Drug Safety-related Labeling Changes (SrLC)

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Drug Safety-related Labeling Changes (SrLC) Database

ANDA	Abbreviated New Drug Application
BLA	Biologics License Application
CDER	Center for Drug Evaluation and Research
MG	Medication Guide
NDA	New Drug Application
PCI	Patient Counseling Information
PI	Patient Information
PLR	Physician Labeling Rule
PLLR	Pregnancy and Lactation Labeling Rule
Italics	For the most part, italics indicate an FDA comment such as: Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section.
Underlines	Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text.

Sections

BW	Box Warning
WP	Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format)
AR	Adverse Reactions (in pre-PLR format, this may be a subheading under precautions).
DI	Drug Interactions (in pre-PLR format, this may be a subheading under precautions).
USP	Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format.
PCI/PI/MG	Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.

Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.

NUVIGIL (NDA-021875)

(ARMODAFINIL)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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02/07/2017 (SUPPL-23)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Serious Dermatologic Reactions, including Stevens-JohnsonSyndrome and Toxic Epidermal Necrosis

(additions underlined)

Serious rash requiring hospitalization and discontinuation of treatment has been reported in association with the use of NUVIGIL (armodafinil) or modafinil (the racemic mixture of S- and R-enantiomers).

NUVIGIL has not been studied in pediatric patients in any setting and is not approved for use in pediatric patients for any indication.

In clinical trials of modafinil, the incidence of rash resulting in discontinuation was approximately 0.8% (13 per 1,585) in pediatric patients (age <17 years); these rashes included 1 case of possible Stevens-Johnson syndrome (SJS) and 1 case of apparent multi-organ hypersensitivity reaction/ Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) .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 pediatric patients who received placebo.

Skin and mouth sores, blistering, and ulceration have been reported with modafinil and NUVIGIL in the postmarketing setting. Recurrence of signs and symptoms of serious dermatologic reactions following rechallenge has been reported in some cases.

Rare cases of serious or life-threatening rash, including SJS and toxic epidermal necrolysis (TEN),have been reported in adults and children in worldwide post-marketing experience with modafinil and NUVIGIL.

There are no factors, including duration of therapy, that are known to predict the risk of occurrence or the severity of rash associated with modafinil or NUVIGIL. In cases where the time to onset was reported, serious rash occurred 1 day to 2 months after initiation of treatment, but isolated cases of serious dermatologic reactions have been reported with symptoms beginning after prolonged treatment (e.g., 3 months).

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, skin or mouth sores, or blistering or ulceration, 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.

5.2 Drug Reaction with Eosinophilia and System Symptoms (DRESS)/Multiorgan Hypersensitivity

(new subsection added)

DRESS, also known as multi-organ hypersensitivity, has been reported with NUVIGIL. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection. Eosinophilia is often present. This disorder is variable in its expression, and other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present even though rash is not evident.

One fatal case of DRESS that occurred in close temporal association (3 weeks) with the initiation of NUVIGIL treatment has been reported in the postmarketing setting. In addition, 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. Although there have been a limited number of reports, multi-organ hypersensitivity reactions may result in hospitalization or be life-threatening.

If a multi-organ hypersensitivity reaction is suspected, NUVIGIL should be discontinued. Although there are no case reports to indicate cross-sensitivity with other drugs that produce this syndrome, the experience with drugs associated with multi-organ hypersensitivity would indicate this to be a possibility.

5.5 Psychiatric Symptoms

(subsection revised, additions underlined)

In pre-approval narcolepsy, OSA and SWD 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 suicidal 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, consider discontinuing NUVIGIL.

Psychiatric adverse reactions have been reported in patients treated with modafinil. Modafinil and NUVIGIL (armodafinil) 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 reactions associated with the use of NUVIGIL, some of which have resulted in hospitalization, have included mania, delusions, hallucinations, suicidal ideation, and aggression. Many, but not all, patients who developed psychiatric adverse reactions had a prior psychiatric history. In these cases, reported NUVIGIL total daily doses ranged from 50 mg to 450 mg, which includes doses below and above the recommended dosages.

6 Adverse Reactions

6.2 Postmarketing Experience

(new subsection added)

The following adverse reactions have been identified during post approval use of NUVIGIL. 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.

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

(additions underlined)

The following serious adverse reactions are described below and elsewhere in the labeling:

Serious Dermatologic Reactions
Drug Reaction with Eosinophilia and System Symptoms (DRESS)/Multiorgan Hypersensitivity
Angioedema and Anaphylaxis Reactions
Persistent Sleepiness
Psychiatric Symptoms
Effects on Ability to Drive and Use Machinery
Cardiovascular Events

8 Use in Specific Populations

8.1 Pregnancy

(PLLR conversion, please refer to label)

8.2 Lactation

(PLLR conversion)

Risk Summary

There are no data on the presence of armodafinil or its metabolite 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

(PLLR conversion)

The effectiveness of hormonal contraceptives may be reduced when used with NUVIGIL 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 NUVIGIL and for one month after discontinuation of NUVIGIL treatment.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(section revised, additions underlined)

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Serious Dermatologic Reactions

Advise patients and caregivers about the risk of potentially fatal serious skin reactions. Educate patients about the signs and symptoms that may signal a serious skin reaction. Instruct patients to discontinue NUVIGIL and consult with their healthcare provider immediately if a skin reaction such as rash, mouth sores, blisters, or peeling skin occurs during treatment with NUVIGIL.

DRESS/Multi-organ Hypersensitivity

Instruct patients that a fever associated with signs of other organ system involvement (e.g., rash, lymphadenopathy, hepatic dysfunction) may be drug-related and should be reported to their healthcare provider immediately.

Angioedema and Anaphylactic Reactions

Advise patients of life-threatening symptoms suggesting anaphylaxis or angioedema (such as hives, difficulty in swallowing or breathing, hoarseness, or swelling of the face, eyes, lips, or tongue) that can occur with NUVIGIL. Instruct them to discontinue NUVIGIL and immediately report these symptoms to their healthcare provider.

Wakefulness

Advise patients that treatment with NUVIGIL will not eliminate their abnormal tendency to fall asleep. Advise patients that they should not 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 NUVIGIL has been shown to produce levels of wakefulness that permit such activities. Advise patients that NUVIGIL is 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).

Psychiatric Symptoms

Advise patients to stop taking NUVIGIL and contact their physician right away if they experiencedepression, anxiety, or signs of psychosis or mania.

Pregnancy

Advise women that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to NUVIGIL.

Females of Reproductive Potential

Caution females regarding the potential increased risk of pregnancy when using hormonal contraceptives (including depot or implantable contraceptives) with NUVIGIL and advise females 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 NUVIGIL and for one month after discontinuation of NUVIGIL.

Concomitant Medication

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 NUVIGIL and other drugs.

Alcohol

Advise patients that the use of NUVIGIL in combination with alcohol has not been studied. Advise patients that it is prudent to avoid alcohol while taking NUVIGIL.

MEDICATION GUIDE

(additions and revisions, please refer to label)