Safinamide Mesylate

• Idiopathic Parkinson’s Disease (PD):
  Safinamide is approved as an adjunctive therapy to levodopa/carbidopa in patients with mid- to late-stage Parkinson’s disease experiencing motor fluctuations ("wearing-off" phenomena).
• Motor Fluctuations in PD:
  Indicated specifically for reducing "off" time without worsening dyskinesia.
• Off-label Uses (Clinically Accepted):
  Some clinicians may consider safinamide for managing PD symptoms in early-stage patients or as adjunct therapy with dopamine agonists, but this is not universally approved.

• Adults with Parkinson’s Disease:
• Initial dose: 50 mg orally once daily.
• May increase to 100 mg once daily after 2 weeks based on clinical response and tolerability.
• Administration:
• Oral tablets, taken with or without food.
• Tablets should be swallowed whole, not crushed or chewed.
• Special Populations:
• Elderly: No dosage adjustment necessary, but monitor for adverse effects.
• Renal Impairment: No dose adjustment required for mild to moderate impairment; use cautiously in severe renal impairment due to limited data.
• Hepatic Impairment: Contraindicated in severe hepatic impairment. Use with caution in mild to moderate impairment.
• Duration:
• Long-term daily use as prescribed; efficacy and safety established up to 2 years in trials.

Safinamide is a selective and reversible monoamine oxidase B (MAO-B) inhibitor. It increases synaptic dopamine availability by inhibiting MAO-B–mediated dopamine breakdown in the brain. Additionally, safinamide modulates glutamate release through voltage-dependent sodium and calcium channel inhibition, contributing to its neuroprotective and anti-glutamatergic effects. This dual action improves motor symptoms and reduces "off" time in Parkinson’s disease.

• Absorption:
  Rapidly absorbed after oral administration, with peak plasma concentrations reached in approximately 2–4 hours.
• Bioavailability:
  Oral bioavailability is high (above 95%), unaffected significantly by food.
• Distribution:
  Moderate volume of distribution; binds approximately 88% to plasma proteins.
• Metabolism:
  Metabolized mainly via oxidative pathways involving CYP450 enzymes (primarily CYP3A4 and CYP2C9), producing inactive metabolites.
• Elimination:
  Excreted primarily via urine (~76%) and feces (~20%), mostly as metabolites.
• Half-life:
  Elimination half-life ranges from 20 to 26 hours, supporting once-daily dosing.

• Pregnancy:
  Classified as FDA Pregnancy Category C. Animal studies have shown adverse effects on the fetus at high doses; no adequate and well-controlled studies in pregnant women exist. Safinamide should only be used if the potential benefit justifies the potential risk.
• Lactation:
  It is unknown whether safinamide is excreted in human breast milk. Due to potential risks to the nursing infant, breastfeeding is generally not recommended during treatment.
• Caution:
  Use with caution in women of childbearing potential; advise contraception.

• Primary Therapeutic Class:
  Selective reversible Monoamine Oxidase B (MAO-B) inhibitor.
• Subclass:
  Dopaminergic antiparkinsonian agent with additional antiglutamatergic properties.

• Known hypersensitivity to safinamide or any excipients.
• Concurrent use of other MAO inhibitors or serotonergic drugs that increase the risk of serotonin syndrome.
• Severe hepatic impairment (Child-Pugh C).
• Concomitant use with opioid analgesics such as pethidine (meperidine).
• History of hypertensive crisis related to MAO inhibitors.

• Serotonin Syndrome Risk:
  Increased risk when combined with serotonergic agents (SSRIs, SNRIs, tricyclic antidepressants). Monitor for symptoms such as agitation, hallucinations, rapid heartbeat, and hyperthermia.
• Hypertensive Crisis:
  Avoid tyramine-rich foods and sympathomimetic agents to prevent hypertensive episodes.
• Dyskinesia:
  May exacerbate dyskinesia; monitor motor symptoms closely.
• Impulse Control Disorders:
  Patients should be monitored for compulsive behaviors (e.g., gambling, hypersexuality).
• Liver Function:
  Monitor liver enzymes periodically due to rare hepatotoxicity reports.
• High-Risk Groups:
  Caution in patients with cardiovascular disease, psychiatric disorders, or renal impairment.

• Common Adverse Effects:
• Dyskinesia
• Nausea
• Insomnia
• Falls
• Headache
• Hypertension
• Serious Adverse Effects (Rare):
• Serotonin syndrome
• Hypertensive crisis
• Severe skin reactions (e.g., rash, urticaria)
• Hepatotoxicity
• Onset:
  Side effects may occur within days to weeks of therapy initiation.

• Major Interactions:
• Other MAO inhibitors: Risk of hypertensive crisis and serotonin syndrome; contraindicated.
• Serotonergic drugs (SSRIs, SNRIs, TCAs, tramadol): Risk of serotonin syndrome; use caution.
• Sympathomimetic agents: Increased risk of hypertensive crisis.
• Dopaminergic agents: May increase dyskinesia risk.
• CYP3A4 inhibitors (e.g., ketoconazole): May increase safinamide plasma levels; monitor.
• CYP3A4 inducers (e.g., rifampin): May decrease safinamide levels; efficacy reduction possible.
• Food Interactions:
  Avoid high-tyramine foods (aged cheeses, cured meats, fermented products) to reduce hypertensive crisis risk.
• Alcohol:
  No direct interaction but caution advised due to CNS effects.

• Recent Parkinson’s disease treatment guidelines from EMA and other regulatory bodies continue to endorse safinamide as an effective adjunct for managing motor fluctuations.
• No major changes in approved indications or dosing in the last 2 years.
• Ongoing research highlights the potential neuroprotective benefits linked to antiglutamatergic action, but clinical recommendations have not yet incorporated this.
• Safety warnings emphasize serotonin syndrome risk due to wider use with antidepressants in PD patients.

• Store at controlled room temperature: 20°C to 25°C (68°F to 77°F).
• Protect from moisture and light.
• Keep tablets in the original blister packaging until use.
• Do not freeze.
• Keep out of reach of children.
• No special reconstitution or refrigeration required.