Xadago (Page 2 of 7)

5.7 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.

5.8 Retinal Pathology

Retinal degeneration and loss of photoreceptor cells were observed in albino and pigmented rats administered safinamide orally in toxicity studies of up to 6 months duration. In albino rats administered safinamide orally for two years, retinal scarring and cataracts were observed at all doses tested [see Nonclinical Toxicology (13.2)].

Periodically monitor patients for visual changes in patients with a history of retinal/macular degeneration, uveitis, inherited retinal conditions, family history of hereditary retinal disease, albinism, retinitis pigmentosa, or any active retinopathy (e.g., diabetic retinopathy).

6 ADVERSE REACTIONS

The following serious adverse reactions are discussed in greater detail in other sections of labeling:

• Hypertension [see Warnings and Precautions (5.1 )]
• Serotonin Syndrome [see Warnings and Precautions (5.2)]
• Falling Asleep During Activities of Daily Living [see Warnings and Precautions (5.3)]
• Dyskinesia [see Warnings and Precautions (5.4)]
• Hallucinations / Psychotic Behavior [see Warnings and Precautions (5.5)]
• Impulse Control / Compulsive Behaviors [see Warnings and Precautions (5.6)]
• Withdrawal-Emergent Hyperpyrexia and Confusion [see Warnings and Precautions (5.7)]
• Retinal Pathology [see Warnings and Precautions (5.8)]

6.1 Clinical Trials Experience

Clinical trials are conducted under widely varying conditions; therefore, adverse reactions observed in the clinical trials of a drug cannot be directly compared to the incidence in the clinical trials of another drug and may not reflect the incidence observed in clinical practice.

Common Adverse Reactions in Placebo-Controlled PD Studies

Table 1 shows the incidence of adverse reactions with an incidence of at least 2% on XADAGO 100 mg/day and greater than placebo in controlled studies in PD (Study 1 and Study 2). The most common adverse reactions associated with XADAGO treatment in which the incidence for XADAGO 100 mg/day was at least 2% greater than the incidence for placebo were dyskinesia, fall, nausea, and insomnia.

Adverse Reactions Reported as Reason for Discontinuation from Study

In pooled placebo-controlled studies (Study 1 and Study 2) in patients with PD taking a stable dose of carbidopa/levodopa with or without other PD medications, there was an increase in the incidence of XADAGO-treated patients who discontinued from the study because of adverse reactions. The incidence of patients discontinuing from Study 1 and Study 2 for any adverse reaction was 5% for XADAGO 50 mg/day, 6% for XADAGO 100 mg/day, and 4% for placebo. The most frequently reported adverse reaction causing study discontinuation was dyskinesia (1% of patients treated with XADAGO 50 mg/day or XADAGO 100 mg/day vs. 0% for placebo).

Table 1: Percentage of Patients with Adverse Reactions with an Incidence ≥ 2% in the XADAGO 100 mg/day Group and Greater than Placebo in Studies 1 and 2.

	XADAGO50 mg/day(N = 223)	XADAGO100 mg/day(N = 498)	Placebo (N = 497)
Adverse Reaction	%	%	%
Dyskinesia	21	17	9
Fall	4	6	4
Nausea	3	6	4
Insomnia	1	4	2
Orthostatic hypotension	2	2	1
Anxiety	2	2	1
Cough	2	2	1
Dyspepsia	0	2	1

Abnormal Laboratory Changes

In Study 1 and Study 2, the proportion of patients who experienced a shift from normal to above the upper limit of normal for serum alanine aminotransferase (ALT) was 5% for XADAGO 50 mg, 7% for XADAGO 100 mg, and 3% for placebo. No patient treated with XADAGO experienced an increase in ALT that was 3 times the upper limit of normal or higher.

The proportion of patients with a shift from normal to above the upper limit of normal for serum aspartate aminotransferase (AST) was 7% for XADAGO 50 mg, 6% for XADAGO 100 mg, and 3% for placebo. The incidence of patients with an increase in AST to at least 3 times the upper limit of normal was similar for XADAGO and placebo.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of safinamide outside of the United States. 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.

A postmarketing report describes a patient who developed a hypersensitivity reaction consisting of swelling of the tongue and gingiva, dyspnea and skin rash. The symptoms resolved shortly after XADAGO was discontinued, but reappeared following rechallenge a month later.

7 DRUG INTERACTIONS

7.1 MAO Inhibitors (MAOIs)

XADAGO is contraindicated for use with other drugs in the MAOIs class or other drugs that are potent inhibitors of monoamine oxidase (e.g., linezolid, an oxazolidinone antibacterial, which also has reversible nonselective MAO inhibition activity). Co-administration increases the risk of nonselective MAO inhibition, which may lead to hypertensive crisis [see Contraindications (4) and Warnings and Precautions (5.1)]. At least 14 days should elapse between discontinuation of XADAGO and initiation of treatment with other MAOIs.

Isoniazid has some monoamine oxidase inhibiting activity. Monitor for hypertension and reaction to dietary tyramine in patients treated concomitantly with isoniazid and XADAGO.

7.2 Opioid Drugs

Because serious, sometimes fatal reactions have been precipitated with concomitant use of opioid drugs (e.g., meperidine and its derivatives, methadone, propoxyphene, or tramadol) and MAOIs, including selective MAO-B inhibitors, concomitant use of these drugs is contraindicated [see Warnings and Precautions (5.2)]. At least 14 days should elapse between discontinuation of XADAGO and initiation of treatment with these drugs.

7.3 Serotonergic Drugs

Concomitant use of XADAGO with SNRIs; triazolopyridine, tricyclic or tetracyclic antidepressants; cyclobenzaprine (a skeletal muscle relaxant that is a tricyclic antidepressant derivative); or St. John’s wort is contraindicated [see Warnings and Precautions (5.2)]. At least 14 days should elapse between discontinuation of XADAGO and initiation of treatment with these drugs.

Monitor patients for symptoms of serotonin syndrome if SSRIs are used by patients treated with XADAGO [see Warnings and Precautions (5.2)].