Quick Facts

• Primary Use: Adjunctive treatment for motor symptoms in Parkinson’s disease.
• Therapeutic Scope: Managing “off” episodes that occur during levodopa/carbidopa therapy.
• Reported Benefit: Supports an increase in the duration of “on” time (when symptoms are controlled).

---

Xadago is approved for use in adults with Parkinson's disease (PD) who are experiencing episodes of symptom return, often referred to as “off” episodes. This medication is exclusively indicated as an adjunctive treatment, meaning it is administered in combination with levodopa/carbidopa therapy. It is not approved for use as a stand-alone treatment.

Its use provides support for the existing therapeutic regimen by helping to manage motor fluctuations. When added to levodopa/carbidopa, Xadago may support an increase in the amount of daily “on” time, which corresponds to periods when PD symptoms are adequately managed. This may be accompanied by a corresponding decrease in the time spent in the “off” state, thereby assisting in the maintenance of symptom control throughout the day.

Eligibility and Contraindications

Xadago is officially designated for use only in adult patients (aged 18 and older) diagnosed with idiopathic Parkinson's disease who are experiencing motor fluctuations, commonly known as “off” episodes. The medicine is exclusively approved as an adjunctive treatment to be used alongside levodopa/carbidopa, and not as a standalone therapy.

---

Population Status	Eligibility Restriction
Absolute Contraindication	Patients with severe hepatic impairment (Child-Pugh C) or known hypersensitivity to safinamide must not use Xadago.
Condition-Based Ban	Contraindicated in patients with certain severe eye disorders, including albinism, retinal degeneration, and severe progressive diabetic retinopathy.
Concomitant Drug Ban	Prohibited for use with any other MAO inhibitors, specific antidepressants (e.g., SNRIs, tricyclics), opioids (e.g., pethidine), and dextromethorphan.
Conditional Use	Patients with moderate hepatic impairment (Child-Pugh B) are restricted to a maximum daily dose of 50 mg.
Life Stage / Age	Use is not recommended during pregnancy or lactation. Safety and effectiveness have not been established in pediatric patients (under 18 years).

The interaction profile for safinamide is primarily determined by its selective Monoamine Oxidase B (MAO-B) inhibitory activity, which necessitates strict prohibitions against co-administration with other medicines that could increase monoamine or serotonin levels.

Contraindicated Combinations

Co-administration with safinamide is strictly prohibited for several classes of medications due to the risk of severe pharmacodynamic reactions like hypertensive crisis or serotonin syndrome. These contraindicated medicines include:

• Non-selective MAO Inhibitors and other potent MAO inhibitors (e.g., Linezolid).
• Opioid Drugs (including Tramadol and Meperidine).
• Antidepressants such as Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) and specific Tricyclic/Tetracyclic types.
• Sympathomimetics (including Methylphenidate and Amphetamine derivatives).
• The herbal product St John's wort and the cough suppressant Dextromethorphan.

A mandatory washout period of at least 14 days is required when transitioning between safinamide and any of these contraindicated agents.

Other Documented Interactions

Safinamide and its major metabolite are documented to inhibit the intestinal BCRP transporter. This transporter-mediated interaction may lead to an increase in the plasma concentration of co-administered BCRP substrates, such as Rosuvastatin. Official regulatory labeling also requires monitoring when safinamide is used concurrently with Selective Serotonin Reuptake Inhibitors (SSRIs) or over-the-counter sympathomimetic drugs. Furthermore, patients must avoid consumption of foods containing very high levels of tyramine (greater than 150 mg) due to the risk of a severe increase in blood pressure. Safinamide is contraindicated in patients with severe hepatic impairment.

Xadago, which is safinamide, exerts its action through dual mechanistic pathways. Its primary dopaminergic action is as a selective and reversible inhibitor of the enzyme monoamine oxidase B (MAO-B), primarily located in glial cells. The inhibition of MAO-B reduces the catabolism of the neurotransmitter dopamine in the central nervous system, particularly within the striatum. This inhibition increases the local extracellular concentration and availability of dopamine, thereby modulating dopaminergic signaling.

Simultaneously, safinamide possesses a non-dopaminergic action by modulating the excitatory glutamatergic system. This interaction involves the concentration- and state-dependent blockade of voltage-gated sodium (Na^+) channels and subsequent modulation of voltage-gated calcium (Ca^2+) channels on presynaptic nerve terminals. This channel blockade decreases the stimulated release of the excitatory neurotransmitter glutamate from these terminals. The intracellular consequence is a stabilization of neuronal membrane excitability. The system-level physiological outcome is the modulation of neurotransmission involving both the dopaminergic and glutamatergic systems.

How Xadago is Used

This section explains the general principles and guidelines for the administration and dosing of Xadago (safinamide mesylate).

---

Administration and Dosage Protocol

Xadago is administered exclusively via the oral route as a film-coated tablet and is prescribed for once daily use. The tablets are available in two strengths: 50 mg and 100 mg.

Patients can take the tablet with or without food, but it must be swallowed whole and not crushed, chewed, or divided. The once-daily dose should be taken at the same time each day.

---

Standard Dosing and Adjustment

Treatment is initiated with a required starting dose of 50 mg once a day. This is the only established initial dose. The maximum recommended dose is 100 mg once daily.

The established usage pattern allows for a dose adjustment from 50 mg to 100 mg if needed for improved motor control. However, this adjustment, or titration, must not occur until the patient has completed a minimum of two weeks of treatment at the 50 mg level.

If a dose is missed, patients should not double the dose to compensate. Instead, the next scheduled dose should be taken at the usual time the following day.

---

Special Procedural Constraints

• Hepatic Impairment: For patients diagnosed with moderate liver impairment, the maximum recommended daily dose is restricted to 50 mg. No dose adjustment is required for mild liver impairment or for any degree of renal impairment.
• Discontinuation: If the 100 mg dose is being discontinued, the procedure requires that the dose first be reduced to 50 mg daily for one week before treatment is completely stopped.

This medication is used as a continuous, long-term adjunctive therapy and has no defined cycle or short-course duration.

Research Evidence / Overview of Studies for Xadago

---

Evidence for Use in Mid-to-Late Stage Parkinson's Disease with Motor Fluctuations

The research that led to the evaluation of Xadago for use as an add-on treatment for motor fluctuations is based on large-scale, international, short-term randomized controlled trials (RCTs) that typically ran for six months. These studies, which included over a thousand adult patients with mid-to-late stage Parkinson's disease already taking levodopa, was studied for its use alongside existing therapy. These trials were designed to be double-blind and placebo-controlled, meaning neither patients nor researchers knew who received the active medicine. This design is used in research to evaluate the patterns observed when comparing the active treatment to placebo.

The primary outcome that researchers focused on was the change in daily "On" time (periods when movement symptoms are adequately controlled) without troublesome dyskinesia, as recorded by patient diaries. Secondary measures used in research exploring how symptoms change over time included the corresponding change in daily "Off" time, and scores from standardized scales that measure motor function during the "On" phase.

Analyses of these six-month studies reported that, compared to the placebo group, the active treatment group had measured differences in daily "On" time and daily "Off" time. These findings describe group patterns observed in the studies and highlight changes measured during the short study period. Researchers also monitored outcomes related to the patients' overall quality of life and self-reported daily activities.

---

Research on Non-Motor Symptoms and Quality of Life

Research has also explored the effect of Xadago on outcomes related to systemic or functional imbalance commonly experienced by patients, which are known as non-motor symptoms (NMS). This evidence is primarily derived from post-hoc analyses—secondary studies of data collected in the main RCTs—and from prospective, observational studies conducted in real-world settings.

The research for these non-motor outcomes often uses designs that provide less definitive insights compared to the core motor outcomes, because these symptoms were not the primary focus of the large controlled studies.

---

Long-Term Data and Maintenance of Measured Outcomes

Research into the effects of Xadago extends beyond the initial six-month period. Several long-term, double-blind extension studies of the main RCTs were conducted, tracking outcomes for up to 24 months (two years). The data from these extended observation periods reported that the measured differences in "On" and "Off" time were generally observed to be maintained for up to two years. Researchers also continued to monitor overall motor function and aspects of patient-reported emotional well-being over this extended duration.

---

Known Research Gaps and Uncertainties

The research base that was studied for the medicine’s approved use, the broader research landscape still has defined limitations. Comparative evidence is lacking for direct, head-to-head clinical trials that contrast Xadago against other commonly used adjunctive therapies (such as other MAO-B inhibitors).

Furthermore, while the controlled data supports outcomes up to two years, long-term effects are not fully established beyond that time frame. The evidence for some non-motor symptom outcomes is less certain because those findings are derived mainly from post-hoc research, where the studies were not originally designed to measure those specific changes as a primary goal.

Common questions about Xadago (FAQ)

Q: Is Xadago meant to address both the motor and non-motor symptoms of Parkinson's disease?

Xadago is officially indicated only as an add-on treatment for adult patients with Parkinson’s disease who are experiencing motor fluctuations, or "off" periods. Studies and official information indicate that researchers also monitored outcomes related to non-motor symptoms. However, management of non-motor symptoms is not the primary approved purpose of the medicine.

Q: Are there any special warnings about taking Xadago if a person has a history of high blood pressure?

According to regulatory documents, Xadago may cause or worsen high blood pressure (hypertension). For this reason, official product information describes a requirement for monitoring new-onset or inadequately controlled high blood pressure after treatment begins.

Q: Is Xadago suitable for use by older adults (e.g., over the age of 75) with Parkinson's disease?

Official prescribing information indicates that a dosage adjustment is typically not required for elderly patients. However, some regulatory labels note that the documented experience of use in patients over 75 years of age may be limited.

Q: Are there any specific medical conditions, besides Parkinson's, that Xadago is used to treat?

Xadago is approved for a very specific use: as an add-on therapy for adult patients with Parkinson's disease who are experiencing motor fluctuations. Regulatory documents state that it is not approved or indicated for use in any other medical condition.

Q: What is the difference in action between Xadago and other common MAO-B inhibitors like rasagiline?

The active ingredient in Xadago is described as having a unique, dual mechanism of action. Like some other drugs, it works as a selective MAO-B inhibitor to increase the availability of dopamine. Additionally, official regulatory documents note that it also has a non-dopaminergic action by modulating specific signals for the excitatory neurotransmitter glutamate.

Q: What kind of research has been done on Xadago's effects on dyskinesia?

The most common adverse reaction reported in clinical trials was dyskinesia, which means uncontrolled, involuntary movements. The official label describes that if dyskinesia is caused or made worse by Xadago, a reduction in the patient's daily levodopa dosage may be considered.

Q: Why is Xadago treatment generally not recommended for patients with a severe mental health history?

Official product information notes that Xadago can cause or worsen hallucinations and other psychotic behaviors. The drug label states that the medicine is generally not recommended for patients with a history of a major psychotic disorder due to the risk of exacerbating psychosis. Additionally, regulatory documents state that the medicine may also cause impulse control or compulsive behaviors.

Q: What are the less common, but reported, serious adverse reactions of Xadago?

The drug's labeling documents several serious safety concerns. These include the potential risk for Serotonin Syndrome and Hypertensive Crisis, which are severe reactions with other specific drugs. Other documented risks include falling asleep during daily activities, hallucinations or psychotic behavior, and the potential for retinal pathology.

Q: How long after starting treatment can a person expect to see the effects of Xadago?

Studies cited in regulatory documents indicated that the onset of improvement in motor fluctuations occurred early in treatment. The medicine's concentration in the body typically reaches a steady-state in approximately one week.

Q: Can Xadago increase the risk of unusual urges or compulsive behaviors?

Official product information states that patients can experience impulse control or compulsive behaviors while taking Xadago. These behaviors may include things like pathological gambling, increased urges, or hypersexuality.

Q: What are the general signs of Serotonin Syndrome to be aware of while taking Xadago?

Serotonin Syndrome is a serious condition that may occur when Xadago is combined with specific medicines. Symptoms listed in regulatory documents may include: agitation, hallucinations, changes in mental status, problems controlling movements or muscle twitching, or diarrhea. Other signs may include sweating, fever, or fast heartbeat.

Q: Is Xadago available as a generic version, or is it only sold under the brand name?

Xadago is the brand name for the active ingredient, which is safinamide mesylate. Regulatory records indicate that the FDA has approved generic versions of safinamide mesylate tablets.

Q: Is it true that Xadago may help some patients reduce their levodopa dosage?

Official regulatory labeling notes that if uncontrolled, involuntary movements (dyskinesia) develop or worsen due to Xadago, then the official label describes that reducing the patient's daily levodopa dosage may be considered.

Q: Are there any known interactions between Xadago and alcohol consumption?

Official patient information states that using Xadago together with alcohol may increase certain central nervous system side effects. These can include increased dizziness, drowsiness, confusion, and difficulty concentrating.

Q: Are changes in mood or anxiety levels commonly reported by users of Xadago?

Regulatory documents report that anxiety was an adverse reaction observed in clinical trials. It was reported to occur in 2% of patients taking both the 50 mg and 100 mg doses of the medicine.

Q: Is there a reported connection between Xadago and problems like constipation or diarrhea?

Diarrhea is listed in regulatory documents as a potential symptom of the serious condition, Serotonin Syndrome, which is a risk when Xadago is taken alongside certain other medications.

Q: What kind of monitoring (e.g., eye exams) is recommended while taking Xadago?

Regulatory documents state that Xadago is contraindicated for patients with certain severe eye disorders. Additionally, regulatory documents describe that patients with a history of specific retinal or macular conditions are generally monitored for visual changes while taking the medicine.

Xadago (safinamide) tablets must be stored according to official regulatory conditions to maintain their stability.

Storage Requirements

Condition	Requirement
Temperature	Store at controlled room temperature, 20 C to 25 C (68 F to 77 F). Brief excursions between 15 C and 30 C are permitted.
Protection	Keep in the original container and keep the container tightly closed. Store away from moisture, excess heat, and freezing.
Child Safety	The medicine must be stored out of the reach of children.

Disposal Instructions

Unused or expired Xadago must be handled according to official pharmaceutical waste guidelines. Do not dispose of the tablets by flushing them down a toilet or throwing them into household wastewater. The preferred method for discarding unused medicine is using a drug take-back program or following local government instructions for household trash disposal.