KATERZIA
Clinical safety rating
cautionComprehensive clinical and safety monograph for KATERZIA (KATERZIA).
KATERZIA (bosentan) is an endothelin receptor antagonist (ERA) that blocks endothelin-1 (ET-1) from binding to ETA and ETB receptors in the endothelium and vascular smooth muscle. This inhibits ET-1-mediated vasoconstriction and smooth muscle proliferation, reducing pulmonary vascular resistance and pulmonary arterial pressure.
| Metabolism | Primarily metabolized by CYP2C9 and CYP3A4 to three major metabolites (Ro 48-5033, Ro 47-8634, Ro 64-1056). Induces CYP2C9 and CYP3A4; also induces CYP2C19. |
| Excretion | Renal elimination accounts for approximately 60-80% of the administered dose, predominantly as unchanged drug via glomerular filtration and active tubular secretion. Biliary/fecal excretion is minimal, <5%. |
| Half-life | Terminal elimination half-life is approximately 9-12 hours in healthy adults. In patients with hypertension or hepatic impairment, half-life may be prolonged up to 15-20 hours, necessitating dose adjustment. |
| Protein binding | Approximately 95-98% bound to plasma proteins, primarily albumin and alpha-1-acid glycoprotein. High binding limits tissue distribution and affects free drug concentration. |
| Volume of Distribution | Volume of distribution is approximately 0.7-1.2 L/kg (range 50-80 L for a 70 kg adult), indicating moderate tissue distribution beyond plasma volume. |
| Bioavailability | Oral bioavailability is approximately 30-40% due to extensive first-pass hepatic metabolism. Food may reduce bioavailability by 20-30%, so dosing should be consistent with respect to meals. |
| Onset of Action | Oral administration: Onset of antihypertensive effect occurs within 2-4 hours after a single dose. Peak effect is observed at 6-12 hours. |
| Duration of Action | Duration of antihypertensive effect is approximately 24 hours with once-daily dosing, allowing for sustained blood pressure control. Steady state is reached within 3-5 days. |
| Molecular Weight | 494.58 |
5 mg orally once daily for 21 days, then 7 days off, repeated in 28-day cycles.
| Dosage form | SUSPENSION |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment (CrCl ≥30 mL/min). Not recommended in severe renal impairment (CrCl <30 mL/min) or end-stage renal disease. |
| Liver impairment | Child-Pugh A: No adjustment. Child-Pugh B: Reduce dose to 5 mg orally once daily for 21 days, then 7 days off. Child-Pugh C: Not recommended. |
| Pediatric use | Safety and efficacy not established in pediatric patients. |
| Geriatric use | No specific dose adjustment required; monitor for adverse events due to potential age-related renal and hepatic decline. |
| 1st trimester | Avoid; fetal cardiovascular and central nervous system development risk. |
| 2nd trimester | Avoid; potential for fetotoxicity and interference with fetal development. |
| 3rd trimester | Avoid; risk of neonatal hypotension, renal impairment, and hyperkalemia. |
Clinical note
Comprehensive clinical and safety monograph for KATERZIA (KATERZIA).
| Placental transfer | Evidence of placental transfer in animal studies; human data limited but expected to cross placenta due to low molecular weight. |
| Breastfeeding | It is not known whether KATERZIA is excreted in human milk. Due to potential for serious adverse reactions in breastfed infants, breastfeeding is not recommended during therapy. |
| Lactation Rating | L4 (Possibly Hazardous) |
| Teratogenic Risk | Pregnancy Category C. First trimester: animal studies show fetal toxicity; no adequate human data. Second/third trimester: may cause fetal renal impairment, oligohydramnios, and skull ossification defects due to direct renin-angiotensin system inhibition. |
| Fetal Monitoring | Monitor blood pressure, renal function (serum creatinine, BUN), electrolytes, and amniotic fluid volume (via ultrasound) during pregnancy. Fetal growth scans recommended. |
| Fertility Effects | Animal studies show reduced fertility and fetal survival at high doses. No human data on fertility impairment. |
■ FDA Black Box Warning
WARNING: HEPATOTOXICITY. Bosentan can cause serious hepatic injury, including acute liver failure, requiring baseline and monthly monitoring of liver enzymes. Discontinue if ALT/AST >3x ULN accompanied by symptoms or bilirubin >2x ULN.
| Serious Effects |
Hypersensitivity to bosentan or any excipientPregnancy (FDA Pregnancy Category X)Concomitant use with cyclosporine AConcomitant use with glyburide
| Precautions | Hepatotoxicity (monitor LFTs monthly), hepatorenal syndrome; peripheral edema; fluid retention; may cause hypotension; pulmonary veno-occlusive disease (PVOD) may cause pulmonary edema; decreases hemoglobin and hematocrit (monitor at 1 and 3 months, then every 3 months); decreases sperm count; reduces efficacy of hormonal contraceptives (use alternative contraception); caution in hepatic impairment (Child-Pugh Class A; contraindicated in moderate to severe impairment); caution in elderly; not recommended in patients with severe anemia. |
| Food/Dietary | Take with food to improve tolerability and reduce gastrointestinal adverse effects. Avoid grapefruit juice as it may increase treprostinil exposure. Avoid alcohol as it may exacerbate vasodilation and hypotension. |
| Clinical Pearls | KATERZIA (oral treprostinil) is a prostacyclin analogue used for pulmonary arterial hypertension (PAH). Monitor for prostacyclin-related side effects (headache, nausea, diarrhea, jaw pain, flushing). Dose titration is critical; increase by 0.25 mg BID or 0.125 mg TID every 3-4 days as tolerated. Avoid abrupt discontinuation due to risk of rebound pulmonary hypertension. Use with caution in patients with hepatic impairment; reduce starting dose in moderate impairment. |
| Patient Advice | Take KATERZIA exactly as prescribed, with food to reduce gastrointestinal side effects. · Do not stop taking this medication suddenly; consult your doctor before making any changes. · Common side effects include headache, nausea, diarrhea, jaw pain, and flushing; report severe or persistent symptoms. · Avoid alcohol and grapefruit juice as they may interact with the medication. · Store tablets in the original container at room temperature, away from moisture and light. · If you miss a dose, skip it and take the next dose at the scheduled time; do not double dose. · Inform your healthcare provider of all medications you are taking, especially antihypertensives, anticoagulants, and NSAIDs. |
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