Prescription Drug Information: Azilect (Page 2 of 6)

5.7 Dyskinesia

When used as an adjunct to levodopa, AZILECT may cause dyskinesia or potentiate dopaminergic side effects and exacerbate preexisting dyskinesia. In Study 3, the incidence of dyskinesia was 18% for patients treated with 0.5 mg or 1 mg AZILECT as an adjunct to levodopa and 10% for patients treated with placebo as an adjunct to levodopa. Decreasing the dose of levodopa may mitigate this side effect [see Adverse Reactions (6.1)].

5.8 Hallucinations / Psychotic-Like Behavior

In the monotherapy study (Study 1), the incidence of hallucinations reported as an adverse event was 1.3% in patients treated with AZILECT 1 mg and 0.7% in patients treated with placebo. In Study 1, the incidence of hallucinations reported as an adverse reaction and leading to drug discontinuation and premature withdrawal was 1.3% in patients treated with AZILECT 1 mg and 0% in placebo-treated patients.

When studied as an adjunct therapy without levodopa (Study 2), hallucinations were reported as an adverse reaction in 1.2% of patients treated with 1 mg/day AZILECT and 1.8% of patients treated with placebo. Hallucinations led to drug discontinuation and premature withdrawal from the clinical trial in 0.6% of patients treated with AZILECT 1 mg/day and in none of the placebo-treated patients.

When studied as an adjunct to levodopa (Study 3), the incidence of hallucinations was approximately 5% in patients treated with AZILECT 0.5 mg/day, 4% in patients treated with AZILECT 1 mg/day, and 3% in patients treated with placebo. The incidence of hallucinations leading to drug discontinuation and premature withdrawal was about 1% in patients treated with 0.5 mg AZILECT and 1 mg AZILECT/day, and 0% in placebo-treated patients [see Adverse Reactions (6.1)].

Postmarketing reports indicate that patients may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior during treatment with AZILECT or after starting or increasing the dose of AZILECT. Other drugs prescribed to improve the symptoms of Parkinson’s disease can have similar effects on thinking and behavior. This abnormal thinking and behavior can consist of one or more of a variety of manifestations including paranoid ideation, delusions, hallucinations, confusion, psychotic-like behavior, disorientation, aggressive behavior, agitation, and delirium.

Patients should be informed of the possibility of developing hallucinations and instructed to report them to their healthcare provider promptly should they develop.

Patients with a major psychotic disorder should ordinarily not be treated with AZILECT because of the risk of exacerbating the psychosis with an increase in central dopaminergic tone. In addition, many treatments for psychosis that decrease central dopaminergic tone may decrease the effectiveness of AZILECT [see Drug Interactions (7.8)].

Consider dose reduction or stopping the medication if a patient develops hallucinations or psychotic like behaviors while taking AZILECT.

5.9 Impulse Control / Compulsive Behaviors

Case reports suggest that patients can experience intense urges to gamble, increased sexual urges, intense urges to spend money, binge eating, and/or other intense urges, and the inability to control these urges while taking one or more of the medications, including AZILECT, that increase central dopaminergic tone and that are generally used for the treatment of Parkinson’s disease. In some cases, although not all, these urges were reported to have stopped when the dose was reduced or the medication was discontinued. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending, or other urges while being treated with AZILECT. Consider dose reduction or stopping the medication if a patient develops such urges while taking AZILECT.

5.10 Withdrawal-Emergent Hyperpyrexia and Confusion

A symptom complex resembling neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in drugs that increase central dopaminergic tone.

6 ADVERSE REACTIONS

The following adverse reactions are described in more detail in the Warnings and Precautions section of the label:

  • Hypertension [see Warnings and Precautions (5.1)]
  • Serotonin Syndrome [see Warnings and Precautions (5.2)]
  • Falling Asleep During Activities of Daily Living and Somnolence [see Warnings and Precautions (5.3)]
  • Hypotension / Orthostatic Hypotension [see Warnings and Precautions (5.6)]
  • Dyskinesia [see Warnings and Precautions (5.7)]
  • Hallucinations / Psychotic-Like Behavior [see Warnings and Precautions (5.8)]
  • Impulse Control /Compulsive Behaviors [see Warnings and Precautions (5.9)]
  • Withdrawal-Emergent Hyperpyrexia and Confusion [see Warnings and Precautions (5.10)]

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 the incidence of adverse reactions in the clinical trials of another drug and may not reflect the rates of adverse reactions observed in practice.

During the clinical development of AZILECT, Parkinson’s disease patients received AZILECT as initial monotherapy (Study 1) and as adjunct therapy (Study 2, Study 3, Study 4). As the populations in these studies differ, not only in the adjunct use of dopamine agonists or levodopa during AZILECT treatment, but also in the severity and duration of their disease, the adverse reactions are presented separately for each study.

Monotherapy Use of AZILECT

In Study 1, approximately 5% of the 149 patients treated with AZILECT discontinued treatment due to adverse reactions compared to 2% of the 151 patients who received placebo.

The only adverse reaction that led to the discontinuation of more than one patient was hallucinations.

The most commonly observed adverse reactions in Study 1 (incidence in AZILECT-treated patients 3% or greater than the incidence in placebo-treated patients) included flu syndrome, arthralgia, depression, and dyspepsia. Table 1 lists adverse reactions that occurred in 2% or greater of patients receiving AZILECT as monotherapy and were numerically more frequent than in the placebo group in Study 1.

Table 1: Adverse Reactions* in Study 1

AZILECT 1 mg (N=149)

Placebo (N=151)

% of Patients

% of Patients

Headache

14

12

Arthralgia

7

4

Dyspepsia

7

4

Depression

5

2

Fall

5

3

Flu syndrome

5

1

Conjunctivitis

3

1

Fever

3

1

Gastroenteritis

3

1

Rhinitis

3

1

Arthritis

2

1

Ecchymosis

2

0

Malaise

2

0

Neck Pain

2

0

Paresthesia

2

1

Vertigo

2

1

*Incidence 2% or greater in AZILECT 1 mg group and numerically more frequent than in placebo group

There were no significant differences in the safety profile based on age or gender.

Adjunct Use of AZILECT

AZILECT was studied as an adjunct therapy without levodopa (Study 2), or as an adjunct therapy to levodopa, with some patients also taking dopamine agonists, COMT inhibitors, anticholinergics, or amantadine (Study 3 and Study 4).

In Study 2, approximately 8% of the 162 patients treated with AZILECT discontinued treatment due to adverse reactions compared to 4% of the 164 patients who received placebo.

Adverse reactions that led to the discontinuation of more than one patient were nausea and dizziness.

The most commonly observed adverse reactions in Study 2 (incidence in AZILECT-treated patients 3% or greater than incidence in placebo-treated patients) included peripheral edema, fall, arthralgia, cough, and insomnia. Table 2 lists adverse reactions that occurred in 2% or greater in patients receiving AZILECT as adjunct therapy without levodopa and numerically more frequent than in the placebo group in Study 2.

Table 2: Adverse Reactions* in Study 2

AZILECT 1 mg (N=162)

Placebo

(N=164)

% of Patients

% of Patients

Dizziness

7

6

Peripheral edema

7

4

Headache

6

4

Nausea

6

4

Fall

6

1

Arthralgia

5

2

Back pain

4

3

Cough

4

1

Insomnia

4

1

Upper respiratory tract infection

4

2

Orthostatic hypotension

3

1

*Incidence 2% or greater in AZILECT 1 mg group and numerically more frequent than in placebo group

There were no significant differences in the safety profile based on age or gender.

In Study 3, adverse event reporting was considered more reliable than Study 4; therefore, only the adverse event data from Study 3 are presented below.

In Study 3, approximately 9% of the 164 patients treated with AZILECT 0.5 mg/day and 7% of the 149 patients treated with AZILECT 1 mg/day discontinued treatment due to adverse reactions, compared to 6% of the 159 patients who received placebo. The adverse reactions that led to discontinuation of more than one AZILECT-treated patient were diarrhea, weight loss, hallucination, and rash.

The most commonly observed adverse reactions in Study 3 (incidence in AZILECT-treated patients 3% or greater than the incidence in placebo-treated patients) included dyskinesia, accidental injury, weight loss, postural hypotension, vomiting, anorexia, arthralgia, abdominal pain, nausea, constipation, dry mouth, rash, abnormal dreams, fall, and tenosynovitis.

Table 3 lists adverse reactions that occurred in 2% or greater of patients treated with AZILECT 1 mg/day and that were numerically more frequent than the placebo group in Study 3.

Table 3: Adverse Reactions* in Study 3

AZILECT 1 mg

(N=149)

AZILECT 0.5 mg (N=164)

Placebo (N=159)

% of Patients

% of Patients

% of Patients

Dyskinesia

18

18

10

Accidental injury

12

8

5

Nausea

12

10

8

Headache

11

8

10

Fall

11

12

8

Weight loss

9

2

3

Constipation

9

4

5

Postural hypotension

9

6

3

Arthralgia

8

6

4

Vomiting

7

4

1

Dry mouth

6

2

3

Rash

6

3

3

Somnolence

6

4

4

Abdominal pain

5

2

1

Anorexia

5

2

1

Diarrhea

5

7

4

Ecchymosis

5

2

3

Dyspepsia

5

4

4

Paresthesia

5

2

3

Abnormal dreams

4

1

1

Hallucinations

4

5

3

Ataxia

3

6

1

Dyspnea

3

5

2

Infection

3

2

2

Neck pain

3

1

1

Sweating

3

2

1

Tenosynovitis

3

1

0

Dystonia

3

2

1

Gingivitis

2

1

1

Hemorrhage

2

1

1

Hernia

2

1

1

Myasthenia

2

2

1

*Incidence 2% or greater in AZILECT 1 mg group and numerically more frequent than in placebo group

Several of the more common adverse reactions seemed dose-related, including weight loss, postural hypotension, and dry mouth.

There were no significant differences in the safety profile based on age or gender.

During all Parkinson’s disease phase 2/3 clinical trials, the long-term safety profile was similar to that observed with shorter duration exposure.

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