Note: Safety: Concomitant vitamin A supplementation is advised at appropriate recommended daily allowances during therapy due to patisiran-associated decreases in serum vitamin A concentrations. Premedication: At least 60 minutes prior to administration of patisiran, premedicate with a corticosteroid, acetaminophen, an H1 blocker, and an H2 blocker to reduce the risk of infusion-related reactions; see “Premedications” below.
Polyneuropathy of hereditary-transthyretin mediated amyloidosis:
<100 kg (Actual body weight): IV: 0.3 mg/kg once every 3 weeks.
≥100 kg (Actual body weight): IV: 30 mg once every 3 weeks.
Missed dose:
Within 3 days of missed dose: Administer missed dose as soon as possible, then continue dosing according to original schedule.
More than 3 days after missed dose: Administer missed dose as soon as possible, then continue dosing every 3 weeks thereafter.
Premedication:
Premedicate at least 60 minutes prior to each patisiran administration with an IV corticosteroid (eg, dexamethasone 10 mg or equivalent), oral acetaminophen (500 mg), an IV H1 blocker (eg, diphenhydramine 50 mg or equivalent), and an IV H2 blocker (eg, famotidine 20 mg or equivalent) (Ref). An oral equivalent may be administered for premedications not tolerated or not available IV. Additional or higher doses of one or more premedications may be necessary. For patients tolerating patisiran infusions but with adverse effects due to corticosteroid premedication, may reduce IV dexamethasone (or equivalent doses of another corticosteroid) by 2.5 mg increments to a minimum dose of 5 mg.
eGFR ≥30 to <90 mL/minute/1.73 m2: No dosage adjustment necessary.
eGFR <30 mL/minute/1.73 m2: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
Mild impairment (bilirubin ≤1 x ULN and AST >1 x ULN or bilirubin >1 to 1.5 x ULN): No dosage adjustment necessary.
Moderate or severe impairment: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
Infusion-related reactions:
Mild to moderate: Consider slowing or interrupting the infusion and resuming at a slower infusion rate when symptoms have resolved; consider additional or higher doses of premedication during subsequent infusions to reduce infusion-related reactions risk.
Serious or life-threatening: Discontinue therapy and do not readminister.
Refer to adult dosing.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in adults.
>10%:
Respiratory: Upper respiratory tract infection (29%)
Miscellaneous: Infusion related reaction (19%)
1% to 10%:
Cardiovascular: Atrioventricular block (3%; including complete atrioventricular block)
Dermatologic: Erythema of skin (7%)
Gastrointestinal: Dyspepsia (8%)
Nervous system: Vertigo (5%)
Neuromuscular & skeletal: Arthralgia (7%), muscle spasm (8%)
Ophthalmic: Blurred vision (3%), dry eye syndrome (5%), vitreous opacity (2%)
Respiratory: Bronchitis (7%), dyspnea (8%)
Frequency not defined:
Endocrine & metabolic: Vitamin A deficiency
Immunologic: Antibody development
There are no contraindications listed in the US manufacturer's labeling.
Canadian labeling: Severe hypersensitivity (eg, anaphylaxis) to patisiran or any component of the formulation.
Concerns related to adverse effects:
• Infusion-related reactions: Infusion-related reactions (IRR) have been reported, with a majority occurring within the first 2 infusions and the frequency decreasing with additional infusions. Common symptoms included abdominal, back or chest pain, dyspnea, facial edema, flushing, headache, nausea, rash, and tachycardia; severe hypotension and syncope have also been reported. Premedicate with a corticosteroid, acetaminophen, and antihistamines (H1 and H2 blockers).
• Reduced vitamin A levels: A decrease in serum vitamin A has been reported with patisiran treatment. Supplement the recommended daily allowance (RDA) of vitamin A during treatment. Do not administer doses higher than the RDA; serum vitamin A levels do not reflect the total vitamin A in the body. If ocular symptoms such as night blindness develop, refer the patient to an ophthalmologist.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Intravenous [preservative free]:
Onpattro: 10 mg/5 mL (5 mL)
No
Solution (Onpattro Intravenous)
10 mg/5 mL (per mL): $2,348.40
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Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Intravenous:
Onpattro: 10 mg/5 mL (5 mL)
IV: Following dilution and filtering, administer via an ambulatory infusion pump through a dedicated free-flowing DEHP-free line. Use a DEHP-free infusion set containing a 1.2 micron polyethersulfone in-line infusion filter. Infuse over ~80 minutes, with an initial infusion rate of ~1 mL/minute for 15 minutes, then increase to ~3 mL/minute for the remainder of the infusion. May extend duration of infusion >80 minutes to manage or prevent infusion-related reactions. After infusion is complete, flush IV administration set with NS. Monitor infusion site for infiltration and manage suspected extravasation using local standard practice for nonvesicants.
Polyneuropathy of hereditary-transthyretin mediated amyloidosis: Treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults.
None known.
There are no known significant interactions.
Patisiran decreases serum concentrations of vitamin A, which is required for normal fetal development. The effects to the fetus of maternal vitamin A supplementation during patisiran therapy, or the effects to the fetus of reducing maternal serum transthyretin, are not known.
Data collection to monitor pregnancy and infant outcomes following exposure to patisiran is ongoing. Health care providers are encouraged to enroll females exposed to patisiran during pregnancy in the Pregnancy Registry (877-256-9526 or [email protected]). Pregnant women may also register themselves.
It is not known if patisiran is present in breast milk.
According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother
Infusion-related reactions; ocular symptoms indicative of vitamin A deficiency (eg, night blindness)
Patisiran is a double-stranded small interfering ribonucleic acid (siRNA) that causes degradation of mutant and wild-type transthyretin (TTR) mRNA through RNA interference, which results in a reduction of serum TTR protein and TTR protein deposits in tissues. Serum TTR is a carrier of retinol binding protein, which is involved in the transport of vitamin A in the blood.
Onset: 10 to 14 days (mean serum TTR reduced by ~80%)
Distribution: Vdss: 0.26 ± 0.2 L/kg
Protein binding: Plasma protein: ≤2.1% (albumin and human alpha1-acid glycoprotein)
Metabolism: By nucleases to nucleotides of various lengths
Half-life elimination: 3.2 ± 1.8 days
Excretion: Urine: <1% as unchanged drug
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