others, and is against the law. Tell your doctor if you have ever abused or been dependent on alcohol, prescription medicines, or street drugs.
Who should not take modafinil tablets?
Do not take modafinil tablet if you:
- are allergic or developed a rash to modafinil or armodafinil (NUVIGIL®) or any of the ingredients in modafinil tablets. See the end of this Medication Guide for a complete list of ingredients in modafinil tablets.
What should I tell my doctor before taking modafinil tablets?
Tell your doctor about all of your medical conditions including, if you:
- have a history of mental health problems, including psychosis
- have heart problems or had a heart attack
- have high blood pressure. Your blood pressure may need to be checked more often while taking modafinil tablets.
- have liver or kidney problems
- have a history of drug or alcohol abuse or addiction
- are pregnant or planning to become pregnant. It is not known if modafinil tablets will harm your unborn baby.
- are breastfeeding. It is not known if modafinil passes into your breast milk. Talk to your doctor about the best way to feed your baby if you take modafinil tablets.
Tell your doctor about all the medicines you take , including prescription and over-the-counter medicines, vitamins, and herbal supplements. Modafinil tablets and many other medicines can interact with each other, sometimes causing side effects. Modafinil tablets may affect the way other medicines work, and other medicines may affect how modafinil tablets work. Your dose of modafinil tablets or certain other medicines may need to be changed.
Especially, tell your doctor if you use or take:
- a hormonal birth control method, such as birth control pills, shots, implants, patches, vaginal rings, and intrauterine devices (IUDs). Hormonal birth control methods may not work while you take modafinil tablets. Women who use one of these methods of birth control may have a higher chance for getting pregnant while taking modafinil tablets, and for one month after stopping modafinil tablets. Talk to your doctor about birth control choices that are right for you while taking modafinil tablets.
Know the medicines you take. Keep a list of them and show it to your doctor and pharmacist when you get a new medicine. Your doctor or pharmacist will tell you if it is safe to take modafinil tablets and other medicines together. Do not start any new medicines with modafinil tablets unless your doctor has told you it is okay.
How should I take modafinil tablets?
- Take modafinil tablets exactly as prescribed by your doctor. Your doctor will prescribe the dose of modafinil tablets that is right for you. Do not change your dose of modafinil tablets without talking to your doctor.
- Your doctor will tell you the right time of day to take modafinil tablets.
- People with narcolepsy or OSA usually take modafinil tablets 1 time each day in the morning.
- People with SWD usually take modafinil tablets about 1 hour before their work shift.
- Do not change the time of day you take modafinil tablets unless you have talked to your doctor. If you take modafinil tablets too close to your bedtime, you may find it harder to go to sleep.
- You can take modafinil tablets with or without food.
- If you take more than your prescribed dose or if you take an overdose of modafinil tablets, call your doctor or go to the nearest hospital emergency room right away.
Symptoms of an overdose of modafinil tablets may include:
- trouble sleeping
- feeling disoriented
- feeling excited
- hearing, seeing, feeling, or sensing things that are not really there (hallucinations)
- nausea and diarrhea
- a fast or slow heartbeat
- chest pain
- increased blood pressure
What should I avoid while taking modafinil tablets?
- Do not drive a car or do other dangerous activities until you know how modafinil tablets affect you. People with sleep disorders should always be careful about doing things that could be dangerous. Do not change your daily habits until your doctor tells you it is okay.
- You should avoid drinking alcohol. It is not known how drinking alcohol will affect you when taking modafinil tablets.
What are possible side effects of modafinil tablets?
Modafinil tablets may cause serious side effects. Stop taking modafinil tablets and call your doctor right away or get emergency help if you get any of the following:
- a serious rash or serious allergic reaction. ( See “What is the most important information I should know about modafinil tablets?”)
- mental (psychiatric) symptoms, including:
- feeling anxious
- hearing, seeing, feeling, or sensing things that are not really there (hallucinations)
- an extreme increase in activity and talking (mania)
- thoughts of suicide
- aggressive behavior
- other mental problems
- symptoms of a heart problem, including chest pain, abnormal heartbeat, and trouble breathing.
Common side effects that can happen in anyone who takes modafinil tablets include:
- back pain
- feeling nervous
- stuffy nose
- feeling anxious
- trouble sleeping
- upset stomach
Modafinil tablets are not approved for use in children for any medical condition including Attention Deficit Hyperactivity Disorder (ADHD). In studies of modafinil tablets in children with narcolepsy, side effects included:
- Tourette’s syndrome
- hostile behavior
- increase in sudden loss of muscle tone and severe muscle weakness
- increase in seeing and hearing things when falling asleep
- increase in suicidal thoughts
- low white blood count
- painful menstrual periods
Tell your doctor if you get any side effect that bothers you or that does not go away while taking modafinil tablets.
These are not all the side effects of modafinil tablets. For more information, ask your doctor or pharmacist.
Some effects of modafinil tablets on the brain are the same as other medicines called “stimulants”. These effects may lead to abuse or dependence on modafinil tablets.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store modafinil tablets?
- Store modafinil tablets at room temperature between 20° and 25°C (68°and 77°F).
- Keep modafinil tablets and all medicines out of the reach of children.
General information about the safe and effective use of modafinil tablets.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use modafinil tablets for a condition for which they were not prescribed. Do not give modafinil tablets to other people, even if they have the same symptoms you have. They may harm them and it is against the law.
This Medication Guide summarizes the most important information about modafinil tablets. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about modafinil tablets that is written for health professionals. For more information, call PROSAR at 866-562-4590.
What are the ingredients in modafinil tablets?
Active Ingredient: modafinil, USP
Inactive Ingredients: colloidal silicon dioxide, crospovidone, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, pregelatinized starch, and talc.
The brand listed in this Medication Guide is the trademark of its owner and is not trademark of Orchid Healthcare. The makers of this brand are not affiliated with and do not endorse Orchid Healthcare or its products.
This Medication Guide has been approved by the U.S. Food and Drug Administration
Manufactured for: OrchidPharma, Inc.
Princeton, NJ 08540, USA
Manufactured by: Orchid Healthcare
(A Division of Orchid Pharma Ltd.)
Irungattukottai — 602 117, India
| MODAFINIL |
| MODAFINIL |
|Labeler — OrchidPharma Inc (809429207)|
|Registrant — Orchid Pharma Ltd. (650133507)|
|Orchid Healthcare (A Division of Orchid Pharma Ltd)||650288850||analysis (42043-160), analysis (42043-161), manufacture (42043-160), manufacture (42043-161), pack (42043-160), pack (42043-161), label (42043-160), label (42043-161)|
Revised: 01/2022 OrchidPharma Inc
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