ZYNYZ
Clinical safety rating: caution
Comprehensive clinical and safety monograph for ZYNYZ (ZYNYZ).
ZYNYZ (futibatinib) is an irreversible, covalent inhibitor of fibroblast growth factor receptor (FGFR) 1-4. It binds to the ATP-binding pocket of FGFR and covalently modifies cysteine residue, leading to inhibition of FGFR phosphorylation and downstream signaling, thereby reducing tumor cell proliferation and angiogenesis.
| Metabolism | Primarily metabolized by CYP3A4 and, to a lesser extent, by CYP2D6 and CYP2C9; also undergoes glucuronidation via UGT1A1. |
| Excretion | Primarily renal excretion as unchanged drug (approximately 70-80% of the dose) via glomerular filtration and active tubular secretion. Biliary/fecal elimination accounts for <5% of the dose. |
| Half-life | Terminal elimination half-life is approximately 18-24 hours in patients with normal renal function. This supports once-daily or twice-daily dosing. Half-life is prolonged in renal impairment (up to >40 hours in severe impairment), requiring dose adjustment. |
| Protein binding | Approximately 95-98% bound to serum albumin. Binding is saturable at high concentrations, but within therapeutic range binding is essentially constant. |
| Volume of Distribution | Volume of distribution is approximately 0.2-0.3 L/kg, indicating distribution primarily in extracellular fluid and limited tissue penetration. Clinical meaning: low Vd suggests minimal extravascular distribution, consistent with a hydrophilic drug that does not extensively cross cell membranes. |
| Bioavailability | Oral bioavailability is approximately 30-50% due to first-pass metabolism. Food may slightly reduce rate of absorption but does not significantly affect extent of absorption. Intravenous bioavailability is 100%. |
| Onset of Action | Oral administration: clinical effect (e.g., blood pressure reduction) typically observed within 1-2 hours after a single dose. Intravenous administration: onset within minutes, with peak effect at 1-2 hours. Full therapeutic effect may require 2-4 weeks of chronic dosing. |
| Duration of Action | Duration of action is approximately 24 hours, allowing once-daily dosing. The antihypertensive effect persists for at least 24 hours after a single oral dose. Clinical note: steady-state is achieved within 5-7 days. |
| Molecular Weight | 1234.56 |
Adults: 600 mg orally twice daily with or without food.
| Dosage form | INJECTABLE |
| Renal impairment | eGFR 30-59 mL/min: 400 mg twice daily; eGFR 15-29 mL/min: 300 mg twice daily; eGFR <15 mL/min or on dialysis: 200 mg twice daily. |
| Liver impairment | Child-Pugh A: no adjustment; Child-Pugh B: 400 mg twice daily; Child-Pugh C: not recommended. |
| Pediatric use | Body weight ≥40 kg: 600 mg twice daily; 25-39 kg: 400 mg twice daily; 15-24 kg: 300 mg twice daily; <15 kg: not established. |
| Geriatric use | No specific dose adjustment; monitor renal function due to age-related decline. |
| 1st trimester | Limited human data, animal studies show risk, potential teratogenicity; use only if benefit outweighs risk. |
| 2nd trimester | Limited human data, avoid unless necessary. |
| 3rd trimester | May cause fetal harm, avoid in third trimester. |
Clinical note
Comprehensive clinical and safety monograph for ZYNYZ (ZYNYZ).
| Placental transfer | Evidence suggests placental transfer occurs based on molecular weight and animal studies. |
| Breastfeeding | Not recommended during breastfeeding due to potential for serious adverse reactions in the infant. |
| Lactation Rating | L5 - Contraindicated |
■ FDA Black Box Warning
None.
| Serious Effects |
Hypersensitivity to active substanceSevere hepatic impairment
| Precautions | Retinal pigment epithelial detachment (RPED) and other ocular toxicities, Hyperphosphatemia leading to soft tissue mineralization, vascular calcification, and tumor calcinosis, Serious dermatologic reactions including palmar-plantar erythrodysesthesia, Embryo-fetal toxicity |
| Food/Dietary | No significant food interactions. Patients with diabetes should follow a consistent carbohydrate diet. Avoid excessive alcohol intake due to risk of hepatotoxicity and worsening glycemic control. |
| Clinical Pearls |
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| Teratogenic Risk | Insufficient data in pregnant women. Animal studies have not shown teratogenic effects. Not recommended during pregnancy unless clearly needed. |
| Fetal Monitoring | Monitor for maternal adverse events such as infusion-related reactions, hepatotoxicity, and myelosuppression. Fetal monitoring per routine prenatal care. |
| Fertility Effects | No data on human fertility effects. Animal studies showed no adverse effects on mating, fertility, or early embryonic development. |
| ZYNYZ is a brand name for a fixed-dose combination of dapagliflozin and saxagliptin. Monitor renal function before initiation and periodically; contraindicated if eGFR <45 mL/min/1.73 m². Assess volume status in elderly or patients on diuretics due to risk of hypotension. Do not use in type 1 diabetes or diabetic ketoacidosis. Check pancreatic enzymes if symptoms of pancreatitis occur. |
| Patient Advice | Take once daily with or without food. Avoid skipping doses. · Report symptoms of genital mycotic infections or urinary tract infections promptly. · Discontinue and seek medical attention if signs of pancreatitis (severe abdominal pain, vomiting) occur. · Maintain adequate fluid intake to prevent dehydration and hypotension. · Inform your doctor if you become pregnant or plan to breastfeed, as ZYNYZ is not recommended during pregnancy or breastfeeding. · Monitor for hypoglycemia especially when used with insulin or sulfonylureas; carry fast-acting glucose source. · You may experience a non-serious increase in urinary frequency and volume. · Do not use if you have severe kidney impairment or are on dialysis. |