PONVORY
Clinical safety rating: caution
Comprehensive clinical and safety monograph for PONVORY (PONVORY).
Sphingosine 1-phosphate receptor modulator; binds to S1P receptors 1, 3, 4, and 5, blocking lymphocyte egress from lymphoid tissues, reducing peripheral blood lymphocyte count.
| Metabolism | Primarily metabolized by CYP3A4 and to a lesser extent by CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP2J2. |
| Excretion | Primarily metabolized via CYP3A4; elimination mainly as metabolites in feces (85-90%) and urine (<1% unchanged). |
| Half-life | Terminal half-life is approximately 11 days (range 8-15 days), supporting once-daily dosing with steady-state reached in about 6-8 weeks. |
| Protein binding | Bound to albumin (~99.7%) and to a lesser extent to α1-acid glycoprotein. |
| Volume of Distribution | Vd ~530 L (approximately 7.6 L/kg for a 70 kg individual); indicates extensive tissue distribution, including into the central nervous system. |
| Bioavailability | Oral bioavailability is approximately 93% (range 81-102%), with no significant food effect. |
| Onset of Action | Oral: Onset of immunosuppression occurs within 2-4 weeks; maximal lymphocyte sequestration achieved at steady-state concentrations. |
| Duration of Action | Duration of immunosuppression persists for up to 6 weeks after discontinuation due to slow elimination; lymphocyte counts recover in approximately 4 weeks. |
0.5 mg orally once daily, starting with a 7-day titration: Days 1-4: 0.25 mg once daily; Days 5-7: 0.5 mg once daily. Maintenance: 0.5 mg once daily thereafter.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment (eGFR ≥30 mL/min/1.73 m²). For severe renal impairment (eGFR <30 mL/min/1.73 m²), the recommended dose is 0.25 mg orally once daily without titration. Not recommended in patients receiving dialysis. |
| Liver impairment | Child-Pugh Class A: No dose adjustment. Child-Pugh Class B: The recommended dose is 0.25 mg orally once daily without titration. Child-Pugh Class C: Not recommended. |
| Pediatric use | Safety and efficacy in pediatric patients (<18 years) have not been established; no recommended dosing. |
| Geriatric use | No specific dose adjustment required for elderly patients (≥65 years) based on age alone. Monitor for adverse effects, as clinical studies did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for PONVORY (PONVORY).
| Breastfeeding | It is unknown whether ponesimod is excreted in human milk. The M/P ratio is not available. Due to potential for serious adverse reactions in nursing infants, breastfeeding is not recommended during treatment and for 1 week after the last dose. |
| Teratogenic Risk | PONVORY (ponesimod) is contraindicated in pregnancy. Based on animal studies, there is evidence of fetal harm including increased fetal mortality, skeletal abnormalities, and decreased fetal body weight. In humans, the risk is unknown but S1P receptor modulators as a class are associated with teratogenicity. Effective contraception is required during treatment and for 1 week after discontinuation. |
■ FDA Black Box Warning
Increased risk of infections, including fatal opportunistic infections; bradyarrhythmia and atrioventricular blocks after initiation; fetal risk; risk of varicella zoster virus reactivation; risk of posterior reversible encephalopathy syndrome (PRES); risk of macular edema.
| Serious Effects |
Within the last 6 months: myocardial infarction, unstable angina, stroke, TIA, decompensated heart failure, NYHA class III/IV heart failure; history of Mobitz type II second-degree or third-degree AV block, sick sinus syndrome, or sinoatrial block unless pacemaker; severe untreated sleep apnea; concurrent use of class Ia or III antiarrhythmics; hypersensitivity to ozanimod or any excipient.
| Precautions | Monitor for bradyarrhythmia after first dose; risk of infections, including herpes zoster; PML; PRES; macular edema; elevated liver enzymes; respiratory effects; fetal harm; immune system effects; prior use of immunosuppressants; avoid live vaccines. |
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| Fetal Monitoring | For women of childbearing potential, confirm negative pregnancy test before initiation. Monitor for bradycardia at treatment initiation. During pregnancy, if exposure occurs, perform fetal ultrasound and monitor fetal growth. Monitor liver function tests and blood pressure regularly, as pregnancy may exacerbate these effects. |
| Fertility Effects | In animal studies, ponesimod did not affect male or female fertility at doses up to 6 times the MRHD (maximum recommended human dose). However, as a class, S1P receptor modulators may impair fertility; clinical data in humans are lacking. |