KYXATA

Clinical safety rating: caution

Comprehensive clinical and safety monograph for KYXATA (KYXATA).

How it works

Selective endothelin receptor antagonist (ERA) targeting endothelin type A (ETA) receptors, reducing pulmonary vascular resistance and remodeling in pulmonary arterial hypertension (PAH).

What the body does with it

Metabolism	Primarily hepatic via CYP3A4 and CYP2C19; minor contribution from UGT1A1, UGT1A3, UGT1A9. Active metabolite (M14) via dealkylation.
Excretion	Renal excretion accounts for approximately 70% of elimination (60% unchanged, 10% as metabolites); biliary/fecal excretion accounts for 25% (primarily as metabolites); minor metabolic clearance (5%) via CYP3A4.
Half-life	Terminal elimination half-life is 12–15 hours in adults with normal renal function; extends to 22–30 hours in moderate renal impairment (CrCl 30–50 mL/min) and up to 48 hours in severe impairment (CrCl <30 mL/min).
Protein binding	88–92% bound to albumin and alpha-1-acid glycoprotein.
Volume of Distribution	0.8–1.2 L/kg, indicating extensive extravascular distribution into tissues including brain and myocardium.
Bioavailability	Oral: 35–45% (due to first-pass metabolism); IM: 80–90%; IV: 100%.
Onset of Action	Oral: 30–60 minutes; intravenous: 2–5 minutes (peak effect at 15–30 min).
Duration of Action	Oral: 6–8 hours; IV: 4–6 hours. Extended-release oral formulation provides 12–24 hour coverage.

Classification & Brands

Dosing & administration

KYXATA (landiolol) intravenously: For atrial fibrillation/flutter (AF/AFL) with rapid ventricular rate: Initial intravenous bolus dose of 0.125 mg/kg over 1 minute, followed by continuous intravenous infusion of 0.05 to 0.2 mg/kg/min, titrated to heart rate control. Maximum infusion rate is 0.4 mg/kg/min.

Dosage form	SOLUTION
Renal impairment	No dosage adjustment is required for renal impairment. Landiolol is minimally renally excreted (approximately 1% unchanged). However, use caution in patients with severe renal impairment (CrCl < 30 mL/min) due to limited data.
Liver impairment	For mild hepatic impairment (Child-Pugh Class A): No dosage adjustment needed. For moderate to severe hepatic impairment (Child-Pugh Class B or C): Reduce initial infusion rate to 0.05 mg/kg/min and titrate cautiously; maximum infusion rate of 0.2 mg/kg/min is recommended due to reduced clearance.
Pediatric use	Weight-based dosing: Loading dose of 0.125 mg/kg intravenously over 1 minute, followed by continuous infusion starting at 0.05 mg/kg/min, titrated to effect. Maximum infusion rate is 0.3 mg/kg/min. Safety and efficacy established in pediatric patients aged 1 to <18 years.
Geriatric use	Elderly patients (≥65 years): Start at the lower end of the dosing range (initial infusion rate of 0.05 mg/kg/min) and titrate slowly due to potential decreased hepatic function and increased sensitivity. No specific dose adjustment mandated, but monitor heart rate and blood pressure closely.

Use during pregnancy

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

Clinical note

Comprehensive clinical and safety monograph for KYXATA (KYXATA).

Breastfeeding	No human data; M/P ratio unknown. Due to potential for serious adverse reactions in nursing infants, advise against breastfeeding during therapy.
Teratogenic Risk	No human data; animal studies not available. Risk cannot be excluded; avoid in pregnancy unless benefit outweighs potential fetal risk.
Fetal Monitoring	Monitor maternal liver function tests and renal function; fetal ultrasound if exposure occurs in pregnancy.

Warnings & precautions

■ FDA Black Box Warning

Embryofetal toxicity: Must be avoided in pregnancy; females of reproductive potential must use reliable contraception and have monthly pregnancy tests.

Side Effect Profile

Serious Effects

Absolute Contraindications

Pregnancy (absolute); hypersensitivity to macitentan or any component; concomitant use with strong CYP3A4 inducers (e.g., rifampin) (relative); severe hepatic impairment (Child-Pugh C) (relative).

Clinical Precautions

Precautions

Hepatotoxicity (requires monthly liver function monitoring); fluid retention (peripheral edema, may require diuretics); hematologic changes (hemoglobin decrease, requires periodic monitoring); pulmonary veno-occlusive disease (PVOD) should be excluded.

Clinical Tips & Counseling

Drug interactions

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KYXATA

Clinical safety rating: caution

Comprehensive clinical and safety monograph for KYXATA (KYXATA).

How it works

Selective endothelin receptor antagonist (ERA) targeting endothelin type A (ETA) receptors, reducing pulmonary vascular resistance and remodeling in pulmonary arterial hypertension (PAH).

What the body does with it

Metabolism	Primarily hepatic via CYP3A4 and CYP2C19; minor contribution from UGT1A1, UGT1A3, UGT1A9. Active metabolite (M14) via dealkylation.
Excretion	Renal excretion accounts for approximately 70% of elimination (60% unchanged, 10% as metabolites); biliary/fecal excretion accounts for 25% (primarily as metabolites); minor metabolic clearance (5%) via CYP3A4.
Half-life	Terminal elimination half-life is 12–15 hours in adults with normal renal function; extends to 22–30 hours in moderate renal impairment (CrCl 30–50 mL/min) and up to 48 hours in severe impairment (CrCl <30 mL/min).
Protein binding	88–92% bound to albumin and alpha-1-acid glycoprotein.
Volume of Distribution	0.8–1.2 L/kg, indicating extensive extravascular distribution into tissues including brain and myocardium.
Bioavailability	Oral: 35–45% (due to first-pass metabolism); IM: 80–90%; IV: 100%.
Onset of Action	Oral: 30–60 minutes; intravenous: 2–5 minutes (peak effect at 15–30 min).
Duration of Action	Oral: 6–8 hours; IV: 4–6 hours. Extended-release oral formulation provides 12–24 hour coverage.

Classification & Brands

Dosing & administration

Dosage form	SOLUTION
Renal impairment	No dosage adjustment is required for renal impairment. Landiolol is minimally renally excreted (approximately 1% unchanged). However, use caution in patients with severe renal impairment (CrCl < 30 mL/min) due to limited data.
Liver impairment	For mild hepatic impairment (Child-Pugh Class A): No dosage adjustment needed. For moderate to severe hepatic impairment (Child-Pugh Class B or C): Reduce initial infusion rate to 0.05 mg/kg/min and titrate cautiously; maximum infusion rate of 0.2 mg/kg/min is recommended due to reduced clearance.
Pediatric use	Weight-based dosing: Loading dose of 0.125 mg/kg intravenously over 1 minute, followed by continuous infusion starting at 0.05 mg/kg/min, titrated to effect. Maximum infusion rate is 0.3 mg/kg/min. Safety and efficacy established in pediatric patients aged 1 to <18 years.
Geriatric use	Elderly patients (≥65 years): Start at the lower end of the dosing range (initial infusion rate of 0.05 mg/kg/min) and titrate slowly due to potential decreased hepatic function and increased sensitivity. No specific dose adjustment mandated, but monitor heart rate and blood pressure closely.

Use during pregnancy

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

Clinical note

Comprehensive clinical and safety monograph for KYXATA (KYXATA).

Breastfeeding	No human data; M/P ratio unknown. Due to potential for serious adverse reactions in nursing infants, advise against breastfeeding during therapy.
Teratogenic Risk	No human data; animal studies not available. Risk cannot be excluded; avoid in pregnancy unless benefit outweighs potential fetal risk.
Fetal Monitoring	Monitor maternal liver function tests and renal function; fetal ultrasound if exposure occurs in pregnancy.

Warnings & precautions

■ FDA Black Box Warning

Embryofetal toxicity: Must be avoided in pregnancy; females of reproductive potential must use reliable contraception and have monthly pregnancy tests.

Side Effect Profile

Serious Effects

Absolute Contraindications

Pregnancy (absolute); hypersensitivity to macitentan or any component; concomitant use with strong CYP3A4 inducers (e.g., rifampin) (relative); severe hepatic impairment (Child-Pugh C) (relative).