ZAROXOLYN
Clinical safety rating: caution
Comprehensive clinical and safety monograph for ZAROXOLYN (ZAROXOLYN).
Inhibits sodium reabsorption in the distal convoluted tubule by blocking the thiazide-sensitive sodium-chloride symporter (NCC).
| Metabolism | Metabolized primarily via cytochrome P450 (CYP) enzymes, including CYP3A4, with minor contribution from CYP1A2 and CYP2C8. |
| Excretion | Primarily renal (approximately 70% as unchanged drug and metabolites) and biliary (approximately 30% as unchanged drug and metabolites into feces). |
| Half-life | Terminal elimination half-life ranges from 6 to 15 hours (mean ~8 hours) in patients with normal renal function. In renal impairment, half-life is prolonged and accumulation may occur. |
| Protein binding | Approximately 95% bound, primarily to albumin. |
| Volume of Distribution | Volume of distribution is approximately 2 L/kg, indicating extensive tissue distribution. |
| Bioavailability | Oral: Approximately 75% (range 60-90%), with food potentially decreasing absorption. |
| Onset of Action | Oral: Diuresis begins within 1 hour, with peak effect at 2-4 hours. |
| Duration of Action | Oral: Duration of diuretic effect is 12-24 hours, with blood pressure reduction lasting up to 24 hours. Clinical note: Use once daily for hypertension. |
| Molecular Weight | 365.81 |
2.5 to 5 mg orally once daily; may increase up to 20 mg daily based on response.
| Dosage form | TABLET |
| Renal impairment | eGFR 10-50 mL/min: use with caution; eGFR <10 mL/min: not recommended due to ineffectiveness. |
| Liver impairment | Child-Pugh A: no adjustment; Child-Pugh B or C: consider dose reduction due to reduced clearance. |
| Pediatric use | Not established; safety and efficacy not determined in pediatric patients. |
| Geriatric use | Start at lower end of dosing range (2.5 mg) due to increased risk of electrolyte imbalance and hypotension. |
| 1st trimester | Avoid due to potential teratogenicity; thiazide-like diuretics may cause fetal harm. Use only if clearly needed and no alternative. |
| 2nd trimester | Use only if clearly needed; monitor for maternal hypotension, electrolyte imbalance, and reduced placental perfusion. |
| 3rd trimester | Avoid, as it may cause fetal or neonatal jaundice, thrombocytopenia, and electrolyte disturbances. |
Clinical note
Comprehensive clinical and safety monograph for ZAROXOLYN (ZAROXOLYN).
| Placental transfer | Crosses the placenta; detectable in fetal blood and amniotic fluid. Degree of transfer not fully quantified but considered significant. |
| Breastfeeding | Metolazone passes into breast milk in small amounts; limited human data. Use with caution in nursing mothers, especially in high doses or prolonged use, due to potential for electrolyte disturbances and dehydration in the infant. Monitor infant for signs of diuretic effects. |
■ FDA Black Box Warning
No FDA black box warnings reported.
| Serious Effects |
AnuriaHepatic coma or precomaKnown hypersensitivity to metolazone or other sulfonamide-derived drugs
| Precautions | May cause hypokalemia, hyponatremia, and metabolic alkalosis., Can precipitate azotemia in patients with impaired renal function., Risk of hyperuricemia and new-onset gout., Use with caution in patients with hepatic impairment due to risk of hepatic encephalopathy. |
| Food/Dietary | Avoid high-sodium foods which can reduce diuretic efficacy. Increase potassium intake (bananas, oranges, spinach) unless advised otherwise. Limit excessive salt substitutes containing potassium. Grapefruit juice may increase metolazone absorption; avoid large amounts. |
Loading safety data…
| Lactation Rating | L3 (Moderately Safe) |
| Teratogenic Risk | Pregnancy Category D. Crosses placenta. First trimester: No evidence of teratogenicity in humans, but animal studies show fetal toxicity (skeletal anomalies, growth retardation) at high doses. Second/third trimesters: Associated with decreased placental perfusion, fetal jaundice, electrolyte disturbances, and possible neonatal thrombocytopenia. Not recommended in pregnancy, especially for gestational hypertension or preeclampsia due to maternal hypovolemia risk. |
| Fetal Monitoring | Monitor maternal blood pressure, serum electrolytes (sodium, potassium, chloride, magnesium), renal function, and uric acid. Fetal assessment includes ultrasound for growth restriction and amniotic fluid volume (oligohydramnios risk). In neonates, monitor for jaundice, thrombocytopenia, and electrolyte disturbances. |
| Fertility Effects | No specific human data; animal studies show no effect on fertility. Potential indirect effects via electrolyte imbalance or hemodynamic changes affecting pregnancy outcomes. |
| Clinical Pearls | Zaroxolyn (metolazone) is a thiazide-like diuretic effective in patients with severe renal impairment (eGFR < 20 mL/min) where thiazides typically fail. It is often used synergistically with loop diuretics in resistant edema. Onset of action is 2-4 hours; duration up to 24 hours. Monitor for severe hyponatremia, hypokalemia, and metabolic alkalosis. May cause hyperuricemia and gout. Avoid in patients with sulfonamide allergy due to cross-reactivity. |
| Patient Advice | Take this medication exactly as prescribed, usually once daily in the morning to avoid nighttime urination. · Avoid sudden position changes to prevent dizziness from low blood pressure. · Weigh yourself daily at the same time and report rapid weight gain or loss greater than 2-3 pounds in a day. · Limit alcohol and NSAIDs (like ibuprofen) which can worsen side effects. · Do not stop taking abruptly without consulting your doctor. |