ONPATTRO
Clinical safety rating: caution
Comprehensive clinical and safety monograph for ONPATTRO (ONPATTRO).
ONPATTRO (patisiran) is a small interfering RNA (siRNA) targeting transthyretin (TTR) mRNA. It binds to a genetically conserved sequence in the 3' untranslated region of mutant and wild-type TTR mRNA, leading to its degradation via RNA interference. This reduces hepatic synthesis of both mutant and wild-type TTR, thereby decreasing amyloid deposition in tissues.
| Metabolism | Patisiran is metabolized by nucleases to oligonucleotides of varying lengths. It is not a substrate for CYP450 enzymes. |
| Excretion | Primarily excreted via the liver as unchanged drug and metabolites into bile, with fecal elimination accounting for >95% of the administered dose. Renal excretion is minimal (<1% of dose). |
| Half-life | Terminal elimination half-life is approximately 3.2 days (range 2.5–4.1 days). This long half-life supports monthly subcutaneous dosing. |
| Protein binding | Highly protein-bound (>96%) to human plasma proteins, primarily albumin. |
| Volume of Distribution | Approximately 0.2 L/kg (or about 14 L in a 70 kg individual), indicating limited distribution, consistent with plasma compartment binding. |
| Bioavailability | Subcutaneous dosing yields approximately 80–90% bioavailability relative to intravenous administration. |
| Onset of Action | Reduction in serum transthyretin (TTR) levels is observed within 7–14 days after the first subcutaneous dose. Clinical improvement in neuropathy may take several months. |
| Duration of Action | The therapeutic effect (TTR knockdown) persists for the entire dosing interval (3 weeks). After discontinuation, TTR levels return to baseline over approximately 6 months. |
0.3 mg/kg intravenously once every 3 weeks.
| Dosage form | SOLUTION |
| Renal impairment | No dose adjustment is recommended for patients with mild to moderate renal impairment; no data for severe renal impairment or end-stage renal disease. |
| Liver impairment | No dose adjustment for mild hepatic impairment (Child-Pugh A); no data for moderate or severe hepatic impairment (Child-Pugh B or C). |
| Pediatric use | Safety and efficacy in pediatric patients have not been established; no dosing recommendations. |
| Geriatric use | No dose adjustment based on age; limited data in patients ≥75 years and no specific geriatric considerations. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for ONPATTRO (ONPATTRO).
| Breastfeeding | There are no data on the presence of patisiran in human milk, effects on the breastfed infant, or effects on milk production. The molecular weight of patisiran (lipid complex) suggests it is unlikely to cross into breast milk in significant amounts. The M/P ratio is unknown. Because of the potential for adverse reactions in nursing infants, advise patients that breastfeeding is not recommended during treatment and for at least 3 months after the last dose. |
| Teratogenic Risk | ONPATTRO (patisiran) is an RNAi therapeutic indicated for hereditary transthyretin-mediated amyloidosis. In animal reproductive studies, no adverse developmental effects were observed in pregnant rats and rabbits at exposures up to 63 and 26 times the human clinical exposure, respectively. However, because animal studies are not always predictive of human response, ONPATTRO should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. There are no adequate and well-controlled studies in pregnant women. The drug is not known to be teratogenic, but caution is advised for all trimesters. |
■ FDA Black Box Warning
No FDA black box warning.
| Serious Effects |
["None (no absolute contraindications listed in prescribing information)."]
| Precautions | ["Infusion-related reactions: Monitor during infusion; premedicate with corticosteroids, antihistamines, and acetaminophen.","Reduced serum vitamin A levels: Supplement with recommended daily allowance of vitamin A; monitor ocular symptoms.","Hepatotoxicity: Monitor liver function tests; reduce or discontinue if severe elevations occur."] |
Loading safety data…
| Fetal Monitoring | If ONPATTRO is administered during pregnancy, monitor for infusion-related reactions and hepatic function. Fetal monitoring should include standard prenatal care, with no specific additional fetal assessments required based on known data. However, consider periodic ultrasound to assess fetal growth and well-being, especially if maternal health complications arise. |
| Fertility Effects | In animal studies, patisiran had no adverse effects on male or female fertility in rats at exposures up to 63 times the human clinical exposure. There are no human data on fertility effects. It is not anticipated to impair fertility in humans based on mechanism of action. |