Xadago: Package Insert and Label Information

XADAGO- safinamide mesylate tablet, film coated
US WorldMeds, LLC

1 INDICATIONS AND USAGE

XADAGO is indicated as adjunctive treatment to levodopa/carbidopa in patients with Parkinson’s disease (PD) experiencing “off” episodes.

Limitations of Use:

XADAGO has not been shown to be effective as monotherapy for the treatment of PD.

2 DOSAGE AND ADMINISTRATION

2.1 Dosing Information

The recommended starting dosage of XADAGO is 50 mg administered orally once daily (at the same time of day), without regard to meals. After two weeks, the dosage may be increased to 100 mg once daily, based on individual need and tolerability.

Daily dosages of XADAGO above 100 mg have not been shown to provide additional benefit, and higher dosages increase the risk for adverse reactions. XADAGO has been shown to be effective only in combination with levodopa/carbidopa [see Indications and Usage (1)].

If a dose is missed, the next dose should be taken at the same time the next day.

XADAGO 100 mg should be tapered by decreasing the dose to 50 mg for one week before stopping [see Warnings and Precautions (5.7)].

2.2 Dosing in Patients with Hepatic Impairment

In patients with moderate hepatic impairment (Child-Pugh B: 7-9), the maximum recommended dosage of XADAGO is 50 mg orally once daily. XADAGO is contraindicated in patients with severe hepatic impairment (Child-Pugh C: 10-15) [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. If a patient taking 50 mg XADAGO progresses from moderate to severe hepatic impairment, discontinue XADAGO.

3 DOSAGE FORMS AND STRENGTHS

  • 50 mg tablets: Orange to copper with metallic gloss, round, biconcave shaped embossed with “50″ on one side
  • 100 mg tablets: Orange to copper with metallic gloss, round, biconcave shaped embossed with “100″ on one side

4 CONTRAINDICATIONS

XADAGO is contraindicated in patients with:

  • Concomitant use of other drugs in the monoamine oxidase inhibitor (MAOI) class or other drugs that are potent inhibitors of monoamine oxidase, including linezolid. The combination may result in increased blood pressure, including hypertensive crisis [see Warnings and Precautions (5.1) and Drug Interactions (7.1)].
  • Concomitant use of opioid drugs (e.g., meperidine and its derivatives, methadone, propoxyphene, or tramadol); serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic, tetracyclic, or triazolopyridine antidepressants; cyclobenzaprine; methylphenidate, amphetamine, and their derivatives; or St John’s wort. Concomitant use could result in life-threatening serotonin syndrome [see Warnings and Precautions (5.2) and Drug Interactions (7.2, 7.3, 7.5)].
  • Concomitant use of dextromethorphan. The combination of MAO inhibitors and dextromethorphan has been reported to cause episodes of psychosis or abnormal behavior [see Drug Interactions (7.4)].
  • A history of a hypersensitivity to safinamide. Reactions have included swelling of the tongue and oral mucosa, and dyspnea.
  • Severe hepatic impairment (Child-Pugh C: 10-15) [see Use in Specific Populations (8.6)].

5 WARNINGS AND PRECAUTIONS

5.1 Hypertension

XADAGO may cause hypertension or exacerbate existing hypertension. In clinical trials, the incidence of hypertension was 7% for XADAGO 50 mg, 5% for XADAGO 100 mg, and 4% for placebo. Monitor patients for new onset hypertension or hypertension that is not adequately controlled after starting XADAGO. Medication adjustment may be necessary if elevation of blood pressure is sustained.

Monitor for hypertension if XADAGO is prescribed concomitantly with sympathomimetic medications, including prescription or nonprescription nasal, oral, and ophthalmic decongestants and cold remedies [see Drug Interactions (7.5)].

XADAGO is a selective inhibitor of MAO-B at the recommended dosages of 50 mg or 100 mg daily. Selectivity for inhibiting MAO-B decreases above the recommended daily dosages [see Clinical Pharmacology (12.2)]. Therefore, XADAGO should not be used at daily dosages exceeding those recommended because of the risks of hypertension, exacerbation of existing hypertension, or hypertensive crisis.

Dietary tyramine restriction is not required during treatment with recommended doses of XADAGO. However, use with certain foods that contain very high amounts (i.e., more than 150 mg) of tyramine could cause severe hypertension, resulting from an increased sensitivity to tyramine in patients taking recommended dosages of XADAGO, and patients should be advised to avoid such foods.

Isoniazid has some monoamine oxidase inhibiting activity. Monitor for hypertension and reaction to dietary tyramine in patients treated concomitantly with isoniazid and XADAGO [see Drug Interactions (7.1, 7.6)].

5.2 Serotonin Syndrome

The development of a potentially life-threatening serotonin syndrome has been reported in patients on concomitant treatment with MAO inhibitors (including selective MAO-B inhibitors), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, tetracyclic antidepressants, triazolopyridine antidepressants, cyclobenzaprine, opioid drugs (e.g., meperidine and meperidine derivatives, propoxyphene, tramadol), and methylphenidate, amphetamine, and their derivatives. Concomitant use of XADAGO with these drugs is contraindicated.

In clinical trials, serotonin syndrome was reported in a patient treated with XADAGO and an SSRI. Use the lowest effective dose of SSRIs in patients treated with concomitant XADAGO.

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

5.3 Falling Asleep During Activities of Daily Living

Patients treated with dopaminergic medications have reported falling asleep while engaged in activities of daily living, including the operation of motor vehicles, which sometimes has resulted in accidents. Patients may not perceive warning signs, such as excessive drowsiness, or they may report feeling alert immediately prior to the event.

In clinical studies, sleep attacks/sudden onset of sleep were reported in patients treated with XADAGO 100 mg/day.

If a patient develops daytime sleepiness or episodes of falling asleep during activities that require full attention (e.g., driving a motor vehicle, conversations, eating), XADAGO should ordinarily be discontinued. If a decision is made to continue these patients on XADAGO, advise them to avoid driving and other potentially dangerous activities.

5.4 Dyskinesia

XADAGO may cause dyskinesia or exacerbate pre-existing dyskinesia.

In clinical trials, the incidence of dyskinesia was 21% for XADAGO 50 mg, 18% for XADAGO 100 mg, and 9% for placebo. There was a greater incidence of dyskinesia causing study discontinuation in Parkinson’s disease patients treated with XADAGO 50 mg or 100 mg (1%), compared to placebo (0%) [see Adverse Reactions (6.1)].

Reducing the patient’s daily levodopa dosage or the dosage of another dopaminergic drug may mitigate dyskinesia.

5.5 Hallucinations / Psychotic Behavior

Patients with a major psychotic disorder should ordinarily not be treated with XADAGO because of the risk of exacerbating the psychosis with an increase in central dopaminergic tone. In addition, treatments for psychosis that antagonize the effects of dopaminergic medications may exacerbate the symptoms of Parkinson’s disease [see Drug Interactions (7.8)].

Consider dosage reduction or stopping the medication if a patient develops hallucinations or psychotic-like behaviors while taking XADAGO.

5.6 Impulse Control / Compulsive Behaviors

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 XADAGO, that increase central dopaminergic tone. In some cases, 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 XADAGO. Consider dose reduction or stopping the medication if a patient develops such urges while taking XADAGO.

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:

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 Parkinson’s Disease 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 Parkinson’s disease (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 Parkinson’s disease 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 of 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

XADAGO is contraindicated for use with other drugs in the MAO inhibitor 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 XADAGO with opioid drugs (e.g., meperidine and its derivatives, methadone, propoxyphene, or tramadol) and MAO inhibitors, 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.

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