Included as part of the PRECAUTIONS section.
Infusion-related reactions (IRRs) have been observed in patients treated with ONPATTRO. In clinical studies, all patients received premedication with a corticosteroid, acetaminophen, and antihistamines (H1 and H2 blockers) to reduce the risk of IRRs. In a controlled clinical study, 19% of ONPATTRO-treated patients experienced IRRs, compared to 9% of placebo-treated patients. Among ONPATTRO-treated patients who experienced an IRR, 79% experienced the first IRR within the first 2 infusions. The frequency of IRRs decreased over time. IRRs led to infusion interruption in 5% of patients. IRRs resulted in permanent discontinuation of ONPATTRO in less than 1% of patients in clinical studies. Across clinical studies, the most common symptoms (reported in greater than 2% of patients) of IRRs with ONPATTRO were flushing, back pain, nausea, abdominal pain, dyspnea, and headache [see ADVERSE REACTIONS]. One patient in the ONPATTRO expanded access program had a severe adverse reaction of hypotension and syncope during an ONPATTRO infusion.
Patients should receive premedications on the day of ONPATTRO infusion, at least 60 minutes prior to the start of infusion [see DOSAGE AND ADMINISTRATION]. Monitor patients during the infusion for signs and symptoms of IRRs. If an IRR occurs, consider slowing or interrupting the ONPATTRO infusion and instituting medical management (e.g., corticosteroids or other symptomatic treatment), as clinically indicated. If the infusion is interrupted, consider resuming at a slower infusion rate only if symptoms have resolved. In the case of a serious or life-threatening IRR, the infusion should be discontinued and not resumed.
Some patients who experience IRRs may benefit from a slower infusion rate or additional or higher doses of one or more of the premedications with subsequent infusions to reduce the risk of IRRs [see DOSAGE AND ADMINISTRATION].
Reduced Serum Vitamin A Levels And Recommended Supplementation
ONPATTRO treatment leads to a decrease in serum vitamin A levels. Supplementation at the recommended daily allowance of vitamin A is advised for patients taking ONPATTRO. Higher doses than the recommended daily allowance of vitamin A should not be given to try to achieve normal serum vitamin A levels during treatment with ONPATTRO, as serum vitamin A levels do not reflect the total vitamin A in the body.
Patients should be referred to an ophthalmologist if they develop ocular symptoms suggestive of vitamin A deficiency (e.g., night blindness).
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Patisiran-LC was not carcinogenic in TgRasH2 mice when administered at intravenous (IV) doses of 0, 0.5, 2, or 6 mg/kg every two weeks for 26 weeks.
Patisiran-LC was negative for genotoxicity in in vitro (bacterial mutagenicity assay, chromosomal aberration assay in human peripheral blood lymphocytes) and in vivo (mouse bone marrow micronucleus) assays.
Impairment Of Fertility
Intravenous (IV) administration of patisiran-LC (0, 0.03, 0.1, or 0.3 mg/kg) or a rodent-specific (pharmacologically active) surrogate (0.1 mg/kg) to male rats every two weeks prior to and throughout mating to untreated females produced no adverse effects on fertility.
Intravenous administration of patisiran-LC (0, 0.15, 0.50, or 1.5 mg/kg) or a rodent-specific (pharmacologically active) surrogate (1.5 mg/kg) to female rats every week for two weeks prior to mating and continuing throughout organogenesis resulted in no adverse effects on fertility or on embryofetal development.
Intravenous administration of patisiran-LC (0, 0.3, 1, or 2 mg/kg) to adult monkeys every three weeks for 39 weeks produced no adverse effects on male reproductive organs or on sperm morphology or count.
Use In Specific Populations
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ONPATTRO during pregnancy. Physicians are encouraged to enroll pregnant patients, or pregnant women may register themselves in the program by calling 1-877-256-9526 or by contacting [email protected]
There are no available data on ONPATTRO use in pregnant women to inform a drug-associated risk of adverse developmental outcomes. ONPATTRO treatment leads to a decrease in serum vitamin A levels, and vitamin A supplementation is advised for patients taking ONPATTRO. Vitamin A is essential for normal embryofetal development; however, excessive levels of vitamin A are associated with adverse developmental effects. The effects on the fetus of a reduction in maternal serum TTR caused by ONPATTRO and of vitamin A supplementation are unknown [see CLINICAL PHARMACOLOGY, WARNINGS AND PRECAUTIONS].
In animal studies, intravenous administration of patisiran lipid complex (patisiran-LC) to pregnant rabbits resulted in developmental toxicity (embryofetal mortality and reduced fetal body weight) at doses that were also associated with maternal toxicity. No adverse developmental effects were observed when patisiran-LC or a rodent-specific (pharmacologically active) surrogate were administered to pregnant rats (see Data).
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.
Intravenous administration of patisiran-LC (0, 0.15, 0.50, or 1.5 mg/kg) or a rodent-specific (pharmacologically active) surrogate (1.5 mg/kg) to female rats every week for two weeks prior to mating and continuing throughout organogenesis resulted in no adverse effects on fertility or embryofetal development.
Intravenous administration of patisiran-LC (0, 0.1, 0.3, or 0.6 mg/kg) to pregnant rabbits every week during the period of organogenesis produced no adverse effects on embryofetal development. In a separate study, patisiran-LC (0, 0.3, 1, or 2 mg/kg), administered to pregnant rabbits every week during the period of organogenesis, resulted in embryofetal mortality and reduced fetal body weight at the mid and high doses, which were associated with maternal toxicity.
Intravenous administration of patisiran-LC (0, 0.15, 0.50, or 1.5 mg/kg) or a rodent-specific surrogate (1.5 mg/kg) to pregnant rats every week throughout pregnancy and lactation resulted in no adverse developmental effects on the offspring.
There is no information regarding the presence of ONPATTRO in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the motherâ€™s clinical need for ONPATTRO and any potential adverse effects on the breastfed infant from ONPATTRO or from the underlying maternal condition.
In lactating rats, patisiran was not detected in milk; however, the lipid components (DLin-MC3-DMA and PEG2000-CDMG) were present in milk.
Safety and effectiveness in pediatric patients have not been established.
No dose adjustment is required in patients ≥65 years old [see CLINICAL PHARMACOLOGY]. A total of 62 patients ≥65 years of age, including 9 patients ≥75 years of age, received ONPATTRO in the placebo-controlled study. No overall differences in safety or effectiveness were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
No dose adjustment is necessary in patients with mild hepatic impairment (bilirubin ≤1 x ULN and AST >1 x ULN, or bilirubin >1.0 to 1.5 x ULN) [see CLINICAL PHARMACOLOGY]. ONPATTRO has not been studied in patients with moderate or severe hepatic impairment.
No dose adjustment is necessary in patients with mild or moderate renal impairment (estimated glomerular filtration rate [eGFR] ≥30 to <90 mL/min/1.73m²) [see CLINICAL PHARMACOLOGY]. ONPATTRO has not been studied in patients with severe renal impairment or end-stage renal disease.