모다피닐

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

No specific antidote to the toxic effects of modafinil overdose has been identified to date. Such overdoses should be managed with primarily supportive care, including cardiovascular monitoring. If there are no contraindications, induced emesis or gastric lavage should be considered. (L1712)

The effects of alcohol use in patients receiving modafinil are unknown; avoiding drinking alcohol is recommended.

Based on in vitro data, modafinil is metabolized partially by the 3A isoform subfamily of hepatic cytochrome P450 (CYP3A4). In addition, modafinil has the potential to inhibit CYP2C19, suppress CYP2C9, and induce CYP3A4, CYP2B6, and CYP1A2. Because modafinil and modafinil sulfone are reversible inhibitors of the drug-metabolizing enzyme CYP2C19, co-administration of modafinil with drugs such as diazepam, phenytoin and propranolol, which are largely eliminated via that pathway, may increase the circulating levels of those compounds. In addition, in individuals deficient in the enzyme CYP2D6 (i.e., 7-10% of the Caucasian population; similar or lower in other populations), the levels of CYP2D6 substrates such as tricyclic antidepressants and selective serotonin reuptake inhibitors, which have ancillary routes of elimination through CYP2C19, may be increased by co-administration of modafinil. Dose adjustments may be necessary for patients being treated with these and similar medications.

The absorption of modafinil may be delayed by approximately one hour when coadministered with methylphenidate or dextroamphetamine, although the extent of absorption and the disposition of both agents are unchanged.

Additive CNS simulation may occur /when modafinil is used concurrently with other CNS stimulation-producing medications/, causing nervousness, irritability, insomnia, or possibly seizures or cardiac arrhythmias; close observation is recommended during concurrent use with modafinil.

For more Interactions (Complete) data for MODAFINIL (6 total), please visit the HSDB record page.

Using large amounts of these drugs can result in a condition known as amphetamine psychosis -- which can result in auditory, visual and tactile hallucinations, intense paranoia, irrational thoughts and beliefs, delusions, and mental confusion. Using large amounts of these drugs can result in a condition known as amphetamine psychosis -- which can result in auditory, visual and tactile hallucinations, intense paranoia, irrational thoughts and beliefs, delusions, and mental confusion.

Modafinil is generally a well-tolerated stimulant. The most commonly reported adverse effects of modafinil (less than 10% of users) are headache, nausea, and decreased appetite. Other commonly reported adverse effects (5% to 10% of users) include anxiety, insomnia, dizziness, diarrhea, and rhinitis. Regarding serious adverse effects, cases of Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug rash with eosinophilia and systemic symptoms have been reported in postmarketing surveillance. These life-threatening rashes associated with modafinil appear extremely rare, although the precise incidence rates are not known. Most of the reported cases have occurred within six weeks of drug initiation. Therefore, any patient who develops a rash during this time frame is advised to notify the prescribing physician immediately.；Abuse Potential: In clinical trials, modafinil use produces euphoric and psychoactive effects, altering thinking, mood, feelings, and perception like other central nervous system stimulants. Assess the risk of potential abuse and use it with caution in patients with a history of drug abuse.；Withdrawal: In one placebo-controlled clinical trial, after nine weeks of modafinil use, the effects of modafinil withdrawal were observed. No withdrawal symptoms were observed in patients with modafinil treatment cessation during 14 days of observation, but in patients with narcolepsy, sleepiness returned.

Case reports of modafinil overdose/toxicity are rare. Clinical manifestations of modafinil overdose are relatively mild but may include hypertension, tachycardia, agitation, and/or psychosis. The most frequently reported clinical effects were tachycardia, insomnia, agitation, dizziness, and anxiety. About 20% of overdose cases require medical treatment. Symptoms typically respond to supportive therapy, although augmentation with benzodiazepines is occasionally required. Other treatments include diphenhydramine, beta-blockers, haloperidol, IV fluid hydration, nitroglycerin, epinephrine, benztropine, and promethazine based on precipitating symptoms.

The exact mechanism of action is unclear, although <i>in vitro</i> studies have shown it to inhibit the reuptake of dopamine by binding to the dopamine reuptake pump, and lead to an increase in extracellular dopamine. Modafinil activates glutamatergic circuits while inhibiting GABA. Modafinil is thought to have less potential for abuse than other stimulants due to the absence of any significant euphoric or pleasurable effects. It is possible that modafinil acts by a synergistic combination of mechanisms including direct inhibition of dopamine reuptake, indirect inhibition of noradrenalin reuptake in the VLPO and orexin activation. Modafinil has partial alpha 1B-adrenergic agonist effects by directly stimulating the receptors.

Side-effects can include sweating, dry mouth, blurred vision, insomnia, loss of appetite, and dizziness. In addition users can feel restless, anxious and moody, become excitable and have a false sense of power and security. Amphetamine overdose can also cause cardiac arrhythmias, headaches, convulsions, hypertension, rapid heart rate, coma and death. Amphetamines are psychologically and physically addictive.

/SIGNS AND SYMPTOMS/ Overdose experience is limited. Signs and symptoms generally consist of mild CNS stimulation and include agitation, insomnia, tremor, confusion, palpitations, tachycardia, and hypertension.

/SIGNS AND SYMPTOMS/ Serious rash, including Stevens-Johnson Syndrome requiring hospitalization and discontinuation of treatment has been reported in adults and children in association with the use of modafinil. ... Rare cases of serious or life-threatening rash, including Stevens-Johnson Syndrome, Toxic Epidermal Necrolysis, and Drug Rash with Eosinophilia and Systemic Symptoms have been reported in adults and children in worldwide post-marketing experience. The reporting rate of Toxic Epidermal Necrolysis and Stevens-Johnson Syndrome 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. There are no factors that are known to predict the risk of occurrence or the severity of rash associated with modafinil. Nearly all cases of serious rash associated with modafinil 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 modafinil, it is not possible to reliably predict which rashes will prove to be serious. Accordingly, modafinil should ordinarily be discontinued at the first sign of rash, 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.

/SIGNS AND SYMPTOMS/ In clinical trials, a total of 151 protocol-specified doses of 1000 to 1600 mg/day (5 to 8 times the recommended daily dose of 200 mg), have been administered to 32 subjects, including 134 subjects who received doses of 1000 or 1200 mg/day for 7 to 21 consecutive days. In addition, several intentional acute overdose occurred; the 2 largest being 4500 mg and 4000 mg taken by 2 subjects participating in foreign depression studies. None of these study subjects experienced any unexpected or life-threatening effects. Adverse experiences that were reported at these dose included excitation or agitation, insomnia, and slight or moderate elevation in hemodynamic parameters. Other observed high dose effects in clinical studies have included anxiety, irritability, aggressiveness, confusion, nervousness, tremor, palpitations, sleep disturbances, nausea, diarrhea, and decreased prothrombin time.

/CASE REPORTS/ A case of weight loss associated with modafinil-initiation in a clozapine-treated man with schizoaffective disorder /was reported/. ... The impact of modafinil, a wake promoting agent that lacks the unwanted side affects brought on by many psychostimulants, on weight in a clozapine-treated patient /was discussed/. Modafinil was initiated, and over the course of 1 year, /the patient/ experienced a weight loss of 40 lbs (from 280 lbs to 240 lbs) and a reduction in body mass index (BMI) of 5.08 Kg/sq m (from 35.52 Kg/sq m to 30.44 Kg/sq m). After 3 years on the combination of clozapine and modafinil, his weight stabilized at 230 lbs (BMI = 29.59 Kg/sq m). A 30-lb weight gain over a 6-month period occurred following discontinuation of modafinil. Reinstitution of modafinil resulted in a 10-lb. weight loss over a 6-week period. Modafinil treatment resulted in a significant weight loss in this patient, possibly due to reducing clozapine-associated fatigue. ...

Drug Induced Liver Injury Rank (DILIrank 2.0)

Modafinil

vLess-DILI-concern

3

Warnings & precautions

DOI:10.1016/j.drudis.2016.02.015

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Carcinogenicity studies were conducted in which 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 dose studied is 1.5 (mouse) or 3 (rat) times greater than the recommended adult human daily dose of modafinil (200 mg) on a mg/sq m basis. There was no evidence of tumorigenesis associated with modafinil administration in these studies. However, since the mouse study used an inadequate high dose that was not representative of a maximum tolerated dose, a subsequent carcinogenicity study was conducted in the Tg.AC transgenic mouse. Doses evaluated in the Tg.AC assay were 125, 250, and 500 mg/kg/day, administered dermally. There was no evidence of tumorigenicity associated with modafinil administration; however, this dermal model may not adequately assess the carcinogenic potential of an orally administered drug.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ 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 (plasma modafinil AUC approximately 0.1 times the AUC in humans at the recommended daily dose (RHD)). No effects on postnatal developmental and neurobehavioral parameters were observed in surviving offspring.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Modafinil administered orally to pregnant rabbits throughout the period of organogenesis at doses of 45, 90, and 180 mg/kg/day increased the incidences of fetal structural alterations and embryofetal death at the highest dose. The highest no-effect dose for developmental toxicity was associated with a plasma modafinil AUC approximately equal to the AUC in humans at the recommended daily dose (RHD).

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Modafinil (50, 100, or 200 mg/kg/day) administered orally to pregnant rats throughout the period of organogenesis caused, in the absence of maternal toxicity, an increase in resorptions and an increased incidence of visceral and skeletal variations in the offspring at the highest dose. The higher no-effect dose for rat embryofetal developmental toxicity was associated with a plasma modafinil exposure approximately 0.5 times the AUC in humans at the recommended daily dose (RHD) of 200 mg. However, in a subsequent study of up to 480 mg/kg/day (plasma modafinil exposure approximately 2 times the AUC in humans at the RHD) no adverse effects on embryofetal development were observed.

While data specific to modafinil were not located(SRC, 2008), the literature suggests that some pharmaceutically active compounds originating from human and veterinary therapy are not eliminated completely in municipal sewage treatment plants and are therefore discharged into receiving waters(1). Wastewater treatment processes often were not designed to remove them from the effluent(2). Selected organic waste compounds may be degrading to new and more persistent compounds that may be released instead of or in addition to the parent compound(2). Studies have indicated that several polar pharmaceutically active compounds can leach through subsoils into aquifers(1).

Schedule IV shall consist of the drugs and other substances, by whatever official name, common or usual name, chemical name, or brand name designated, listed in this section. Each drug or substance has been assigned the DEA Controlled Substances Code Number set forth opposite it. Stimulants: Unless specifically excepted or unless listed in another schedule, any material, compound, mixture, or preparation which contains any quantity of the following substances having a stimulant effect on the central nervous system, including its salts, isomers and salts of isomers: Modafinil (DEA Code Number: 1680) is included on this list.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl modafinil, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl Armodafinil, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Armodafinil/

MEDICATION

Therapeutic Category: CNS Stimulant

Wakefulness promoting agent used to reduce excessive sleepiness.

Use (kg; approx.) in Germany (2009): >250；Use (kg) in USA (2002): 6050；Consumption (g per capita; approx.) in Germany (2009): 0.00305；Consumption (g per capita) in the USA (2002): 0.0214；Calculated removal (%): 22.1

In the U.S, only for the treatment of narcolepsy, obstructive sleep apnea/hypopnea and shift work sleep disorder. In some countries, it is also approved for idiopathic hypersomnia. [Wikipedia]

Oral: Tablets: 100 mg Provigil (C-IV), (Cephalon), 200 mg Provigil (C-IV scored), (Cephalon).

Available as 100 and 200 mg tablets.