Patisiran
FDA Drug Information • Also known as: Onpattro
- Brand Names
- Onpattro
- Route
- INTRAVENOUS
- Dosage Form
- INJECTION, LIPID COMPLEX
- Product Type
- HUMAN PRESCRIPTION DRUG
Description
11 DESCRIPTION ONPATTRO contains patisiran, a double-stranded small interfering ribonucleic acid (siRNA), formulated as a lipid complex for delivery to hepatocytes. Patisiran specifically binds to a genetically conserved sequence in the 3' untranslated region (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, thymidine ONPATTRO is supplied as a sterile, preservative-free, white to off-white, opalescent, homogeneous solution for intravenous infusion in a single-dose glass vial. Each 1 mL of solution contains 2 mg of patisiran (equivalent to 2.1 mg of patisiran sodium). Each 1 mL also contains 6.2 mg cholesterol USP, 13.0 mg (6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-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 (PEG 2000 -C-DMG), 0.2 mg potassium phosphate monobasic anhydrous NF, 8.8 mg sodium chloride USP, 2.3 mg sodium phosphate dibasic heptahydrate USP, and Water for Injection USP. The pH is ~7.0. The molecular formula of patisiran sodium is C 412 H 480 N 148 Na 40 O 290 P 40 and the molecular weight is 14304 Da. Chemical Structure
What Is Patisiran Used For?
1 INDICATIONS AND USAGE ONPATTRO is indicated for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults. ONPATTRO contains a transthyretin-directed small interfering RNA and is indicated for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults.
Dosage and Administration
2 DOSAGE AND ADMINISTRATION For patients weighing less than 100 kg, the recommended dosage is 0.3 mg/kg every 3 weeks by intravenous infusion. For patients weighing 100 kg or more, the recommended dosage is 30 mg ( 2.1 ) Premedicate with a corticosteroid, acetaminophen, and antihistamines ( 2.2 ) Filter and dilute prior to administration ( 2.3 ) Infuse over approximately 80 minutes ( 2.4 ) 2.1 Dosing Information ONPATTRO should be administered by a healthcare professional. ONPATTRO is administered via intravenous (IV) infusion. Dosing is based on actual body weight. For patients weighing less than 100 kg, the recommended dosage is 0.3 mg/kg once every 3 weeks. For patients weighing 100 kg or more, the recommended dosage is 30 mg once every 3 weeks. Missed Dose If a dose is missed, administer ONPATTRO as soon as possible. If ONPATTRO is administered within 3 days of the missed dose, continue dosing according to the patient's original schedule. If ONPATTRO is administered more than 3 days after the missed dose, continue dosing every 3 weeks thereafter. 2.2 Required Premedication All patients should receive premedication prior to ONPATTRO administration to reduce the risk of infusion-related reactions (IRRs) [see Warnings and Precautions (5.1) ] . Each of the following premedications should be given on the day of ONPATTRO infusion at least 60 minutes prior to the start of infusion: Intravenous corticosteroid (e.g., dexamethasone 10 mg, or equivalent) Oral acetaminophen (500 mg) Intravenous H1 blocker (e.g., diphenhydramine 50 mg, or equivalent) Intravenous H2 blocker (e.g., famotidine 20 mg, or equivalent) For premedications not available or not tolerated intravenously, equivalents may be administered orally. For patients who are tolerating their ONPATTRO infusions but experiencing adverse reactions related to the corticosteroid premedication, the corticosteroid may be reduced by 2.5 mg increments to a minimum dose of 5 mg of dexamethasone (intravenous), or equivalent. Some patients may require additional or higher doses of one or more of the premedications to reduce the risk of IRRs [see Warnings and Precautions (5.1) ] . 2.3 Preparation Instructions ONPATTRO must be filtered and diluted prior to intravenous infusion. The diluted solution for infusion should be prepared by a healthcare professional using aseptic technique as follows: Remove ONPATTRO from the 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. ONPATTRO 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. Calculate the required dose of ONPATTRO based on the recommended weight-based dosage [see Dosage and Administration (2.1) ]....
Side Effects (Adverse Reactions)
6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Infusion-Related Reactions [see Warnings and Precautions (5.1) ] The most frequently reported adverse reactions (that occurred in at least 10% of ONPATTRO-treated patients and at least 3% more frequently than on placebo) were upper respiratory tract infections and infusion-related reactions ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Alnylam Pharmaceuticals at 1-877-256-9526 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of ONPATTRO cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. A total of 224 patients with polyneuropathy caused by hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) received ONPATTRO in the placebo-controlled and open-label clinical studies, including 186 patients exposed for at least 1 year, 137 patients exposed for at least 2 years, and 52 patients exposed for at least 3 years. In the placebo-controlled study, 148 patients received ONPATTRO for up to 18 months (mean exposure 17.7 months). Baseline demographic and disease characteristics were generally similar between treatment groups. The median age of study patients was 62 years and 74% were male. Seventy-two percent of study patients were Caucasian, 23% were Asian, 2% were Black, and 2% were reported as other. At baseline, 46% of patients were in Stage 1 of the disease and 53% were in Stage 2. Forty-three percent of patients had Val30Met mutations in the transthyretin gene; the remaining patients had 38 other point mutations. Sixty-two percent of ONPATTRO-treated patients had non-Val30Met mutations, compared to 48% of the placebo-treated patients. Upper respiratory tract infections and infusion-related reactions were the most common adverse reactions. One patient (0.7%) discontinued ONPATTRO because of an infusion-related reaction. Patients were instructed to take the recommended daily allowance of vitamin A [see Warnings and Precautions (5.2) ] . Sixty-four percent of patients treated with ONPATTRO had normal vitamin A levels at baseline, and 99% of those with a normal baseline developed low vitamin A levels. In one case, the decreased vitamin A level was reported as an adverse reaction. Table 1 lists the adverse reactions that occurred in at least 5% of patients in the ONPATTRO-treated group and that occurred at least 3% more frequently than in the placebo-treated group in the randomized controlled clinical trial. Table 1: Adverse Reactions from the Placebo-Controlled Trial that Occurred in at Least 5% of ONPATTRO-treated Patients and at Least 3% More Frequently than in Placebo-treated Patients Adverse Reaction ONPATTRO N=148 % Placebo N=77 % Upper respiratory tract infections Includes nasopharyngitis, upper respiratory tract infection, respiratory tract infection, pharyngitis, rhinitis, sinusitis, viral upper respiratory tract infection, upper respiratory tract congestion. 29 21 Infusion-related reaction Infusion-related reaction symptoms include, but are not limited to: arthralgia or pain (including back, neck, or musculoskeletal pain), flushing (including erythema of face or skin warm), nausea, abdominal pain, dyspnea or cough, chest discomfort or chest pain, headache, rash, chills, dizziness, fatigue, increased heart rate or palpitations, hypotension, hypertension, facial edema. 19 9 Dyspepsia 8 4 Dyspnea Not part of an infusion-related reaction. , Includes dyspnea and exertional dyspnea. 8 0 Muscle spasms 8 1 Arthralgia 7 0 Erythema 7 3 Bronchitis Includes bronchitis, bronchiolitis, bronchitis viral, lower respiratory tract infection, lung infection. 7 3 Vertigo 5 1 Four serious adverse reactions of atrioventricular (AV) heart block (2.7%) occurred in ONPATTRO-treated...
Contraindications
4 CONTRAINDICATIONS None. None
Pregnancy and Breastfeeding
8.1 Pregnancy 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]. Risk Summary 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 (12.2) , Warnings and Precautions (5.2) ] . 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. Data Animal Data 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...
How Supplied
16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied ONPATTRO is a sterile, preservative-free, white to off-white, opalescent, homogeneous solution for intravenous infusion supplied as a 10 mg/5 mL (2 mg/mL) solution in a single-dose glass vial. The vial stopper is not made with natural rubber latex. ONPATTRO is available in cartons containing one single-dose vial each. The NDC is: 71336-1000-1. 16.2 Storage and Handling Store at 2°C to 8°C (36°F to 46°F). Do not freeze. Discard vial if it has been frozen. If refrigeration is not available, ONPATTRO can be stored at room temperature up to 25°C (up to 77°F) for up to 14 days. For storage conditions of ONPATTRO after dilution in the infusion bag, see Dosage and Administration (2.3) .
About This Information
This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.
What are side effects?
Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.
What are drug interactions?
Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.