patisiran (Rx)

>10%

Upper respiratory tract infections (29%)

Infusion-related reaction (19%)

1-10%

Dyspepsia (8%)

Dyspnea (8%)

Muscle spasms (8%)

Arthralgia (7%)

Erythema (7%)

Bronchitis (7%)

Vertigo (5%)

Blurred vision (3%)

AV heart block (2.7%)

Vitreous floaters (2%)

<1%

Hypotension

Syncope

Extravasation

Postmarketing Reports

Pruritus

Contraindications

None

Cautions

Infusion-related reactions

• Infusion-related reactions (IRRs) observed in patients receiving therapy
• The most common symptoms reported include flushing, back pain, nausea, abdominal pain, dyspnea, and headache; severe hypotension and syncope reported as symptoms of IRRs in the expanded access program and postmarketing setting
• Patients should receive premedications on day of infusion, at least 60 min prior to infusion; monitor patients during infusion for signs and symptoms of IRRs; if IRR occurs, consider slowing or interrupting infusion and instituting medical management (eg, corticosteroids or other symptomatic treatment), as clinically indicated (see Dosing)
• If infusion interrupted, consider resuming at slower infusion rate only if symptoms have resolved; in case of a serious or life-threatening IRR, infusion should be discontinued and not resumed
• Some patients may benefit from slower infusion rate or, additional or higher doses of other premedications with subsequent infusions to reduce risk
• Severe hypotension and syncope reported as symptoms of IRRs

Reduced serum vitamin A levels and recommended supplementation

• May decrease serum vitamin A levels
• Vitamin A supplementation advised; higher doses than recommended daily allowance of vitamin A should not be given to try to achieve normal serum vitamin A levels during treatment; serum vitamin A levels do not reflect total vitamin A in the body
• Refer to ophthalmologist if patient develops ocular symptoms of vitamin A deficiency (eg, night blindness)

Pregnancy

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed 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 alnylampregnancyprogram@iqvia.com

No data are available on use in pregnant women to inform a drug-associated risk of adverse developmental outcomes

Treatment leads to a decrease in serum vitamin A levels, and vitamin A supplementation is advised; vitamin A is essential for normal embryofetal development; however, excessive levels of vitamin A are associated with adverse developmental effects; effects on the fetus of a reduction in maternal serum transthyretin caused by therapy and of vitamin A supplementation are unknown

Animal data

• 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 was administered to pregnant rats

Lactation

There is no information regarding presence of drug in human milk, effects on breastfed infant, or on milk production

Consider developmental and health benefits of breastfeeding along with mother’s clinical need for therapy and any potential adverse effects on breastfed infant from therapy or from the underlying maternal condition

In lactating rats, patisiran was not detected in milk; however, lipid components (DLin-MC3-DMA and PEG2000-CDMG) were present in milk

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Contains a double-stranded small interfering ribonucleic acid (siRNA), formulated as a lipid complex for delivery to hepatocytes; drug specifically binds to a genetically conserved sequence in the 3' untranslated region (3'UTR) of mutant and wild-type transthyretin (TTR) messenger RNA (mRNA); drug causes degradation of mutant and wild-type TTR mRNA through RNA interference, which results in a reduction of serum TTR protein and TTR protein deposits in tissues

Absorption

Steady state peak concentrations: 7.15 mcg/mL

Trough concentrations (Ctrough): 0.021 mcg/mL

AUC: 184 mcg·hr/mL

Distribution

Vd (steady-state): 0.26 L/kg

Metabolism

Metabolized by nucleases to nucleotides of various lengths

Elimination

Half-life: 3.2 days

Clearance (steady-state): 3 L/hr/kg

Excretion: <1% (urine, unchanged)

IV Preparation

Must filter and dilute solution prior to IV infusion; the solution should be prepared by a healthcare professional using aseptic technique

Remove vial from refrigerator and allow to warm to room temperature; do not shake or vortex

Inspect visually for particulate matter and discoloration; do not use if discoloration or foreign particles are present; the product is a white to off-white, opalescent, homogeneous solution; a white to off-white coating may be observed on inner surface of vial, typically at liquid-headspace interface; product quality is not impacted by presence of white to off-white coating

Calculate required dose based on recommended weight-based dosage

Withdraw entire contents of one or more vials into single sterile syringe

Filter solution through a sterile 0.45-micron polyethersulfone (PES) syringe filter into a sterile container

Withdraw required volume of filtered solution from sterile container using a sterile syringe

Dilute required volume of filtered solution into an infusion bag containing 0.9% NaCl for a total volume of 200 mL; use infusion bags that are di(2-ethylhexyl)phthalate-free (DEHPfree)

Gently invert bag to mix solution; do not shake; do not mix or dilute with other drugs

Discard any unused portion

Product does not contain preservatives; the diluted solution should be administered immediately after preparation; if not used immediately, store infusion bag at room temperature (up to 30°C [86°F]) for up to 16 hr (including infusion time); do not freeze

IV Administration

Use a dedicated line with an infusion set containing a 1.2-micron PES in-line infusion filter

Use infusion sets and lines that are DEHP-free

Infuse diluted solution intravenously, via an ambulatory infusion pump, over ~80 minutes, at an initial infusion rate of approximately 1 mL/min for the first 15 minutes, then increase to ~3 mL/min for the remainder of the infusion; duration of the infusion may be extended in the event of an IRR

Administer only through a free-flowing venous access line; monitor infusion site for possible infiltration during drug administration; suspected extravasation should be managed according to local standard practice for nonvesicants

Observe patient during infusion and, if clinically indicated, following infusion

After completion of infusion, flush IV line with 0.9% NaCl to ensure that all the drug has been administered

Missed dose

• If dose is missed, administer as soon as possible
• If drug is administered within 3 days of missed dose, continue dosing according to original dosing schedule
• If drug is administered more than 3 days after missed dose, continue dosing q3Weeks thereafter

Storage

Unopened vials: Store at 2-8°C (36-46°F); do not freeze; discard vial if it has been frozen; if refrigeration is not available, store at room temperature up to 25°C (up to 77°F) for up to 14 days

Diluted solution: If not administered immediately after preparation, store infusion bag at room temperature up to 30°C (86°F) for up to 16 hr (including infusion time); do not freeze