Patisiran is a parenteral small interfering ribonucleic acid (siRNA) that is given by intravenous (IV) infusion every 3 weeks. Patisiran is indicated for the treatment of peripheral nerve disease (polyneuropathy) due to hereditary transthyretin-mediated amyloidosis (hATTR) in adults. In a randomized, placebo-controlled trial, patisiran-treated patients experienced significantly greater improvements in the modified Neuropathy Impairment Score +7 (mNIS+7) and the Quality of Life-Diabetic Neuropathy (QoL-DN) total score after 18 months of treatment compared to patients who received placebo. Improvements in these scores reflect gains in physiological outcomes (such as muscle strength, reflexes, sensation) and functional outcomes (such as walking, nutritional status, and performance of activities of daily living) with patisiran treatment. Infusion-related adverse reactions are common with patisiran; premedication against infusion-related reactions is necessary for all patients. The choice of transthyretin silencing therapy (i.e., inotersen, patisiran) may depend on patient accessibility, dominant phenotype, adverse reaction profile, and ease of administration. Vitamin A must be supplemented during patisiran therapy to avoid vitamin A deficiency.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
-To reduce the risk of infusion-related reactions, premedicate all patients at least 60 minutes before the start of patisiran infusion with an IV corticosteroid (e.g., dexamethasone 10 mg or equivalent), oral acetaminophen (500 mg), IV H1 blocker (e.g., diphenhydramine 50 mg or equivalent), and IV H2 blocker (e.g., famotidine 20 mg or equivalent).
-Additional or higher doses of the premedications may be given if needed.
-Reduce the corticosteroid dose by 2.5 mg increments to a minimum dose of 5 mg of IV dexamethasone (or equivalent) for patients experiencing corticosteroid-related adverse reactions.
-For premedications not available or tolerated by IV administration, equivalents may be given orally.
Route-Specific Administration
Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Do not use if discoloration or foreign particles are present. Patisiran is a white to off-white, opalescent, homogeneous solution. A white to off-white coating may be observed on the inner surface of the vial, typically at the liquid-headspace interface. Product quality is not impacted by presence of the white to off-white coating.
Intravenous Administration
Reconstitution:
-Allow product to warm to room temperature. Do not shake.
-Withdraw the entire contents of 1 or more vials as necessary for calculated dose into a single syringe.
-Filter through a sterile 0.45 micron polyethersulfone (PES) syringe filter into a sterile container.
-Withdraw the required volume of filtered product for the calculated dose from the sterile container using a sterile syringe.
Dilution:
-Dilute the required volume of filtered patisiran into an infusion bag of 0.9% Sodium Chloride Injection for a total volume of 200 mL. Use infusion bags that are di(2-ethylhexyl)phthalate-free (DEHP-free).
-Gently invert the bag to mix. Do not shake. Do not mix or dilute with other drugs.
-Storage: If not used immediately, diluted solution may be stored in the infusion bag at room temperature (up to 30 degrees C [86 degrees F]) for up to 16 hours (including infusion time). Do not freeze.
Intermittent IV infusion:
-Use a dedicated line with an infusion set containing a 1.2 micron PES in-line infusion filter. Use DEHP-free infusion sets and lines.
-Administer only through a free-flowing venous access line. Monitor the infusion site for infiltration. Manage extravasation according to local standard practice for non-vesicants.
-Infuse IV over approximately 80 minutes, at an initial infusion rate of approximately 1 mL/minute for the first 15 minutes, then increase to 3 mL/minute for the remainder of the infusion.
-Observe the patient during the infusion, and after the infusion if clinically indicated. The infusion duration may be extended for patients who experience an infusion-related reaction.
-Flush the administration set with 0.9% Sodium Chloride Injection after completion of the infusion.
-If a dose is missed, administer the dose as soon as possible. If the dose is given within 3 days of the missed dose, continue dosing according to the patient's original schedule. If the dose is given more than 3 days after the missed dose, continue dosing every 3 weeks thereafter.
In a placebo-controlled trial, infusion-related reactions were reported in 19% of patients who received patisiran (n = 148) for up to 18 months compared to 9% of patients who received placebo (n = 77). All patients were premedicated with a corticosteroid, acetaminophen, and histamine antagonists (H1 and H2 blockers). The most common symptoms (more than 2%) associated with patisiran infusion-related reactions include flushing (redness of the face or warm skin), back pain, nausea, abdominal pain, dyspnea, and headache. Other infusion-related reaction symptoms reported include arthralgia or pain (including neck or musculoskeletal pain), cough, chest discomfort or chest pain (unspecified), rash, chills, dizziness, fatigue, increased heart rate or palpitations, hypotension, hypertension, and facial edema. Infusion-related syncope, severe hypotension, and pruritus have been reported. Infusion-related reactions occurred within the first 2 infusions in 79% of patients who experienced reactions. The frequency of infusion-related reactions decreased over time. Infusion interruption occurred in 5% of patients who experienced infusion-related reactions; patisiran was permanently discontinued due to infusion-related reactions in less than 1% of patients. To reduce the risk of an infusion-related reaction, premedicate patients at least 60 minutes prior to the start of patisiran infusion with an intravenous corticosteroid (e.g., dexamethasone 10 mg or equivalent), oral acetaminophen (500 mg), intravenous H1 blocker (e.g., diphenhydramine 50 mg or equivalent), and an intravenous H2 blocker (e.g., ranitidine 50 mg or equivalent). Monitor patients during the infusion for signs and symptoms of infusion-related reactions. If an infusion-related reaction occurs, consider slowing or interrupting the infusion and beginning symptomatic treatment (e.g., corticosteroids), as clinically indicated. If the infusion is interrupted, consider resuming at a slower infusion rate only if symptoms have resolved. Discontinue and do not resume the infusion if serious or life-threatening reactions occur. A slower infusion rate or additional or higher doses of 1 or more of the premedications with subsequent infusions may benefit some patients who experience infusion-related reactions. Arthralgia (7% patisiran vs. 0% placebo), dyspnea, including exertional dyspnea, (8% vs. 0%), and muscle cramps (spasms) (8% vs. 1%) were also reported unrelated to an infusion reaction.
In a placebo-controlled trial, upper respiratory infection, including nasopharyngitis, pharyngitis, rhinitis, sinusitis, viral upper respiratory tract infection, unspecified respiratory tract infection, or upper respiratory tract congestion, was reported in 29% of patients who received patisiran (n = 148) for up to 18 months vs. 21% of patients who received placebo (n = 77). Bronchitis (includes bronchiolitis, viral bronchitis, lower respiratory tract infection, lung infection) was reported in 7% of patients treated with patisiran and 3% of patients treated with placebo.
In a placebo-controlled trial, vertigo was reported in 5% of patients who received patisiran (n = 148) for up to 18 months compared to 1% of patients who received placebo (n = 77).
In a placebo-controlled trial, dyspepsia was reported in 8% of patients who received patisiran (n = 148) for up to 18 months compared to 4% of patients who received placebo (n = 77).
Antidrug antibodies to patisiran were detected in 7 of 194 patients (3.6%) during placebo-controlled and open label clinical trials. An additional patient had pre-existing antidrug antibodies. Antibody formation did not appear to impact clinical efficacy, safety, or pharmacokinetic or pharmacodynamic profiles of patisiran.
In a placebo-controlled trial, AV block occurred in 2.7% of patients who received patisiran (n = 148) for up to 18 months. Complete AV block occurred in 3 cases. No cases of AV block were reported among patients who received placebo (n = 77).
In a placebo-controlled trial, ocular adverse reactions that occurred more frequently in patients who received patisiran than in patients who received placebo include xerophthalmia (5% vs. 3%), blurred vision (3% vs. 1%), and vitreous floaters (2% vs. 1%).
Extravasation was observed in less than 0.5% of patisiran infusions during clinical studies. Signs and symptoms included phlebitis or thrombophlebitis, dermatitis, cellulitis, or an injection site reaction including burning, erythema, swelling, or pain. In a clinical trial, erythema was also reported unrelated to an infusion reaction in 7% of patients who received patisiran (n = 148) for up to 18 months compared to 3% of patients who received placebo (n = 77).
Decreased vitamin A serum concentrations were observed during clinical studies with patisiran. Among patients treated with patisiran (n = 224), 64% had normal vitamin A serum concentrations at baseline. Low vitamin A serum concentrations developed in 99% of these patients who had normal baseline concentrations. Supplementation at the recommended daily allowance of vitamin A is advised for patients taking patisiran. Refer patients to an ophthalmologist if they develop ocular symptoms suggestive of vitamin A deficiency (e.g., night blindness).
Infusion-related reactions may occur in patients treated with patisiran. Premedicate patients at least 60 minutes prior to the start of patisiran infusion with an intravenous corticosteroid (e.g., dexamethasone 10 mg or equivalent), oral acetaminophen (500 mg), intravenous H1 blocker (e.g., diphenhydramine 50 mg or equivalent), and an intravenous H2 blocker (e.g., ranitidine 50 mg or equivalent). Monitor patients during the infusion for signs and symptoms of infusion-related reactions. If an infusion-related reaction occurs, consider slowing or interrupting the infusion and beginning symptomatic treatment (e.g., corticosteroids), as clinically indicated. If the infusion is interrupted, consider resuming at a slower infusion rate only if symptoms have resolved. Discontinue and do not resume the infusion if serious or life-threatening reactions occur. A slower infusion rate or additional or higher doses of 1 or more of the premedications with subsequent infusions may benefit some patients who experience infusion-related reactions. Common symptoms of infusion-related reactions include flushing, back pain, nausea, abdominal pain, dyspnea, and headache.
There are no data available on patisiran use during human pregnancy to inform a drug-associated risk of adverse developmental outcomes. Vitamin A supplementation is recommended for patients taking patisiran due to a decrease in serum vitamin A concentrations with treatment. Vitamin A is essential for normal embryofetal development; however, excessive vitamin A concentrations are associated with adverse developmental effects. The effects on the fetus from vitamin A supplementation or a reduction in maternal serum transthyretin (TTR) are unknown. In animal reproductive studies, increased embryofetal mortality, reduced fetal weight, and maternal toxicity were observed when patisiran lipid complex was administered intravenously at doses of 1 or 2 mg/kg to pregnant rabbits during organogenesis. No developmental adverse effects were observed when patisiran lipid complex was administered to pregnant rats. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to patisiran (Onpattro); information about the registry can be obtained at [email protected] or by calling 1-877-256-9526.
There are no data on the presence of patisiran in human milk, the effects of patisiran on the breast-fed infant, or the effects on milk production. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for patisiran and any potential adverse effects on the breast-fed infant from patisiran or the underlying maternal condition. In lactating rats, patisiran was not detected in milk; however, the lipid components were present.
Supplementation with the recommended daily allowance of vitamin A is advised for patients receiving patisiran. Patisiran treatment leads to a decrease in serum vitamin A concentrations. Do not give higher doses than the recommended daily allowance of vitamin A to try to normalize serum vitamin A concentrations, as serum concentrations do not reflect the total amount of vitamin A in the body. Refer patients to an ophthalmologist for evaluation if they develop ocular symptoms of vitamin A deficiency (e.g., night blindness).
For the treatment of hereditary transthyretin amyloidosis-associated polyneuropathy:
Intravenous dosage:
Adults weighing 100 kg or more: 30 mg IV every 3 weeks. The choice of transthyretin silencing therapy may depend on accessibility, dominant phenotype, adverse reaction profile, and ease of administration.
Adults weighing less than 100 kg: 0.3 mg/kg/dose IV every 3 weeks. The choice of transthyretin silencing therapy may depend on patient accessibility, dominant phenotype, adverse reaction profile, and ease of administration.
Maximum Dosage Limits:
-Adults
Adults weighing less than 100 kg: 0.3 mg/kg IV every 3 weeks.
Adults weighing 100 kg or more: 30 mg IV every 3 weeks.
-Geriatric
Adults weighing less than 100 kg: 0.3 mg/kg IV every 3 weeks.
Adults weighing 100 kg or more: 30 mg IV every 3 weeks.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Mild hepatic impairment (bilirubin up to 1 times the upper limit of normal (ULN) and AST more than 1 times the ULN, or bilirubin more than 1 and up to 1.5 times the ULN): No dosage adjustment is necessary.
Moderate or severe hepatic impairment: Patisiran has not been studied in these patients.
Patients with Renal Impairment Dosing
No dose adjustment is necessary in patients with mild or moderate renal impairment (estimated GFR 30 to 89 mL/minute/1.73 m2). Patisiran has not been studied in patients with severe renal impairment or end-stage renal disease.
*non-FDA-approved indication
There are no drug interactions associated with Patisiran products.
Patisiran is a double-stranded small interfering ribonucleic acid (siRNA) that causes degradation of mutant and wild-type transthyretin (TTR) messenger RNA (mRNA) through RNA interference. Patisiran specifically binds to a genetically conserved sequence in the 3' untranslated region of mutant and wild-type TTR mRNA. As a result, serum TTR protein and TTR protein tissue deposits are reduced.
Patisiran is administered intravenously. Plasma protein binding of patisiran is low, with 2.1% or less binding observed in vitro with human serum albumin and human alpha-1-acid glycoprotein. Patisiran is distributed primarily to the liver. More than 95% of patisiran in circulation is associated with the lipid complex. The steady-state volume of distribution (mean +/- SD) observed with the recommended dosing regimen of 0.3 mg/kg every 3 weeks is 0.26 +/- 0.2 L/kg. Patisiran is metabolized by nucleases to nucleotides of various lengths. Patisiran is mainly cleared through metabolism, and the total body clearance (mean +/- SD) at steady-state is 3 +/- 2.5 mL/hour/kg. Less than 1% of the administered dose of patisiran is excreted unchanged in the urine. The terminal elimination half-life (mean +/- SD) of patisiran is 3.2 +/- 1.8 days.
Affected cytochrome P450 isoenzymes and drug transporters: none
Patisiran is not a substrate of cytochrome P450 isoenzymes. It does not induce or inhibit cytochrome P450 isoenzymes or transporters.
-Route-Specific Pharmacokinetics
Intravenous Route
Systemic exposure to patisiran increases in a linear and dose-proportional manner after single dose IV administration over the range of 0.01 to 0.5 mg/kg. Steady-state is reached by 24 weeks of treatment with the recommended dosing regimen of 0.3 mg/kg IV every 3 weeks. The estimated steady-state peak (Cmax) and trough concentrations (mean +/- SD) were 7.15 +/- 2.14 mcg/mL and 0.021 +/- 0.044 mcg/mL, respectively. The mean steady-state AUC was 184 +/- 159 mcg x hour/mL. The accumulation of AUC was 3.2-fold at steady-state, compared to the first dose.
-Special Populations
Hepatic Impairment
Population pharmacokinetic analyses indicated no impact of mild hepatic impairment (bilirubin up to 1 times the upper limit of normal (ULN) and AST more than 1 times the ULN, or bilirubin more than 1 and up to 1.5 times the ULN) on patisiran exposure or transthyretin (TTR) protein reduction. Patisiran has not been studied in patients with moderate or severe hepatic impairment.
Renal Impairment
Population pharmacokinetic analyses indicated no impact of mild to moderate renal impairment (estimated GFR 30 to 89 mL/minute/1.73 m2) on patisiran exposure or transthyretin (TTR) protein reduction. Patisiran has not been studied in patients with severe renal impairment or end-stage renal disease.
Geriatric
Age had no impact on the steady-state pharmacokinetics of patisiran or transthyretin (TTR) protein reduction.
Gender Differences
Gender had no impact on the steady-state pharmacokinetics of patisiran or transthyretin (TTR) protein reduction.
Ethnic Differences
Race (non-Caucasian vs. Caucasian) had no impact on the steady-state pharmacokinetics of patisiran or transthyretin (TTR) protein reduction.
Other
Liver Transplantation
Prior liver transplantation had no impact on the steady-state pharmacokinetics of patisiran or transthyretin (TTR) protein reduction.