ent
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 (12.3)]. ONPATTRO has not been studied in patientswith severe renal impairment or end-stage renal disease.
11 DESCRIPTION
ONPATTRO contains patisiran, a double-stranded small interfering ribonucleic acid (siRNA), formulated as a lipidcomplex for delivery to hepatocytes. Patisiran specifically binds to a genetically conserved sequence in the 3’ untranslatedregion (3’UTR) of mutant and wild-type transthyretin (TTR) messenger RNA (mRNA).
The structural formula is:
A, adenosine; C, cytidine; G, guanosine; U, uridine; Cm, 2’-O-methylcytidine; Um, 2’-O-methyluridine; dT, thymidineONPATTRO is supplied as a sterile, preservative-free, white to off-white, opalescent, homogeneous solution forintravenous infusion in a single-dose glass vial. Each 1 mL of solution contains 2 mg of patisiran (equivalent 2.1 mg ofpatisiran sodium). Each 1 mL also contains 6.2 mg cholesterol USP, 13.0 mg (6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31tetraen-19-yl-4-(dimethylamino) butanoate (DLin-MC3-DMA), 3.3 mg 1,2-distearoyl-sn-glycero-3-phosphocholine(DSPC), 1.6 mg α-(3’-{[1,2-di(myristyloxy)propanoxy] carbonylamino}propyl)-ω-methoxy, polyoxyethylene (PEG2000C-DMG), 0.2 mg potassium phosphate monobasic anhydrous NF, 8.8 mg sodium chloride USP, 2.3 mg sodium phosphatedibasic heptahydrate USP, and Water for Injection USP. The pH is ~7.0.
The molecular formula of patisiran sodium is C412 H480 N148 Na40 O290 P40 and the molecular weight is 14304 Da.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Patisiran is a double-stranded siRNA that causes degradation of mutant and wild-type TTR mRNA through RNAinterference, which results in a reduction of serum TTR protein and TTR protein deposits in tissues.
12.2 Pharmacodynamics
The pharmacodynamic effects of ONPATTRO were eva luated in hATTR amyloidosis patients treated with 0.3 mg/kgONPATTRO via intravenous infusion once every 3 weeks.Mean serum TTR was reduced by approximately 80% within 10 to 14 days after a single dose. With repeat dosing every3 weeks, mean reductions of serum TTR after 9 and 18 months of treatment were 83% and 84%, respectively. The meanmaximum reduction of serum TTR over 18 months was 88%. Similar TTR reductions were observed regardless of TTR
2.3 Preparation Instructions
ONPATTRO must be filtered and diluted prior to intravenous infmutation, sex, age, or race. In a dose-ranging study, greater TTR reduction was maintained over the dosing interval with
the recommended dosing regimen of 0.3 mg/kg every 3 weeks compared to 0.3 mg/kg every 4 weeks.
Serum TTR is a carrier of retinol binding protein, which is involved in the transport of vitamin A in the blood. Mean
reductions in serum retinol binding protein of 45% and serum vitamin A of 62% were observed over 18 months [see
Warnings and Precautions (5.2)].
12.3 Pharmacokinetics
Following a single intravenous administration, systemic exposure to patisiran increases in a linear and dose-proportionalmanner over the range of 0.01 to 0.5 mg/kg. Greater than 95% of patisiran in the circulation is associated with the lipidcomplex. At the recommended dosing regimen of 0.3 mg/kg every 3 weeks, steady state is reached by 24 weeks oftreatment. The estimat |
