ARMODAFINIL (Page 3 of 7)

6.2 Postmarketing Experience

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

Cardiovascular: Stroke

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

7 DRUG INTERACTIONS

Effects of ARMODAFINIL on CYP3A4/5 Substrates

The clearance of drugs that are substrates for CYP3A4/5 (e.g., steroidal contraceptives, cyclosporine, midazolam, and triazolam) may be increased by ARMODAFINIL via induction of metabolic enzymes, which results in lower systemic exposure. Dosage adjustment of these drugs should be considered when these drugs are used concomitantly with ARMODAFINIL [see Clinical Pharmacology (12.3)].

The effectiveness of steroidal contraceptives may be reduced when used with ARMODAFINIL and for one month after discontinuation of therapy. Alternative or concomitant methods of contraception are recommended for patients taking steroidal contraceptives (e.g., ethinyl estradiol) when treated concomitantly with ARMODAFINIL and for one month after discontinuation of ARMODAFINIL treatment.

Blood levels of cyclosporine may be reduced when used with ARMODAFINIL. Monitoring of circulating cyclosporine concentrations and appropriate dosage adjustment for cyclosporine should be considered when used concomitantly with ARMODAFINIL.

Effects of ARMODAFINIL on CYP2C19 Substrates

Elimination of drugs that are substrates for CYP2C19 (e.g., phenytoin, diazepam, propranolol, omeprazole, and clomipramine) may be prolonged by ARMODAFINIL via inhibition of metabolic enzymes, with resultant higher systemic exposure. Dose reduction of these drugs may be required when these drugs are used concomitantly with ARMODAFINIL.

Warfarin

More frequent monitoring of prothrombin times/INR should be considered whenever ARMODAFINIL is coadministered with warfarin [see Clinical Pharmacology (12.3)].

Monoamine Oxidase (MAO) Inhibitors

Caution should be used when concomitantly administering MAO inhibitors and ARMODAFINIL.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Registry

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

Risk Summary

Limited available data on armodafinil use in pregnant women are insufficient to inform a drug associated risk of adverse pregnancy outcomes. Intrauterine growth restriction and spontaneous abortion have been reported in association with armodafinil and modafinil. Although the pharmacology of armodafinil is not identical to that of the sympathomimetic amines, armodafinil shares some pharmacologic properties with this class [see Clinical Pharmacology (12.1)]. Some sympathomimetics have been associated with intrauterine growth restriction and spontaneous abortions.

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

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

Data

Animal Data

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

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

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

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

8.2 Lactation

Risk Summary

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

8.3 Females and Males of Reproductive Potential

The effectiveness of hormonal contraceptives may be reduced when used with ARMODAFINIL and for one month after discontinuation of therapy. Advise women who are using a hormonal method of contraception to use an additional barrier method or an alternative non-hormonal method of contraception during treatment with ARMODAFINIL and for one month after discontinuation of ARMODAFINIL treatment [see Drug Interactions (7) and Clinical Pharmacology (12.3)].

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established. Serious rash has been seen in pediatric patients receiving modafinil [see Warnings and Precautions (5.1)].

8.5 Geriatric Use

In elderly patients, elimination of armodafinil and its metabolites may be reduced as a consequence of aging. Therefore, consideration should be given to the use of lower doses and close monitoring in this population [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].

8.6 Hepatic Impairment

The dosage of ARMODAFINIL should be reduced in patients with severe hepatic impairment [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

ARMODAFINIL contains armodafinil, a Schedule IV controlled substance.

9.2 Abuse

Abuse of ARMODAFINIL has been reported in patients treated with ARMODAFINIL. Patterns of abuse have included euphoric mood and use of increasingly large doses or recurrent use of ARMODAFINIL for a desired effect. Drug diversion has also been noted. During the postmarketing period, misuse of ARMODAFINIL has been observed (e.g., taking ARMODAFINIL against a physician’s advice, and obtaining ARMODAFINIL from multiple physicians).

Abuse of armodafinil, the active ingredient of ARMODAFINIL, poses a risk of overdosage similar to that seen for modafinil, which may lead to tachycardia, insomnia, agitation, dizziness, anxiety, nausea, headache, dystonia, tremor, chest pain, hypertension, seizures, delirium, or hallucinations. Other signs and symptoms of CNS stimulant abuse include tachypnea, sweating, dilated pupils, hyperactivity, restlessness, decreased appetite, loss of coordination, flushed skin, vomiting, and abdominal pain.

In humans, modafinil produces psychoactive and euphoric effects, alterations in mood, perception, thinking and feelings, typical of other CNS stimulants. In in vitro binding studies, modafinil binds to the dopamine reuptake site and causes an increase in extracellular dopamine, but no increase in dopamine release. Modafinil is reinforcing, as evidenced by its self-administration in monkeys previously trained to self-administer cocaine. In some studies, modafinil was also partially discriminated as stimulant-like.

Physicians should follow patients closely, especially those with a history of drug and/or stimulant (e.g., methylphenidate, amphetamine, or cocaine) abuse. Patients should be observed for signs of misuse or abuse (e.g., incrementation of doses or drug-seeking behavior).

The abuse potential of modafinil (200, 400, and 800 mg) was assessed relative to methylphenidate (45 and 90 mg) in an inpatient study in individuals experienced with drugs of abuse. Results from this clinical study demonstrated that modafinil produced psychoactive and euphoric effects and feelings consistent with other scheduled CNS stimulants (methylphenidate).

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