ALYFTREK
Clinical safety rating: caution
Comprehensive clinical and safety monograph for ALYFTREK (ALYFTREK).
ALYFTREK (vutrisiran) is a transthyretin-directed small interfering RNA that binds to the 3' untranslated region of mutant and wild-type TTR mRNA, leading to its degradation via RNA interference, thereby reducing hepatic production of TTR protein and decreasing amyloid deposition.
| Metabolism | Metabolized via nuclease-mediated degradation to oligonucleotides of various lengths. |
| Excretion | Primarily hepatic metabolism, with ~70% excreted in feces as metabolites and ~20% in urine (mostly as metabolites). <1% excreted unchanged in urine. |
| Half-life | Terminal elimination half-life is approximately 72 hours after single dose and extends to ~120 hours at steady state due to dose-dependent elimination; allows once-weekly dosing. |
| Protein binding | >99% bound, primarily to albumin and α1-acid glycoprotein. |
| Volume of Distribution | Distribution volume approximately 10–12 L/kg, suggesting extensive extravascular distribution into tissues. |
| Bioavailability | Oral bioavailability is approximately 70–80% when taken with food; reduced by ~40% under fasted conditions. |
| Onset of Action | Oral: Initial clinical effect observed within 7–14 days with continued improvement over 4–6 weeks. |
| Duration of Action | Therapeutic effect persists for approximately 1 week due to long half-life; dosing interval is once weekly. |
For patients with cystic fibrosis (CF) who are heterozygous for the F508del mutation in the CFTR gene and a minimal function mutation (F/MF genotypes): elexacaftor 200 mg/tezacaftor 100 mg/ivacaftor 125 mg orally, two tablets in the morning, and ivacaftor 150 mg orally, one tablet in the evening, approximately 12 hours apart. For patients homozygous for F508del (F/F genotypes): elexacaftor 200 mg/tezacaftor 100 mg/ivacaftor 125 mg orally, two tablets in the morning, and ivacaftor 150 mg orally, one tablet in the evening.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment is required for mild to moderate renal impairment (eGFR ≥30 mL/min/1.73 m²). For severe renal impairment (eGFR <30 mL/min/1.73 m²) or end-stage renal disease, use is not recommended due to limited data. |
| Liver impairment | Child-Pugh Class A (mild): No dose adjustment. Child-Pugh Class B (moderate): Initiate with reduced dose: in the morning, two tablets of elexacaftor 150 mg/tezacaftor 75 mg/ivacaftor 94 mg (instead of 200/100/125 mg), and in the evening, one tablet of ivacaftor 75 mg (instead of 150 mg). Child-Pugh Class C (severe): Not recommended. |
| Pediatric use | Approved for children aged 6 years and older weighing ≥30 kg: same adult dosing. For children aged 6 to <12 years weighing <30 kg: morning dose: two tablets of elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg; evening dose: one tablet of ivacaftor 75 mg. For children aged 2 to <6 years weighing ≥14 kg: morning dose: two packets of oral granules (elexacaftor 80 mg/tezacaftor 40 mg/ivacaftor 60 mg per packet); evening dose: one packet of oral granules (ivacaftor 59.5 mg per packet). |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for ALYFTREK (ALYFTREK).
| Breastfeeding | Contraindicated during breastfeeding. No M/P ratio available; drug is excreted into breast milk and may cause serious adverse reactions in nursing infants due to known toxicity. |
| Teratogenic Risk | Pregnancy Category X. First trimester: High risk of major congenital malformations including craniofacial defects, neural tube defects, and cardiac anomalies. Second and third trimesters: Increased risk of spontaneous abortion, intrauterine growth restriction, and fetal death. Human data show teratogenicity at therapeutic doses. |
■ FDA Black Box Warning
No black box warnings.
| Serious Effects |
None.
| Precautions | ["Reduced serum vitamin A levels: Supplement with recommended daily allowance of vitamin A.","Hypersensitivity reactions including angioedema have occurred; discontinue if severe."] |
| Food/Dietary | No specific food interactions are known with ALYFTREK. However, delayed gastric emptying may be exacerbated by high-fat or high-calorie meals; patients are advised to consume smaller, low-fat meals to improve tolerability. Alcohol may increase the risk of hypoglycemia when combined with insulin secretagogues. |
| Clinical Pearls |
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| Geriatric use | No specific dose adjustment is recommended for elderly patients (≥65 years). Pharmacokinetic data are limited; monitor for adverse effects. |
| Fetal Monitoring |
| Confirm negative pregnancy test prior to initiation. Monthly pregnancy tests during therapy. Fetal ultrasound for anomaly screening at 18-20 weeks gestation. Monitor for signs of fetal distress and growth restriction via serial ultrasound. Postnatal monitoring for infant abnormalities. |
| Fertility Effects | May impair fertility in females by disrupting ovarian function and menstrual cycle. In males, may cause decreased sperm count and motility. Effects are potentially reversible upon discontinuation. |
| ALYFTREK (tirzepatide) is a dual GIP and GLP-1 receptor agonist. It is administered once weekly subcutaneously. Rapid dose escalation may worsen gastrointestinal tolerability; follow the titration schedule strictly. Consider holding the dose prior to procedures requiring prolonged fasting. Monitor for signs of pancreatitis, gallbladder disease, and hypoglycemia, especially when used with sulfonylureas or insulin. In patients with renal impairment, monitor for gastrointestinal adverse effects leading to dehydration. Not recommended in patients with severe gastrointestinal disease (e.g., gastroparesis). |
| Patient Advice | Inject ALYFTREK once weekly on the same day. If a dose is missed and 4 or more days remain until the next scheduled dose, administer it as soon as possible; if less than 4 days, skip the missed dose. · Store in the refrigerator (2°C to 8°C). After first use, can be stored at room temperature (up to 30°C) for up to 21 days. · Common side effects include nausea, diarrhea, vomiting, constipation, and abdominal pain; these often improve over time. · Seek medical attention if you experience severe abdominal pain (possible pancreatitis) or signs of gallbladder issues (upper right abdominal pain, jaundice). · Inform your healthcare provider if you are taking sulfonylureas or insulin; dose adjustments may be needed to prevent hypoglycemia. · Avoid skipping meals or drastically reducing fluid intake, as this may worsen gastrointestinal symptoms. |