XYROSA

Clinical safety rating: caution

Comprehensive clinical and safety monograph for XYROSA (XYROSA).

How it works

XYROSA is a fixed-dose combination of sacubitril, a neprilysin inhibitor, and valsartan, an angiotensin II receptor blocker. Sacubitril inhibits neprilysin, increasing natriuretic peptides and other vasoactive peptides, leading to vasodilation, natriuresis, and inhibition of fibrosis. Valsartan blocks the angiotensin II type 1 receptor, reducing vasoconstriction, aldosterone release, and cardiac remodeling.

What the body does with it

Metabolism	Sacubitril is metabolized by esterases to sacubitrilat (active metabolite); further metabolism via CYP450 enzymes (minor). Valsartan is minimally metabolized (<20%) via CYP2C9. Both are substrates of OATP1B1/1B3 and MRP2 transporters.
Excretion	Primarily renal excretion of unchanged drug (~60%) and glucuronide metabolite (~30%); biliary/fecal elimination accounts for <10%.
Half-life	Terminal elimination half-life is 12–15 hours in healthy adults; prolonged to >24 hours in severe renal impairment (CrCl <30 mL/min), requiring dose adjustment.
Protein binding	Approximately 85–90% bound to albumin and alpha-1-acid glycoprotein.
Volume of Distribution	0.2–0.4 L/kg, indicating moderate distribution into extracellular fluid and limited tissue penetration.
Bioavailability	Oral: 60% (first-pass metabolism). Intramuscular: 90%.
Onset of Action	Oral: 1–2 hours; intravenous: within 5 minutes.
Duration of Action	Oral: 12–24 hours; IV: 8–12 hours. Duration extended in hepatic impairment due to reduced clearance.

Classification & Brands

Dosing & administration

1.5 mg/kg IV once weekly; maximum 100 mg per dose.

Dosage form	TABLET
Renal impairment	CrCl 30-89 mL/min: 1.5 mg/kg IV once weekly; CrCl <30 mL/min: not recommended.
Liver impairment	Child-Pugh A: no adjustment; Child-Pugh B: 0.75 mg/kg IV once weekly; Child-Pugh C: not recommended.
Pediatric use	Not approved for pediatric use; safety and efficacy not established.
Geriatric use	No specific adjustments required; monitor renal function due to age-related decline.

Use during pregnancy

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

Clinical note

Comprehensive clinical and safety monograph for XYROSA (XYROSA).

Breastfeeding	Contraindicated during breastfeeding. M/P ratio: 3.5; active drug excreted in human milk; potential for serious adverse reactions in nursing infants.
Teratogenic Risk	Pregnancy Category X. First trimester: high risk of structural anomalies (neural tube, cardiovascular). Second trimester: risk of fetal growth restriction and oligohydramnios. Third trimester: neonatal complications (respiratory distress, hypoglycemia).
Fetal Monitoring

Warnings & precautions

■ FDA Black Box Warning

WARNING: FETAL TOXICITY. Drugs acting directly on the renin-angiotensin system can cause injury and death to the developing fetus. Discontinue as soon as possible once pregnancy is detected.

Side Effect Profile

Serious Effects

Absolute Contraindications

["History of angioedema with ACE inhibitors or ARBs","Concomitant use with ACE inhibitors (within 36 hours)","Concomitant use with aliskiren in patients with diabetes","Severe hepatic impairment (Child-Pugh C)","Pregnancy"]

Clinical Precautions

Precautions

["Angioedema","Hypotension","Renal impairment","Hyperkalemia","Hepatic impairment","Avoid concomitant use with ACE inhibitors (risk of angioedema) or aliskiren in diabetes","Monitor serum potassium, renal function, and blood pressure"]

Clinical Tips & Counseling

Drug interactions

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XYROSA

Clinical safety rating: caution

Comprehensive clinical and safety monograph for XYROSA (XYROSA).

How it works

What the body does with it

Metabolism	Sacubitril is metabolized by esterases to sacubitrilat (active metabolite); further metabolism via CYP450 enzymes (minor). Valsartan is minimally metabolized (<20%) via CYP2C9. Both are substrates of OATP1B1/1B3 and MRP2 transporters.
Excretion	Primarily renal excretion of unchanged drug (~60%) and glucuronide metabolite (~30%); biliary/fecal elimination accounts for <10%.
Half-life	Terminal elimination half-life is 12–15 hours in healthy adults; prolonged to >24 hours in severe renal impairment (CrCl <30 mL/min), requiring dose adjustment.
Protein binding	Approximately 85–90% bound to albumin and alpha-1-acid glycoprotein.
Volume of Distribution	0.2–0.4 L/kg, indicating moderate distribution into extracellular fluid and limited tissue penetration.
Bioavailability	Oral: 60% (first-pass metabolism). Intramuscular: 90%.
Onset of Action	Oral: 1–2 hours; intravenous: within 5 minutes.
Duration of Action	Oral: 12–24 hours; IV: 8–12 hours. Duration extended in hepatic impairment due to reduced clearance.

Classification & Brands

Dosing & administration

1.5 mg/kg IV once weekly; maximum 100 mg per dose.

Dosage form	TABLET
Renal impairment	CrCl 30-89 mL/min: 1.5 mg/kg IV once weekly; CrCl <30 mL/min: not recommended.
Liver impairment	Child-Pugh A: no adjustment; Child-Pugh B: 0.75 mg/kg IV once weekly; Child-Pugh C: not recommended.
Pediatric use	Not approved for pediatric use; safety and efficacy not established.
Geriatric use	No specific adjustments required; monitor renal function due to age-related decline.

Use during pregnancy

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

Clinical note

Comprehensive clinical and safety monograph for XYROSA (XYROSA).

Breastfeeding	Contraindicated during breastfeeding. M/P ratio: 3.5; active drug excreted in human milk; potential for serious adverse reactions in nursing infants.
Teratogenic Risk	Pregnancy Category X. First trimester: high risk of structural anomalies (neural tube, cardiovascular). Second trimester: risk of fetal growth restriction and oligohydramnios. Third trimester: neonatal complications (respiratory distress, hypoglycemia).
Fetal Monitoring

Warnings & precautions

■ FDA Black Box Warning

WARNING: FETAL TOXICITY. Drugs acting directly on the renin-angiotensin system can cause injury and death to the developing fetus. Discontinue as soon as possible once pregnancy is detected.