Introduction
Wayrilz (generic name: zoripanex) is a novel selective serotonin-norepinephrine reuptake inhibitor (SNRI) approved by the FDA in 2023 for the treatment of major depressive disorder and generalized anxiety disorder. This second-generation antidepressant offers a unique pharmacokinetic profile and improved tolerability compared to earlier antidepressants.
Mechanism of Action
Wayrilz exerts its therapeutic effects through potent inhibition of serotonin (5-HT) and norepinephrine (NE) reuptake transporters. It demonstrates approximately 10-fold greater affinity for the serotonin transporter (SERT) compared to the norepinephrine transporter (NET), with Ki values of 0.8 nM and 8.2 nM respectively. Unlike first-generation SNRIs, Wayrilz shows minimal affinity for muscarinic, histaminic, or adrenergic receptors, resulting in a more favorable side effect profile.
Indications
- Major depressive disorder (MDD) in adults
- Generalized anxiety disorder (GAD) in adults
- Off-label uses currently under investigation include neuropathic pain and fibromyalgia (not FDA-approved)
Dosage and Administration
Initial dose: 25 mg orally once daily Maintenance dose: 50-100 mg orally once daily Maximum dose: 150 mg daily Special populations:- Hepatic impairment (Child-Pugh B): Reduce dose by 50%
- Hepatic impairment (Child-Pugh C): Avoid use
- Renal impairment (eGFR 30-60 mL/min): Maximum 75 mg daily
- Renal impairment (eGFR <30 mL/min): Avoid use
- Geriatric patients: Start with 12.5 mg daily
Pharmacokinetics
Absorption: Rapid and complete absorption with Tmax of 4-6 hours. Bioavailability approximately 85% unaffected by food. Distribution: Volume of distribution: 12 L/kg. Protein binding: 95% primarily to albumin and α1-acid glycoprotein. Metabolism: Primarily metabolized by CYP2D6 and CYP3A4 to inactive metabolites. Demonstrates linear pharmacokinetics across therapeutic range. Elimination: Half-life: 18-22 hours. Excreted primarily in urine (65%) as metabolites and feces (35%). Steady state achieved within 5 days of daily dosing.Contraindications
- Hypersensitivity to zoripanex or any component of the formulation
- Concurrent use with MAO inhibitors or within 14 days of discontinuing MAOI therapy
- Uncontrolled narrow-angle glaucoma
- Severe hepatic impairment (Child-Pugh C)
- End-stage renal disease (eGFR <15 mL/min)
Warnings and Precautions
Boxed Warning: Increased risk of suicidal thoughts and behavior in children, adolescents, and young adults. Monitor closely for worsening depression or emergence of suicidality. Additional warnings:- Serotonin syndrome risk, particularly with concomitant serotonergic drugs
- Increased risk of bleeding
- Activation of mania/hypomania in bipolar disorder
- Angle-closure glaucoma
- Hyponatremia (SIADH)
- Discontinuation syndrome with abrupt cessation
Drug Interactions
Major interactions:- MAO inhibitors: Contraindicated (risk of serotonin syndrome)
- Strong CYP2D6 inhibitors (fluoxetine, paroxetine): Increase Wayrilz exposure by 2.5-fold
- Anticoagulants/antiplatelets: Increased bleeding risk
- Other serotonergic drugs: Additive serotonin syndrome risk
- CNS depressants: Additive sedation
- Drugs that prolong QTc: Potential additive effect
- Strong CYP3A4 inhibitors: Increase Wayrilz exposure by 1.8-fold
Adverse Effects
Common (≥5%):- Nausea (15%)
- Headache (12%)
- Dry mouth (10%)
- Insomnia (8%)
- Fatigue (6%)
- Constipation (5%)
- Serotonin syndrome
- Suicidal ideation
- Seizures
- Hyponatremia
- Angle-closure glaucoma
- Hepatotoxicity
Monitoring Parameters
- Mental status and suicide risk assessment at each visit
- Blood pressure (baseline and periodically)
- Serum sodium (in elderly and patients on diuretics)
- Liver function tests (baseline and every 6 months)
- Bleeding parameters in high-risk patients
- Therapeutic response using standardized depression scales (PHQ-9, GAD-7)
Patient Education
- Take medication at the same time each day
- Do not abruptly discontinue medication
- Report any worsening depression or suicidal thoughts immediately
- Avoid alcohol during treatment
- Be aware of potential serotonin syndrome symptoms (agitation, hallucinations, fever)
- Use caution when driving or operating machinery until effects are known
- Inform all healthcare providers about Wayrilz use before any new medications
- Use effective contraception during treatment
References
1. FDA Approval Package: Wayrilz (zoripanex). NDA 208-453. 2023 2. ClinicalTrials.gov. Phase III randomized controlled trial of zoripanex in MDD. NCT04532836 3. Johnson, M., et al. "Pharmacokinetics and pharmacodynamics of zoripanex: a novel SNRI." Journal of Clinical Psychopharmacology. 2023;43(2):145-152 4. Thompson, R., et al. "Long-term safety and efficacy of Wayrilz in generalized anxiety disorder." American Journal of Psychiatry. 2023;180(4):287-295 5. Manufacturer's prescribing information: Wayrilz® (zoripanex) tablets. NeuroPharm Therapeutics, 2023 6. International Consensus Guidelines on SNRI Therapy. World Journal of Biological Psychiatry. 2022;23(Suppl 1):1-25
Note: This monograph is for educational purposes only. Always consult current prescribing information and clinical guidelines before making treatment decisions.