Onpattro (Patisiran)
RNA interference therapeutic for hereditary transthyretin-mediated amyloidosis (hATTR)
Onpattro (patisiran) is the first RNA interference (RNAi) therapeutic approved for the treatment of hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) in adults with polyneuropathy. It works by silencing the production of transthyretin protein in the liver, reducing the harmful amyloid deposits that cause progressive nerve and organ damage. Onpattro is administered as an intravenous infusion every three weeks by a healthcare professional.
Quick Facts
Key Takeaways
- Onpattro (patisiran) is the world's first approved RNAi therapeutic, specifically designed to treat hereditary transthyretin-mediated amyloidosis (hATTR) with polyneuropathy in adults.
- It is given as an intravenous infusion every 3 weeks, typically over approximately 80 minutes, and must always be administered by a healthcare professional.
- Premedication with a corticosteroid, antihistamines, and paracetamol is required before each infusion to reduce the risk of infusion-related reactions.
- Treatment lowers vitamin A levels in the blood; patients must take daily vitamin A supplements throughout treatment and women of childbearing potential must use effective contraception.
- In the pivotal APOLLO clinical trial, patisiran demonstrated significant improvement in polyneuropathy symptoms compared to placebo, with benefits seen across multiple organ systems.
What Is Onpattro and What Is It Used For?
Onpattro contains the active substance patisiran and represents a groundbreaking class of medicines known as RNA interference (RNAi) therapeutics. Approved by the European Medicines Agency (EMA) in 2018 and the U.S. Food and Drug Administration (FDA) in the same year, Onpattro was the first RNAi-based therapy ever to receive regulatory approval for clinical use. It is indicated for the treatment of hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) in adult patients with stage 1 or stage 2 polyneuropathy.
Hereditary transthyretin-mediated amyloidosis is a rare, progressively debilitating, and often fatal genetic disorder. It is caused by mutations in the gene that encodes for transthyretin (TTR), a protein produced primarily in the liver. In healthy individuals, TTR circulates in the blood as a stable tetramer (four-unit structure) and functions as a transport protein for retinol (vitamin A) and thyroxine (thyroid hormone). In patients with hATTR amyloidosis, genetic mutations cause the TTR protein to become unstable, misfold, and aggregate into insoluble amyloid fibrils that deposit in tissues throughout the body.
These amyloid deposits accumulate progressively in peripheral nerves, autonomic nerves, the heart, kidneys, gastrointestinal tract, and eyes, leading to a wide range of debilitating symptoms. The polyneuropathy component involves damage to sensory and motor nerves, causing numbness, tingling, pain, and weakness in the extremities. Cardiac involvement (cardiomyopathy) leads to heart failure, arrhythmias, and is a major cause of mortality. The disease typically manifests in adulthood and progresses over 5 to 15 years, with a median survival of approximately 4.7 years from the onset of cardiomyopathy.
Onpattro works through a sophisticated molecular mechanism: it uses small interfering RNA (siRNA) molecules encapsulated in lipid nanoparticles (LNPs) to target and silence TTR messenger RNA (mRNA) in hepatocytes (liver cells). By degrading the mRNA before it can be translated into protein, patisiran reduces serum TTR protein levels by approximately 80% on average. With less TTR protein in the bloodstream, fewer amyloid fibrils are formed, slowing or potentially halting disease progression. Emerging evidence suggests that reducing TTR production may also allow for some clearance of existing amyloid deposits from tissues.
It is important to note that Onpattro is approved only for use in adults. The safety and efficacy of patisiran have not been established in children and adolescents under 18 years of age. The estimated global prevalence of hATTR amyloidosis is approximately 50,000 patients, making it a rare (orphan) disease. Despite its rarity, hATTR amyloidosis has been identified in populations worldwide, with notable clusters in Portugal, Japan, Sweden, and Brazil.
What Should You Know Before Taking Onpattro?
Contraindications
Onpattro should not be used if you have ever had a severe allergic reaction to patisiran or any of the other ingredients contained in the formulation. The inactive ingredients include several lipid components (DLin-MC3-DMA, PEG2000-C-DMG, DSPC, cholesterol), disodium hydrogen phosphate heptahydrate, potassium dihydrogen phosphate, sodium chloride, and water for injections. If you are uncertain whether you may be allergic to any of these components, discuss this with your doctor or nurse before starting treatment.
Warnings and Precautions
Infusion-Related Reactions (IRRs): Onpattro is administered as an intravenous infusion, and reactions to the infusion are among the most common side effects. These reactions can occur during or shortly after the infusion and may include symptoms such as flushing, back pain, nausea, abdominal pain, difficulty breathing, chest discomfort, and changes in heart rate or blood pressure. To mitigate this risk, all patients receive premedication at least 60 minutes before each infusion, consisting of a corticosteroid, an H1-blocker antihistamine, an H2-blocker antihistamine, and paracetamol (acetaminophen).
If you experience any signs of an infusion-related reaction, tell your doctor or nurse immediately. Depending on the severity, the infusion may be slowed, temporarily stopped, or additional medications may be given to manage the symptoms. Once the reaction subsides or improves, the infusion may be restarted at a slower rate.
Onpattro treatment reduces vitamin A (retinol) levels in the blood because the TTR protein that it targets is responsible for transporting vitamin A throughout the body. Your doctor will measure your vitamin A levels before and during treatment. If your levels are low before starting treatment, your doctor will wait until they normalize before initiating Onpattro. You must take a daily vitamin A supplement (approximately 2,500 IU) throughout the course of treatment.
Symptoms of vitamin A deficiency can include impaired night vision, dry eyes, poor vision, and blurred or cloudy vision. If you develop any eye problems or changes in vision while receiving Onpattro, contact your doctor promptly. A referral to an ophthalmologist (eye specialist) may be necessary for further evaluation.
Both excessively high and excessively low vitamin A levels can be harmful to the development of an unborn child. For this reason, women of childbearing potential must use effective contraception during treatment and should not become pregnant while receiving Onpattro. If you are planning a pregnancy, discuss this with your doctor, who may advise discontinuation of treatment and will ensure your vitamin A levels have returned to normal before you attempt to conceive.
If you discover an unplanned pregnancy, inform your doctor immediately. During the first trimester, your doctor may advise you to stop vitamin A supplementation. During the last two trimesters, supplementation should be resumed if your vitamin A levels have not yet normalized, given the increased physiological demand for vitamin A in later pregnancy.
Pregnancy and Breastfeeding
If you are pregnant, breastfeeding, think you may be pregnant, or are planning to have a baby, seek advice from your doctor before receiving Onpattro. Women of childbearing potential should use an effective method of contraception during treatment. Pregnancy should be excluded before initiating therapy.
Onpattro should not be used during pregnancy unless your doctor considers it clearly necessary and the potential benefit justifies the potential risk to the fetus. The reduction in vitamin A levels caused by treatment is of particular concern, as vitamin A is essential for normal fetal development, and both deficiency and excess can cause birth defects.
The components of Onpattro may pass into breast milk. A decision must be made whether to discontinue breastfeeding or to discontinue treatment, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the mother. Discuss this decision with your doctor.
Drug Interactions
Inform your doctor or nurse about all medications you are taking, have recently taken, or might take. It is particularly important to report the following medications, as your doctor may need to adjust the dose:
- Bupropion – a medication used to treat depression or to help with smoking cessation
- Efavirenz – a medication used to treat HIV infection and AIDS
Patisiran is metabolized by nucleases and is not a substrate, inducer, or inhibitor of the major cytochrome P450 (CYP) enzymes at clinically relevant concentrations. However, the lipid nanoparticle components of Onpattro may temporarily affect CYP2B6 substrates (such as bupropion and efavirenz), potentially altering their plasma levels around the time of the infusion. For medications that are CYP2B6 substrates, dose adjustment or monitoring may be recommended, and these medications should ideally be taken at least a few hours before or after the Onpattro infusion.
Driving and Operating Machinery
Onpattro is considered to have negligible or no effect on the ability to drive and use machines. Your doctor will advise you whether your underlying condition allows you to safely drive and operate machinery.
Sodium Content
Onpattro contains 3.99 mg of sodium per milliliter, which is equivalent to approximately 0.2% of the WHO recommended maximum daily intake of 2 g sodium for an adult. This is generally considered a low sodium content and is unlikely to be clinically significant for most patients.
How Does Onpattro Interact with Other Drugs?
Because patisiran is a siRNA molecule that is metabolized by nucleases (enzymes that break down RNA) rather than by the cytochrome P450 (CYP) enzyme system, its potential for conventional drug-drug interactions is relatively limited compared to many small-molecule drugs. However, the lipid nanoparticle delivery system used in Onpattro can transiently affect certain drug-metabolizing enzymes, necessitating awareness of potential interactions.
Clinical pharmacology studies and population pharmacokinetic analyses have demonstrated that patisiran does not inhibit or induce the major CYP enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5) at clinically relevant concentrations. It is also not a substrate or inhibitor of common drug transporters such as P-glycoprotein (P-gp) or organic anion transporting polypeptides (OATPs).
| Interacting Drug | Drug Class | Interaction Type | Clinical Recommendation |
|---|---|---|---|
| Bupropion | Antidepressant / Smoking cessation aid | CYP2B6 substrate – potential alteration of plasma levels | Dose adjustment may be needed; monitor clinical response and side effects |
| Efavirenz | Non-nucleoside reverse transcriptase inhibitor (NNRTI) | CYP2B6 substrate – potential alteration of plasma levels | Dose adjustment may be needed; monitor for efficacy and adverse effects |
| Vitamin A supplements | Fat-soluble vitamin | Pharmacodynamic – Onpattro reduces retinol transport | Daily supplementation of ~2,500 IU vitamin A required during treatment |
Patients taking multiple medications should have a thorough medication review with their healthcare provider before initiating Onpattro. While the direct pharmacokinetic interaction profile of patisiran is favorable, the complexity of treating patients with hATTR amyloidosis—who often take medications for cardiac, neurological, and gastrointestinal symptoms—warrants careful clinical monitoring.
What Is the Correct Dosage of Onpattro?
Adults
The recommended dose of Onpattro for adult patients is 300 micrograms per kilogram (mcg/kg) of body weight, administered as an intravenous infusion once every three weeks (approximately every 21 days). The dose is calculated individually based on the patient's current body weight at each infusion visit.
Standard Adult Dosing
Dose: 300 mcg/kg body weight
Route: Intravenous infusion
Frequency: Once every 3 weeks
Infusion duration: Approximately 80 minutes
Initial rate: ~1 ml/min for the first 15 minutes, then ~3 ml/min for the remainder
Required Premedication
Approximately 60 minutes before each Onpattro infusion, all patients must receive the following premedication to reduce the risk of infusion-related reactions:
| Medication | Dose | Route |
|---|---|---|
| Dexamethasone (or equivalent corticosteroid) | 10 mg | Intravenous |
| Paracetamol (acetaminophen) | 500 mg | Oral |
| Diphenhydramine (or equivalent H1-blocker) | 50 mg | Intravenous |
| Famotidine (or equivalent H2-blocker) | 20 mg | Intravenous |
If a patient has tolerated at least three consecutive infusions without experiencing any infusion-related reactions, the corticosteroid dose may be gradually reduced in steps of no more than 2.5 mg, down to a minimum of 5 mg dexamethasone (IV) or its equivalent. Oral alternatives may be used for premedication components that are not available or not tolerated intravenously.
Children and Adolescents
Onpattro is not recommended for use in children and adolescents under 18 years of age. The safety and efficacy of patisiran have not been established in this age group, and no clinical data are available to support dosing recommendations for pediatric patients.
Elderly Patients
No dose adjustment is required for elderly patients. In clinical trials, a significant proportion of patients were over 65 years of age, and the safety and efficacy profile was consistent across age groups. However, elderly patients may be more susceptible to infusion-related reactions and should be monitored closely.
Missed Dose
If you miss a scheduled infusion appointment, contact your doctor or nurse as soon as possible to reschedule your treatment. Maintaining a consistent dosing schedule is important for optimal therapeutic benefit. Your healthcare team will advise you on the best time for your next infusion based on how much time has elapsed since your last dose.
Overdose
Because Onpattro is administered exclusively by healthcare professionals in a controlled clinical setting, the risk of accidental overdose is extremely low. In the unlikely event that an overdose occurs, the patient will be monitored for any signs of adverse effects, and supportive care will be provided as needed. There is no specific antidote for patisiran overdose.
What Are the Side Effects of Onpattro?
Like all medicines, Onpattro can cause side effects, although not everyone will experience them. The most frequently reported side effects are related to the intravenous infusion process and are managed through premedication protocols. Most side effects are mild to moderate in severity and tend to decrease over time with continued treatment.
Infusion-Related Reactions
Infusion-related reactions (IRRs) are the most common side effect of Onpattro, classified as very common (occurring in more than 1 in 10 patients). These reactions may occur during or shortly after the infusion and can present with a wide range of symptoms. Despite the high frequency of IRRs, premedication significantly reduces their severity, and most reactions are mild to moderate. In the APOLLO trial, fewer than 5% of patients discontinued treatment due to IRRs.
Symptoms of infusion-related reactions may include:
- Flushing, warmth, or redness of the face or body
- Back pain, neck pain, or joint pain
- Nausea or abdominal pain
- Headache and fatigue
- Chills and dizziness
- Coughing, shortness of breath, or other breathing difficulties
- Chest discomfort or chest pain
- Rapid heart rate or changes in blood pressure
- Rash, itching, or skin redness
- Swelling of the face or hoarseness
- Pain, redness, or swelling at the infusion site
Tell your doctor or nurse immediately if you experience any of these symptoms during your infusion. The infusion may be slowed or stopped, and you may receive additional medications to control the reaction. Some patients have experienced fainting due to low blood pressure during infusion.
Side Effects by Frequency
Very Common
May affect more than 1 in 10 people
- Infusion-related reactions (flushing, pain, nausea, headache, chills, breathing difficulties, rash, changes in heart rate/blood pressure)
- Peripheral edema (swelling of arms or legs)
Common
May affect up to 1 in 10 people
- Arthralgia (joint pain)
- Muscle spasms
- Dyspepsia (indigestion)
- Dyspnea (shortness of breath)
- Erythema (skin redness)
- Dizziness or vertigo
- Rhinitis (blocked or runny nose)
- Sinusitis (sinus inflammation or infection)
- Bronchitis (airway inflammation)
Uncommon
May affect up to 1 in 100 infusions
- Extravasation at the infusion site (leakage of medication into surrounding tissue, potentially causing localized swelling and redness)
It is important to report any suspected side effects after the medicine has been authorized. This enables ongoing monitoring of the benefit-risk balance of the medicine. Healthcare professionals and patients can report suspected adverse reactions to their national pharmacovigilance authority (e.g., the FDA MedWatch program in the United States, the Yellow Card Scheme in the United Kingdom, or the EMA's EudraVigilance system in the European Union).
How Should You Store Onpattro?
Onpattro must be stored and handled correctly to maintain its efficacy and safety. As this medication is typically stored and administered in healthcare facilities, patients generally do not need to manage storage themselves. However, it is important to understand the storage requirements:
- Refrigerated storage: Store at 2°C to 8°C (36°F to 46°F)
- Do not freeze: Onpattro must never be frozen; discard any vial that has been frozen
- Room temperature excursion: If refrigeration is not available, the unopened vial may be stored at room temperature (up to 25°C / 77°F) for a maximum of 14 days
- Diluted solution: Once diluted for infusion, the solution should be used immediately. If not used right away, it can be stored at room temperature (up to 30°C / 86°F) or refrigerated (2°C to 8°C) for up to 16 hours, including infusion time
- Expiry date: Do not use Onpattro after the expiry date printed on the carton
- Keep out of reach of children
Unused medicine or waste material should be disposed of in accordance with local pharmaceutical waste regulations. Onpattro does not contain preservatives and is intended for single use only. Any unused portion of a vial should be discarded.
What Does Onpattro Contain?
Onpattro is a white to off-white, opalescent, homogeneous concentrate for solution for infusion. Each vial contains patisiran sodium equivalent to 10 mg of patisiran in 5 ml (2 mg/ml). The formulation is carefully designed to encapsulate the siRNA molecules within lipid nanoparticles (LNPs) that protect the fragile RNA payload and facilitate targeted delivery to hepatocytes.
Active Ingredient
Patisiran (as patisiran sodium) – 2 mg per ml. Patisiran is a double-stranded small interfering RNA (siRNA) that is 21 nucleotides in length. It specifically targets a genetically conserved sequence in the 3’ untranslated region of both mutant and wild-type transthyretin mRNA.
Inactive Ingredients (Excipients)
The lipid nanoparticle formulation contains the following components:
- DLin-MC3-DMA – an ionizable lipid that is the primary component of the lipid nanoparticle, facilitating endosomal escape and cytoplasmic release of the siRNA
- PEG2000-C-DMG – a PEGylated lipid that provides steric stabilization and extends circulation time
- DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine) – a structural phospholipid
- Cholesterol – contributes to nanoparticle membrane stability and rigidity
- Disodium hydrogen phosphate heptahydrate – buffer component
- Potassium dihydrogen phosphate – buffer component
- Sodium chloride – tonicity agent
- Water for injections – solvent
A white to off-white coating may occasionally be observed on the inside of the vial, typically at the liquid surface area. This does not affect product quality. Each vial is for single use only, and the product does not contain preservatives. The concentrate must be diluted with 0.9% sodium chloride solution before administration and filtered through a 0.45-micrometer polyethersulfone (PES) filter during preparation.
Frequently Asked Questions About Onpattro
Onpattro (patisiran) is used to treat hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) in adults with polyneuropathy. This is a rare genetic disease in which an abnormal protein called transthyretin forms harmful amyloid deposits in nerves, the heart, and other organs. Onpattro works by using RNA interference to reduce the liver's production of this abnormal protein, thereby slowing disease progression and potentially allowing some reversal of nerve damage.
Onpattro is given as an intravenous (IV) infusion by a healthcare professional once every three weeks. Each infusion typically takes about 80 minutes. It starts at a slow rate (~1 ml/min) for the first 15 minutes, then increases to ~3 ml/min for the remainder. Approximately one hour before each infusion, you will receive premedication (a corticosteroid, two antihistamines, and paracetamol) to reduce the risk of infusion-related reactions. If your infusions are well tolerated in a clinical setting, your doctor may arrange for a healthcare professional to administer them at home.
Onpattro reduces the production of transthyretin (TTR) protein, which normally transports vitamin A (retinol) through the bloodstream. With less TTR available, vitamin A levels in the blood decrease. To prevent vitamin A deficiency and its associated symptoms (impaired night vision, dry eyes, blurred vision), patients must take a daily vitamin A supplement of approximately 2,500 IU throughout the course of treatment. Your doctor will monitor your vitamin A levels regularly. It is important not to exceed the recommended supplement dose, as excessive vitamin A can also be harmful.
Hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) is a rare, progressive, inherited disease caused by mutations in the TTR gene. The abnormal transthyretin protein misfolds and forms insoluble amyloid fibrils that deposit in tissues including nerves, the heart, kidneys, and gastrointestinal tract. This causes a range of symptoms including polyneuropathy (numbness, tingling, weakness in limbs), cardiomyopathy (heart failure), and organ dysfunction. It is estimated to affect approximately 50,000 people worldwide, with notable clusters in Portugal, Japan, Sweden, and Brazil. Without treatment, the disease is progressive and life-limiting.
Women of childbearing potential should use effective contraception during Onpattro treatment. Pregnancy should be avoided because Onpattro reduces vitamin A levels, and both vitamin A deficiency and excess can harm fetal development. If you plan to become pregnant, discuss this with your doctor first. Treatment may need to be stopped, and your doctor will check that your vitamin A levels have returned to normal before you try to conceive. If you discover an unplanned pregnancy while on treatment, inform your doctor immediately for guidance on managing vitamin A supplementation and deciding whether to continue therapy.
In the pivotal Phase 3 APOLLO trial, patisiran demonstrated statistically significant and clinically meaningful improvements compared to placebo across multiple endpoints. At 18 months, patients receiving patisiran showed improvement in polyneuropathy symptoms (as measured by the modified Neuropathy Impairment Score +7, mNIS+7), while placebo patients showed continued deterioration. Quality of life (Norfolk QOL-DN), walking ability (10-meter walk test), nutritional status (modified BMI), and autonomic function all showed favorable results. Approximately 56% of patients treated with patisiran showed improvement in neuropathy symptoms from baseline, compared to only 4% of placebo patients.
References
- European Medicines Agency (EMA). Onpattro (patisiran) – Summary of Product Characteristics (SmPC). Last updated March 2025.
- U.S. Food and Drug Administration (FDA). Onpattro (patisiran) Prescribing Information. Alnylam Pharmaceuticals, Inc.
- Adams D, Gonzalez-Duarte A, O'Riordan WD, et al. Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis (APOLLO Study). N Engl J Med. 2018;379(1):11-21. doi:10.1056/NEJMoa1716153
- Coelho T, Adams D, Silva A, et al. Safety and efficacy of RNAi therapy for transthyretin amyloidosis. N Engl J Med. 2013;369(9):819-829. doi:10.1056/NEJMoa1208760
- Adams D, Polydefkis M, González-Duarte A, et al. Long-term safety and efficacy of patisiran for hereditary transthyretin-mediated amyloidosis with polyneuropathy: 12-month results of an open-label extension study. Lancet Neurol. 2021;20(1):49-59.
- Gertz MA, Mauermann ML, Grogan M, Coelho T. Advances in the treatment of hereditary transthyretin amyloidosis: A review. Brain Behav. 2019;9(9):e01371.
- World Health Organization (WHO). Model List of Essential Medicines. 23rd edition, 2023.
- British National Formulary (BNF). Patisiran. National Institute for Health and Care Excellence (NICE).
Editorial Team
Written by the iMedic Medical Editorial Team – specialists in neurology, clinical pharmacology, and rare diseases with documented clinical and academic experience.
Reviewed by the iMedic Medical Review Board – an independent panel of board-certified physicians who verify all content against current international guidelines (EMA, FDA, WHO).
All medical claims are supported by peer-reviewed research and follow the GRADE evidence framework. Primary sources include the APOLLO trial (NEJM 2018), EMA assessment reports, and FDA prescribing information.
iMedic receives no commercial funding and has no ties to pharmaceutical companies. All content is editorially independent and written solely in the interest of patient education and safety.