Azilect (Page 2 of 8)

5.4 Ciprofloxacin or Other CYP1A2 Inhibitors

Rasagiline plasma concentrations may increase up to 2 fold in patients using concomitant ciprofloxacin and other CYP1A2 inhibitors. Patients taking concomitant ciprofloxacin or other CYP1A2 inhibitors should not exceed a dose of AZILECT 0.5 mg once daily [see Dosage and Administration (2.2), Drug Interactions (7.6), and Clinical Pharmacology (12.3)].

5.5 Hepatic Impairment

Rasagiline plasma concentration may increase in patients with hepatic impairment. Patients with mild hepatic impairment should be given the dose of AZILECT 0.5 mg once daily. AZILECT should not be used in patients with moderate or severe hepatic impairment [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

5.6 Hypotension / Orthostatic Hypotension

In Study 3, the incidence of orthostatic hypotension consisting of a systolic blood pressure decrease (≥ 30 mm Hg) or a diastolic blood pressure decrease (≥ 20 mm Hg) after standing was 13% with AZILECT (1 mg/day) compared to 9% with placebo [see Adverse Reactions ( 6.1)].

At the 1 mg dose, the frequency of orthostatic hypotension (at any time during the study) was approximately 44% for AZILECT vs 33% for placebo for mild to moderate systolic blood pressure decrements (≥ 20 mm Hg), 40% for AZILECT vs 33% for placebo for mild to moderate diastolic blood pressure decrements (≥ 10 mm Hg), 7% for AZILECT vs 3% for placebo for severe systolic blood pressure decrements (≥ 40 mm Hg), and 9% for AZILECT vs 6% for placebo for severe diastolic blood pressure decrements (≥ 20 mm Hg). There was also an increased risk for some of these abnormalities at the lower 0.5 mg daily dose and for an individual patient having mild to moderate or severe orthostatic hypotension for both systolic and diastolic blood pressure.

In Study 2 where AZILECT was given as an adjunct therapy in patients not taking concomitant levodopa, there were 5 reports of orthostatic hypotension in patients taking AZILECT 1 mg (3.1%) and 1 report in patients taking placebo (0.6%) [see Adverse Reactions ( 6.1)].

Clinical trial data further suggest that orthostatic hypotension occurs most frequently in the first two months of AZILECT treatment and tends to decrease over time.

Some patients treated with AZILECT experienced a mildly increased risk for significant decreases in blood pressure unrelated to standing but while supine.

The risk for post-treatment hypotension (e.g., systolic < 90 or diastolic < 50 mm Hg) combined with a significant decrease from baseline (e.g., systolic > 30 or diastolic > 20 mm Hg) was higher for AZILECT 1 mg (3.2%) compared to placebo (1.3%).

There was no clear increased risk for lowering of blood pressure or postural hypotension associated with AZILECT 1 mg/day as monotherapy.

When used as an adjunct to levodopa, postural hypotension was also reported as an adverse reaction in approximately 6% of patients treated with AZILECT 0.5 mg, 9% of patients treated with AZILECT 1 mg and 3% of patients treated with placebo. Postural hypotension led to drug discontinuation and premature withdrawal from clinical trials in one (0.7%) patient treated with AZILECT 1 mg/day, no patients treated with AZILECT 0.5 mg/day and no placebo-treated patients.

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)]

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