Safinamide

Usage

• Safinamide is prescribed as an add-on treatment to levodopa/carbidopa for Parkinson’s disease patients experiencing “off” episodes (periods when the medication’s effects wear off). It is indicated for patients with mid- to late-stage Parkinson’s disease experiencing motor fluctuations. It has shown efficacy in improving motor control and reducing “off” time in these patients. It is not indicated as monotherapy.
• Pharmacological Classification: Monoamine oxidase B (MAO-B) inhibitor, also possessing non-dopaminergic properties like glutamate release inhibition.
• Mechanism of Action: Safinamide primarily works by reversibly inhibiting MAO-B, an enzyme that breaks down dopamine in the brain. This action increases dopamine levels, which helps to control motor symptoms. Additionally, safinamide modulates glutamate release through its effects on sodium and calcium channels, further contributing to its therapeutic benefits.

Alternate Names

• International Nonproprietary Name (INN): Safinamide
• Brand Names: Xadago, Pronstryv

How It Works

• Pharmacodynamics: Safinamide primarily and reversibly inhibits MAO-B, leading to increased dopamine availability in the brain. It also blocks voltage-gated sodium channels and reduces abnormal glutamate release, contributing to motor symptom control.
• Pharmacokinetics:
  • Absorption: Rapidly absorbed after oral administration, with peak plasma concentrations (Cmax) reached within 2-4 hours under fasting conditions. Food intake slightly delays Tmax but does not affect overall absorption.
  • Metabolism: Extensively metabolized primarily via N-dealkylation, forming inactive metabolites. Does not significantly induce or inhibit major CYP450 enzymes (CYP2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A3/5) at clinically relevant concentrations.
  • Elimination: Primarily eliminated through the kidneys (approximately 76%), mainly as inactive metabolites. Only a small percentage (approximately 5%) is excreted unchanged in the urine. The elimination half-life is approximately 20-26 hours, allowing for once-daily dosing.
• Mode of Action: Inhibits MAO-B enzyme, thus increasing dopamine concentration in the synaptic cleft. Also blocks sodium and calcium channels reducing glutamate release.
• Receptor Binding/Enzyme Inhibition/Neurotransmitter Modulation: MAO-B enzyme inhibition, modulation of sodium and calcium channels influencing glutamate release.

Dosage

Standard Dosage

Adults:

• Initial Dose: 50 mg orally once daily.
• Maintenance Dose: After two weeks, the dose may be increased to 100 mg orally once daily, based on individual patient response and tolerability. Doses above 100 mg have not demonstrated additional benefit and increase the risk of adverse reactions.

Children:

• The safety and efficacy of safinamide have not been established in children under 18 years of age.

Special Cases:

• Elderly Patients: No dose adjustment is typically necessary; however, clinical experience in patients older than 75 is limited.
• Patients with Renal Impairment: No dose adjustment required.
• Patients with Hepatic Dysfunction:
  • Mild impairment: No dose adjustment required.
  • Moderate impairment (Child-Pugh B): Maximum dose is 50 mg once daily.
  • Severe impairment (Child-Pugh C): Contraindicated.
• Patients with Comorbid Conditions: Caution and careful monitoring are advised in patients with cardiovascular disease, psychosis, or a history of impulse control disorders.

Clinical Use Cases

Safinamide is specifically indicated as add-on therapy to levodopa/carbidopa for Parkinson’s disease with motor fluctuations. It is not indicated for use in intubation, surgical procedures, mechanical ventilation, intensive care, or emergency situations like status epilepticus or cardiac arrest.

Dosage Adjustments

Dose adjustment may be necessary in moderate hepatic impairment or when specific drug interactions are present.

Side Effects

Common Side Effects:

Dyskinesia (involuntary movements), falls, nausea, insomnia, dizziness (especially orthostatic hypotension), anxiety, cough, heartburn/indigestion, blurred vision, headache, nervousness, palpitations, and tachycardia.

Rare but Serious Side Effects:

Hallucinations, psychotic behavior, impulse control disorders (pathological gambling, increased libido, compulsive spending), serotonin syndrome (when combined with certain medications), withdrawal-emergent hyperpyrexia and confusion (upon abrupt discontinuation), retinal disorders (in patients with pre-existing conditions), and angioedema.

Long-Term Effects:

Potential long-term side effects are not fully established. Regular monitoring for vision changes and impulse control disorders is recommended.

Adverse Drug Reactions (ADR):

Angioedema, serotonin syndrome, hypertensive crisis (with MAOIs), and withdrawal syndrome (hyperpyrexia and confusion) require immediate medical intervention.

Contraindications

• Hypersensitivity to safinamide.
• Severe hepatic impairment (Child-Pugh C).
• Concomitant use of MAO inhibitors (including linezolid), pethidine, dextromethorphan, selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), tetracyclic antidepressants, triazolopyridine antidepressants, cyclobenzaprine, St. John’s wort, methylphenidate, amphetamines, and related derivatives.
• Patients with albinism, retinal degeneration, uveitis, inherited retinopathy, or severe progressive diabetic retinopathy.

Drug Interactions

• MAOIs: Concurrent use is contraindicated due to the risk of hypertensive crisis. At least 14 days should elapse between discontinuing safinamide and starting MAOIs.
• Opioids (e.g., pethidine, tramadol, meperidine): Concomitant use is contraindicated due to the risk of serotonin syndrome.
• Serotonergic Drugs (e.g., SSRIs, SNRIs, TCAs): Concurrent use is contraindicated due to the risk of serotonin syndrome. At least 14 days should elapse between discontinuing these medications and initiating safinamide. Monitor for serotonin syndrome if co-administration with SSRIs is necessary.
• Dextromethorphan: Concurrent use is contraindicated due to the risk of psychosis and bizarre behavior.
• Isoniazid: Monitor for hypertension and tyramine reaction due to isoniazid’s MAO inhibiting activity.
• Tyramine-Containing Foods: Patients should avoid foods high in tyramine (e.g., aged cheese, pickled herring) due to the risk of hypertensive crisis, especially at higher doses of safinamide.
• CYP450 Substrates: No clinically significant interactions with CYP1A2 and CYP3A4 substrates have been observed.
• BCRP Substrates (e.g., rosuvastatin, pravastatin, ciprofloxacin): Monitor for potential increased exposure to these substrates.
• OCT1 Substrates (e.g., metformin, aciclovir): Monitor for potential increased exposure to these substrates.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: C (US FDA). Not recommended during pregnancy due to observed teratogenicity in animal studies. Developmental toxicity was observed at clinically relevant doses and at even lower doses when co-administered with levodopa/carbidopa.
• Breastfeeding: Safinamide is expected to be present in breast milk. It is not recommended during breastfeeding due to the risk of potential adverse effects on the nursing infant, including liver toxicity observed in animal studies.

Drug Profile Summary

• Mechanism of Action: Reversible MAO-B inhibitor, also inhibits glutamate release.
• Side Effects: Dyskinesia, falls, nausea, insomnia, dizziness, hallucinations, psychosis, impulse control disorders, serotonin syndrome (with co-administration of contraindicated drugs).
• Contraindications: Severe hepatic impairment, concomitant use of MAOIs, pethidine, dextromethorphan, serotonergic drugs, retinal disorders.
• Drug Interactions: MAOIs, opioids, serotonergic drugs, dextromethorphan, isoniazid, tyramine-containing foods.
• Pregnancy & Breastfeeding: Not recommended.
• Dosage: 50-100 mg orally once daily.
• Monitoring Parameters: Blood pressure, liver function tests, signs of dyskinesia, impulse control disorders, psychosis, serotonin syndrome, vision changes.

Popular Combinations

Safinamide is typically used in combination with levodopa/carbidopa. Other combinations may be used depending on the patient’s individual needs, however, under strict considerations of potential drug interactions.

Precautions

• General Precautions: Assess for pre-existing hepatic or renal impairment, psychiatric conditions, and retinal disorders. Monitor for blood pressure changes, impulse control issues, and vision changes.
• Specific Populations:
  • Pregnant Women: Avoid use due to risk of fetal harm. Advise effective contraception.
  • Breastfeeding Mothers: Avoid use.
  • Children & Elderly: Not recommended in children; caution in elderly over 75 years old.
  • Menstruating Individuals: No specific precautions.
• Lifestyle Considerations: Advise patients against operating machinery or driving until the effects on alertness are known. Alcohol consumption should be moderated. Counsel patients regarding dietary restrictions (tyramine-containing foods). Safinamide may also induce compulsive behaviours such as gambling and hypersexuality.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Safinamide?

A: Initial dose: 50 mg orally once daily. After two weeks, the dose can be increased to 100 mg orally once daily based on response and tolerability.

Q2: Can Safinamide be used alone to treat Parkinson’s Disease?

A: No, Safinamide is only indicated as add-on therapy to levodopa/carbidopa and has not been shown to be effective as monotherapy.

Q3: What are the most serious side effects of Safinamide?

A: Serious side effects may include hallucinations, psychosis, impulse control disorders, serotonin syndrome (when combined with certain medications), and withdrawal-emergent hyperpyrexia and confusion (upon abrupt discontinuation).

Q4: What medications should be avoided while taking Safinamide?

A: MAOIs (including linezolid), opioids, certain antidepressants (SSRIs, SNRIs, TCAs), dextromethorphan, St. John’s wort, amphetamines, methylphenidate, and pethidine.

Q5: Can Safinamide be used in patients with liver problems?

A: Safinamide is contraindicated in severe hepatic impairment (Child-Pugh C). Dose adjustment is needed for moderate hepatic impairment.

Q6: Is Safinamide safe during pregnancy or breastfeeding?

A: Safinamide is not recommended for use during pregnancy or breastfeeding due to potential risks to the fetus or infant.

Q7: What should patients be advised regarding their diet while taking Safinamide?

A: Patients should avoid foods high in tyramine (e.g., aged cheese, pickled herring, cured meats) to prevent a hypertensive crisis.

Q8: What should be done if a dose of Safinamide is missed?

A: Skip the missed dose and take the next dose at the usual time. Do not double the dose.

Q9: How should Safinamide be discontinued?

A: To avoid withdrawal symptoms, taper the dose from 100 mg to 50 mg daily for one week before completely stopping.

Q10: Does safinamide interact with levodopa/carbidopa?

A: There are no known clinically significant pharmacokinetic interactions between safinamide and levodopa/carbidopa. Safinamide is specifically indicated for use as an adjunct to levodopa/carbidopa in Parkinson’s disease. However, it should be noted that in animal studies, the combination resulted in increased developmental toxicity at lower doses. Close monitoring is advised.