KATERZIA

Clinical safety rating: caution

Comprehensive clinical and safety monograph for KATERZIA (KATERZIA).

How it works

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.

What the body does with it

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.

Classification & Brands

Dosing & administration

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.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for KATERZIA (KATERZIA).

Breastfeeding	No human data; M/P ratio unknown. Excreted in rat milk. Due to potential risk of hypotension and renal impairment in nursing infants, discontinue drug or breastfeeding, considering importance to mother.
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

Warnings & precautions

■ 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.

Side Effect Profile

Serious Effects

Absolute Contraindications

Absolute: Hypersensitivity to bosentan or any component; moderate to severe hepatic impairment (Child-Pugh Class B or C); baseline AST/ALT >3× ULN; concomitant use with cyclosporine A (increases bosentan levels and hepatotoxicity); concomitant use with glyburide (increases risk of liver enzyme elevations); pregnancy (teratogenic in animals – can cause birth defects; must exclude pregnancy before initiation and monthly thereafter).

Clinical Precautions

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.

Clinical Tips & Counseling

Drug interactions

Loading safety data…

KATERZIA

Clinical safety rating: caution

Comprehensive clinical and safety monograph for KATERZIA (KATERZIA).

How it works

What the body does with it

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.

Classification & Brands

Dosing & administration

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.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for KATERZIA (KATERZIA).

Breastfeeding	No human data; M/P ratio unknown. Excreted in rat milk. Due to potential risk of hypotension and renal impairment in nursing infants, discontinue drug or breastfeeding, considering importance to mother.
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