Armodafinil (Page 2 of 7)

5.5 Psychiatric Symptoms

In pre-approval narcolepsy, OSA and SWD controlled trials of armodafinil, anxiety, agitation, nervousness, and irritability were reasons for treatment discontinuation more often in patients on armodafinil compared to placebo (armodafinil 1.2% and placebo 0.3%). Depression was also a reason for treatment discontinuation more often in patients on armodafinil compared to placebo (armodafinil 0.6% and placebo 0.2%). Cases of suicidal ideation were observed in clinical trials. Caution should be exercised when armodafinil is given to patients with a history of psychosis, depression, or mania. If psychiatric symptoms develop in association with armodafinil administration, consider discontinuing armodafinil.

Psychiatric adverse reactions have been reported in patients treated with modafinil. Modafinil and armodafinil are very closely related. Therefore, the incidence and type of psychiatric symptoms associated with armodafinil are expected to be similar to the incidence and type of these events with modafinil.

Postmarketing adverse reactions associated with the use of armodafinil, 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 armodafinil total daily doses ranged from 50 mg to 450 mg, which includes doses below and above the recommended dosages.

5.6 Effects on Ability to Drive and Use Machinery

Although armodafinil has not been shown to produce functional impairment, any drug affecting the central nervous system (CNS) may alter judgment, thinking or motor skills. Patients should be cautioned about operating an automobile or other hazardous machinery until it is reasonably certain that armodafinil therapy will not adversely affect their ability to engage in such activities.

5.7 Cardiovascular Events

In clinical studies of modafinil, cardiovascular adverse reactions, including chest pain, palpitations, dyspnea 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 armodafinil tablets not be used in patients with a history of left ventricular hypertrophy or in patients with mitral valve prolapse who have experienced the mitral valve prolapse syndrome when previously receiving CNS stimulants. Findings suggestive of mitral valve prolapse syndrome include but are not limited to ischemic ECG changes, chest pain, or arrhythmia. If new onset of any of these findings occurs, consider cardiac evaluation.

Blood pressure monitoring in short term (≤ 3 months) pre-approval controlled trials of OSA, SWD, and narcolepsy showed small average increases in mean systolic and diastolic blood pressure in patients receiving armodafinil as compared to placebo (1.2 to 4.3 mmHg in the various experimental groups). There was also a slightly greater proportion of patients on armodafinil requiring new or increased use of antihypertensive medications (2.9%) compared to patients on placebo (1.8%). There was a small, but consistent, average increase in pulse rate over placebo in pre-approval controlled trials. This increase varied from 0.9 to 3.5 BPM. Increased monitoring of heart rate and blood pressure may be appropriate in patients on armodafinil. Caution should be exercised when prescribing armodafinil to patients with known cardiovascular disease.

6 ADVERSE REACTIONS

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

  • Serious Dermatologic Reactions [see Warnings and Precautions (5.1)]
  • Drug Reaction with Eosinophilia and System Symptoms (DRESS)/Multiorgan Hypersensitivity [see Warnings and Precautions (5.2)]
  • Angioedema and Anaphylaxis Reactions [see Warnings and Precautions (5.3)]
  • Persistent Sleepiness [see Warnings and Precautions (5.4)]
  • Psychiatric Symptoms [see Warnings and Precautions (5.5)]
  • Effects on Ability to Drive and Use Machinery [see Warnings and Precautions (5.6)]
  • Cardiovascular Events [see Warnings and Precautions (5.7)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Armodafinil has been evaluated for safety in over 1,100 patients with excessive sleepiness associated with OSA, SWD, and narcolepsy.

Most Common Adverse Reactions

In the placebo-controlled clinical trials, the most common adverse reactions (≥5%) associated with the use of armodafinil more frequently than in placebo-treated patients were headache, nausea, dizziness, and insomnia. The adverse reaction profile was similar across the studies.

Table 1 presents the adverse reactions that occurred at a rate of 1% or more and were more frequent in armodafinil-treated patients than in placebo-treated patients in the placebo-controlled clinical trials.

Table 1: Adverse Reactions in Pooled Placebo-Controlled Clinical Trials * in OSA, Narcolepsy, and SWD with Armodafinil (150 mg and 250 mg)
Armodafinil(%) N=645 Placebo(%) N=445
*
Adverse reactions that occurred in ≥1% of Armodafinil-treated patients and greater incidence than that of placebo.

Headache

17

9

Nausea

7

3

Dizziness

5

2

Insomnia

5

1

Anxiety

4

1

Diarrhea

4

2

Dry Mouth

4

1

Depression

2

0

Dyspepsia

2

0

Fatigue

2

1

Palpitations

2

1

Rash

2

0

Upper Abdominal Pain

2

1

Agitation

1

0

Anorexia

1

0

Constipation

1

0

Contact Dermatitis

1

0

Decreased Appetite

1

0

Depressed Mood

1

0

Disturbance In Attention

1

0

Dyspnea

1

0

Hyperhydrosis

1

0

Increased Gamma-Glutamyltransferase

1

0

Increased Heart Rate

1

0

Influenza-Like Illness

1

0

Loose Stools

1

0

Migraine

1

0

Nervousness

1

0

Pain

1

0

Paresthesia

1

0

Polyuria

1

0

Pyrexia

1

0

Seasonal Allergy

1

0

Thirst

1

0

Tremor

1

0

Vomiting

1

0

Dose-Dependent Adverse Reactions

In the placebo-controlled clinical trials which compared doses of 150 mg/day and 250 mg/day of armodafinil and placebo, the following adverse reactions were dose-related: headache, rash, depression, dry mouth, insomnia, and nausea. See Table 2 for additional information.

Table 2: Dose-Dependent Adverse Reactions in Pooled Placebo-Controlled Clinical Trials in OSA, Narcolepsy and SWD
Armodafinil250 mg(%)N=198 Armodafinil150 mg(%)N=447 ArmodafinilCombined(%)N=645 Placebo(%)N=445

Headache

23

14

17

9

Nausea

9

6

7

3

Insomnia

6

4

5

1

Dry Mouth

7

2

4

<1

Rash

4

1

2

<1

Depression

3

1

2

<1

Adverse Reactions Resulting in Discontinuation of Treatment

In placebo-controlled clinical trials, 44 of the 645 patients (7%) who received armodafinil discontinued due to an adverse reaction compared to 16 of the 445 (4%) of patients that received placebo. The most frequent reason for discontinuation was headache (1%).

Laboratory Abnormalities

Clinical chemistry, hematology, and urinalysis parameters were monitored in the studies. Mean plasma levels of gamma glutamyltransferase (GGT) and alkaline phosphatase (AP) were found to be higher following administration of armodafinil, but not placebo. Few patients, however, had GGT or AP elevations outside of the normal range. No differences were apparent in alanine aminotransferase (ALT), aspartate aminotransferase (AST), total protein, albumin, or total bilirubin, although there were rare cases of isolated elevations of AST and/or ALT. A single case of mild pancytopenia was observed after 35 days of treatment and resolved with drug discontinuation. A small mean decrease from baseline in serum uric acid compared to placebo was seen in clinical trials. The clinical significance of this finding is unknown.

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