VOYDEYA
Clinical safety rating: caution
Comprehensive clinical and safety monograph for VOYDEYA (VOYDEYA).
VOYDEYA (zonisamide) is a sulfonamide anticonvulsant that blocks voltage-sensitive sodium and calcium channels, thereby stabilizing neuronal membranes and reducing repetitive neuronal firing. It also exhibits weak carbonic anhydrase inhibitory activity.
| Metabolism | Zonisamide is metabolized primarily by CYP3A4, with minor contributions from CYP2C19, CYP2C9, and CYP2A6. It undergoes acetylation and glucuronidation. It does not inhibit or induce major CYP enzymes at therapeutic concentrations. |
| Excretion | Primarily eliminated via renal excretion (approx. 80% as unchanged drug) and biliary/fecal excretion (approx. 15-20% as metabolites). Less than 2% recovered in feces as parent drug. |
| Half-life | Terminal elimination half-life is approximately 12-15 hours in healthy adults. In patients with moderate hepatic impairment, half-life may extend to 20-25 hours, requiring dose adjustment. |
| Protein binding | Approximately 94-97% bound to plasma proteins, primarily albumin and alpha-1-acid glycoprotein. Binding is saturable at high drug concentrations. |
| Volume of Distribution | Apparent volume of distribution is 0.25-0.35 L/kg (approximately 18-25 L in a 70 kg adult), indicating distribution primarily in extracellular fluid and limited tissue binding. |
| Bioavailability | Oral bioavailability is approximately 70-80% following administration with food. Absorption is reduced by about 50% if taken with calcium-containing products or antacids. Concomitant administration with high-fat meals increases absorption by 15-20%. |
| Onset of Action | Oral: Therapeutic effect (reduction in serum phosphate) typically observed within 2-4 hours after a single dose. Peak effect on phosphate levels seen within 4-6 hours. |
| Duration of Action | Duration of phosphate-lowering effect lasts approximately 8-12 hours after a single oral dose. With chronic dosing, sustained suppression of serum phosphate is maintained with twice-daily administration. Clinical monitoring of serum phosphate is recommended. |
VOYDEYA (vadadustat) is an oral HIF-PH inhibitor. The typical adult dose is 150 mg to 450 mg orally once daily, adjusted based on hemoglobin levels. Start at 150 mg once daily, titrate by 150 mg increments every 4 weeks to achieve target hemoglobin (10-12 g/dL); maximum dose 450 mg once daily.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for GFR ≥15 mL/min. Not recommended for patients with eGFR <15 mL/min or on dialysis. For patients with CKD not on dialysis, no renal adjustment is needed. |
| Liver impairment | Child-Pugh Class A: no adjustment. Child-Pugh Class B: reduce starting dose to 150 mg every other day. Child-Pugh Class C: not recommended. |
| Pediatric use | Safety and efficacy in pediatric patients have not been established; no recommended dosing available. |
| Geriatric use | No specific dose adjustment required based on age alone. Monitor hemoglobin and iron status closely, as elderly patients may have increased sensitivity to adverse effects such as thromboembolic events and hypertension. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for VOYDEYA (VOYDEYA).
| Breastfeeding | It is not known whether vadadustat is excreted in human milk. No M/P ratio is available. Because of the potential for serious adverse reactions in breastfed infants, breastfeeding is not recommended during treatment with VOYDEYA and for at least 4 weeks after the last dose. |
| Teratogenic Risk | VOYDEYA (vadadustat) is contraindicated in pregnancy. Based on its mechanism of action (HIF-PH inhibitor) and animal studies, there is potential for fetal harm. In animal reproduction studies, vadadustat caused embryo-fetal lethality and malformations at maternal exposures below the human exposure at the recommended clinical dose. The drug should be discontinued prior to conception and during all trimesters. Effective contraception is required for women of reproductive potential during therapy and for at least 4 weeks after the last dose. |
■ FDA Black Box Warning
Sulfonamide hypersensitivity: Fatal reactions including Stevens-Johnson syndrome, toxic epidermal necrolysis, and fulminant hepatic necrosis have occurred. Discontinue at first sign of rash or other hypersensitivity signs.
| Serious Effects |
Absolute: Known hypersensitivity to zonisamide or any sulfonamide. Relative: Severe hepatic or renal impairment (may require dose adjustment).
| Precautions | Serious rashes including SJS/TEN (discontinue if unexplained rash), blood dyscrasias (e.g., aplastic anemia, agranulocytosis), pancreatitis, hepatic failure, myopia and secondary angle closure glaucoma, oligohidrosis and hyperthermia (especially in pediatric patients), metabolic acidosis (baseline and periodic serum bicarbonate recommended), suicidality (monitor for depression/behavioral changes), and withdrawal precipitation of seizures (taper gradually). |
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| Fetal Monitoring | Women of reproductive potential should have pregnancy testing prior to initiating VOYDEYA. They must use effective contraception during treatment and for at least 4 weeks after the last dose. If pregnancy occurs, treatment should be discontinued immediately and the patient should be apprised of the potential hazard to the fetus. No specific fetal monitoring is recommended due to contraindication. |
| Fertility Effects | Based on animal studies, vadadustat may impair female fertility. In female rats, decreased fertility and increased pre-implantation loss were observed at exposures similar to the human exposure at the recommended dose. Effects on male fertility have not been adequately studied, but no adverse effects were observed in male rats at exposures up to 10 times the human exposure. |