Onpattro is a brand-name intravenous (IV) infusion that’s prescribed for nerve damage caused by hATTR amyloidosis. Onpattro contains the active ingredient patisiran.

Onpattro is FDA approved to treat polyneuropathy (damage to multiple nerves) caused by a rare condition called hereditary amyloid transthyretin-mediated (hATTR) amyloidosis in adults.

Drug details

You’ll find key information about Onpattro below.

  • Drug class: RNA interference therapy (sometimes called a gene silencer)
  • Drug form: solution given as an IV infusion (an injection into a vein that lasts a certain length of time) by a healthcare professional
  • Generic available? no
  • Prescription required? yes
  • Controlled substance? no
  • Year of FDA approval: 2018

Onpattro is used to treat polyneuropathy (damage to multiple nerves) caused by hereditary amyloid transthyretin-mediated (hATTR) amyloidosis.

What happens in hATTR amyloidosis?

Amyloidosis is a rare condition in which you have a buildup of abnormal proteins throughout your body. These proteins are called amyloid deposits. They can cause various symptoms, depending on where they occur in your body.

With hATTR amyloidosis, the amyloid deposits are made from abnormal versions of a protein called transthyretin (TTR). TTR is made by your liver. When working properly, its job is to carry thyroid hormones and vitamin A throughout your body.

With hATTR amyloidosis, your liver makes abnormal TTR proteins because of an inherited genetic mutation (abnormal change in one of your genes). Cells in your body usually make proteins by following the instruction codes found in your genes.

People with hATTR amyloidosis have an abnormality in the gene that carries the instruction code for the TTR protein. When your liver cells follow this code, this issue makes them produce abnormal TTR proteins.

Abnormal versions of the TTR protein clump together to form amyloid deposits. These deposits can build up in several parts of your body, particularly your nerves and heart.

The deposits can affect nerves responsible for feeling and movement. They can also affect nerves that control functions such as digestion, storing and releasing urine, and blood pressure.

Onpattro’s mechanism of action

Onpattro is a type of drug called an RNA interference therapy (sometimes called a gene silencer). It blocks the effect of the genetic abnormality in hATTR amyloidosis. This reduces the amount of abnormal TTR proteins that your liver makes.

When your liver cells make TTR proteins, there are several steps involved.

In one of the steps, the instruction code for making the protein is copied from your TTR gene. This is done by a molecule called messenger RNA. The messenger RNA takes the code to another part of the cell, where the TTR protein is built.

Onpattro works by attaching to the messenger RNA and causing it to break down. This stops the cell from making the abnormal TTR proteins.

Onpattro also helps to reduce the buildup of amyloid deposits in the nerves throughout your body. Over time, your body breaks down existing deposits. This helps relieve some of the nerve symptoms these deposits cause. These symptoms can include:

  • tingling sensations
  • burning pain
  • trouble feeling changes in temperature
  • numbness
  • weakness
  • slower reflexes
  • trouble controlling movements
  • dizziness upon standing up
  • bowel and urinary problems

How long does it take to work?

Onpattro starts to lower the amount of TTR protein in your blood soon after your first infusion.

In clinical studies, Onpattro reduced the average amount of TTR in the blood by 80% within 10 to 14 days after the first dose. However, it could take a few months before your existing amyloid deposits break down and you notice a reduction in your symptoms.

Onpattro doesn’t reduce symptoms in everyone. However, it can still slow the progression (worsening) of your condition. In this case, you might not notice the drug working.

Onpattro is available only as a brand-name medication. It’s not currently available in generic form.

A generic drug is an exact copy of the active drug in a brand-name medication. Generics usually cost less than brand-name drugs.

The Onpattro dosage your doctor prescribes will depend on your body weight in kilograms (kg).

The following information describes dosages that are commonly used or recommended. However, your doctor will determine the best dosage to fit your needs.

Drug forms and strengths

Onpattro comes as a liquid solution in a single-dose vial. It’s available in one strength: 10 milligrams (mg) in 5 milliliters (mL) of solution.

Dosage for polyneuropathy caused by hereditary ATTR amyloidosis

Onpattro is given as an intravenous (IV) infusion, which is an injection into a vein that lasts a certain length of time. Each Onpattro infusion takes about 80 minutes.

For adults who weigh less than 220 pounds (100 kg), the recommended dosage of Onpattro is 0.3 mg per kg of body weight. This is given once every 3 weeks.

For adults who weigh 220 pounds (100 kg) or more, the recommended dosage of Onpattro is 30 mg. This is given once every 3 weeks.

What if I miss a dose?

It’s important to keep your appointments for your Onpattro infusions. If you miss an appointment, call your doctor’s office right away to reschedule. You should get the missed infusion as soon as possible.

If you receive your missed dose within 3 days, you can continue with your usual dosing schedule. If you’re more than 3 days late with the dose, talk with your doctor to adjust your Onpattro dosing schedule.

To help make sure you don’t miss an appointment for your infusion, try setting a reminder on your phone.

Will I need to use this drug long term?

Onpattro is meant to be used as a long-term treatment. If you and your doctor determine that Onpattro is safe and effective for you, you’ll likely take it long term.

Other drugs are available that can treat polyneuropathy that’s caused by hereditary amyloid transthyretin-mediated (hATTR) amyloidosis. Some may be a better fit for you than others. If you’re interested in finding an alternative to Onpattro, talk with your doctor. They can tell you about other medications that may work well for you.

Note: Some of the drugs listed below are used off-label to treat this specific condition. Off-label use is when a drug that’s approved to treat one condition is prescribed to treat a different condition.

Examples of other drugs that may be used to treat polyneuropathy caused by hereditary ATTR amyloidosis include:

You may wonder how Onpattro compares with other medications that are prescribed for similar uses. Here we look at how Onpattro and Tegsedi are alike and different.

Ingredients

Onpattro contains patisiran. Tegsedi contains inotersen.

Uses

Onpattro and Tegsedi are both FDA approved to treat polyneuropathy (damage to multiple nerves) caused by hereditary amyloid transthyretin-mediated (hATTR) amyloidosis. hATTR amyloidosis is a rare genetic condition in which abnormal protein deposits build up in your body.

Onpattro and Tegsedi are both approved for use in adults with this condition.

Both of these drugs are RNA interference therapies (sometimes called gene silencers). They reduce the production of the abnormal proteins in your liver.

Drug forms and administration

Onpattro comes as a liquid solution that’s given as an intravenous (IV) infusion (an injection into a vein that lasts a certain length of time).

You’ll get an Onpattro dose every 3 weeks. The IV infusion is usually given at your doctor’s office. However, you may be able to get the injections at home, given to you by a healthcare professional.

Tegsedi comes as a liquid solution in a single-dose prefilled syringe. It’s given by subcutaneous injection (under the skin) once every week. Your doctor can teach you how to give yourself the injection at home.

Side effects and risks

Onpattro and Tegsedi have some similar side effects and others that vary. Below are examples of these side effects.

Mild side effects

These lists contain up to 10 of the most common mild side effects that can occur with Onpattro, with Tegsedi, or with both drugs (when taken individually).

Serious side effects

These lists contain examples of serious side effects that can occur with Onpattro, with Tegsedi, or with both drugs (when taken individually).

  • Can occur with Onpattro:
    • infusion reaction
    • heart block (problems with your heart’s electrical signals)
    • extravasation (when the drug leaks from a vein into the tissue around the infusion site)
  • Can occur with Tegsedi:
  • Can occur with both Onpattro and Tegsedi:

* Tegsedi has boxed warnings for these side effects. A boxed warning is the most serious warning from the Food and Drug Administration (FDA). It alerts doctors and patients about drug effects that may be dangerous.

Effectiveness

Onpattro and Tegsedi haven’t been directly compared in clinical studies. However, studies have found both Onpattro and Tegsedi to be effective for treating this condition.

Costs

Onpattro and Tegsedi are both brand-name drugs. There are currently no generic forms of either drug. Brand-name medications usually cost more than generics.

Your cost for either drug may depend on your dosage. The cost may also depend on your insurance plan, your location, and if applicable, the pharmacy you use.

Onpattro can cause mild or serious side effects. The following lists contain some of the key side effects that may occur while taking Onpattro. These lists don’t include all possible side effects.

For more information on the possible side effects of Onpattro, talk with your doctor or pharmacist. They can give you tips on how to deal with any side effects that may be concerning or bothersome.

Note: The Food and Drug Administration (FDA) tracks side effects of drugs they’ve approved. If you would like to report to the FDA a side effect you’ve had with Onpattro, you can do so through MedWatch.

Mild side effects

Below is a partial list of mild side effects of Onpattro. To learn about other mild side effects, talk with your doctor or pharmacist, or view Onpattro’s prescribing information.

Most of these side effects may go away within a few days or a couple of weeks. But if they become more severe or don’t go away, talk with your doctor or pharmacist.

Serious side effects

Serious side effects from Onpattro aren’t common, but they can occur. Call your doctor right away if you have serious side effects. Call 911 if your symptoms feel life threatening or if you think you’re having a medical emergency.

Serious side effects and their symptoms can include:

  • Heart block (problems with your heart’s electrical signals). Symptoms can include:
    • feeling like you might faint
    • fainting
  • Extravasation (when the drug leaks from a vein into the tissue around the infusion site). Symptoms can include:
    • pain or burning sensation at the infusion site
    • redness, discoloration, or swelling at the infusion site

Other serious side effects are described below in “Side effect details.” These include:

Side effect details

You may wonder how often certain side effects occur with this drug. Here’s some detail on some of the side effects this drug may cause.

Infusion reactions

Some people may have a reaction during, or shortly after, an Onpattro infusion. Symptoms of an infusion reaction can include:

  • flushing
  • pain in the muscles or joints, including back or neck pain
  • nausea
  • abdominal pain
  • shortness of breath
  • cough
  • chest discomfort or pain
  • fast heart rate
  • heart palpitations (feeling like your heart is fluttering or pounding)
  • headache
  • dizziness
  • changes in blood pressure

You’ll be given medications before each infusion of Onpattro to lower your risk for having a reaction. You’ll also be monitored for signs of a reaction during the infusion. If you develop any symptoms of a reaction, such as those listed above, tell your doctor or healthcare professional right away.

You’re most likely to have a reaction with your first or second infusion. If you get a reaction during an infusion, the infusion may be slowed down or stopped temporarily. You may also need to take medications to help the ease the reaction.

If your symptoms improve, your infusion may be started again. However, if your symptoms are severe, the infusion usually won’t be restarted.

If you do have infusion reactions with Onpattro, your risk for continuing to have them lowers once you’ve had your first few infusions.

Upper respiratory infections

Some people may get an upper respiratory infection (such as a common cold or sinus infections) while taking Onpattro.

In clinical studies of Onpattro, upper respiratory infections were the most common side effect.

Symptoms of an upper respiratory infection may include:

  • blocked or runny nose
  • sinus pain
  • sneezing
  • sore throat

If you get symptoms like these that are severe or troublesome, talk with your doctor about medication to help ease them.

Low vitamin A level

Onpattro lowers the production of transthyretin (TTR) proteins by your liver. TTR proteins are responsible for transporting vitamin A around your body through your blood. Therefore, Onpattro can lower the vitamin A levels in your blood. It’s not known exactly how often this occurs.

Your doctor will prescribe you a vitamin A supplement to take during your Onpattro treatment. This will help prevent your vitamin A levels from getting too low.

Be sure to take your supplement exactly as prescribed. Don’t take any extra vitamin A supplements (such as multivitamins that contain vitamin A) in addition to what you’re prescribed.

Contact your doctor if you get any symptoms of vitamin A deficiency while taking Onpattro. These can include trouble seeing at night, dry eyes, and dry skin.

ALLERGIC REACTION

For some people, Onpattro can cause an allergic reaction. But it’s not clear whether this side effect occurred in the drug’s clinical studies.

In general, symptoms of allergic reaction can be mild or serious.

Ways to manage

For mild allergic reaction symptoms, such as a mild rash, call your doctor right away. They may recommend treatments to help manage your symptoms. They’ll also let you know whether you should keep taking the medication.

For severe allergic reaction symptoms, such as swelling or trouble breathing, call 911 or your local emergency number right away. These symptoms require immediate medical care because they can become life threatening. If you’ve had a serious allergic reaction to Onpattro, your doctor may recommend taking a different medication instead.

The Food and Drug Administration (FDA) approves prescription drugs such as Onpattro to treat certain conditions. Onpattro may also be prescribed off-label for other conditions. Off-label use is when a drug that’s approved to treat one condition is prescribed to treat a different condition.

Onpattro for polyneuropathy caused by hereditary ATTR amyloidosis

Onpattro is FDA approved to treat polyneuropathy (damage to multiple nerves) caused by a condition called hereditary amyloid transthyretin-mediated (hATTR) amyloidosis in adults.

Amyloidosis is a rare condition. It’s caused by a buildup of abnormal proteins, called amyloid deposits, in various tissues and organs throughout your body. There are several different types of amyloidosis.

With hATTR amyloidosis, amyloid deposits tend to build up mainly in your heart and nerves. The deposits can affect nerves responsible for feeling and movement. They can also affect nerves that control functions such as digestion, storing and releasing urine, and blood pressure. When several nerves throughout your body are affected, this is called polyneuropathy.

Onpattro treats symptoms of polyneuropathy caused by hATTR. These symptoms can include:

  • tingling sensations
  • burning pain
  • trouble feeling changes in temperature
  • numbness
  • weakness
  • slower reflexes
  • trouble controlling movements
  • dizziness upon standing up
  • bowel and urinary problems

Onpattro reduces the amount of abnormal proteins made by your liver, so there’s less buildup of amyloid deposits. This can help reduce these symptoms.

Effectiveness for polyneuropathy caused by hereditary ATTR amyloidosis

A clinical study of adults with polyneuropathy caused by hATTR amyloidosis found Onpattro to be effective for improving nerve function and quality of life.

This study compared Onpattro with a placebo (a treatment with no active drug). Researchers assessed people’s nerve function and quality of life before treatment and after 18 months of treatment.

Effectiveness for improving nerve function

In the study, nerve function was assessed using a scale called the modified neuropathy impairment score (mNIS+7). This scale measures various aspects of nerve function, including:

  • strength in the arms, legs, hands, and feet
  • reflexes
  • response to temperature and vibration
  • changes in blood pressure upon standing up

The overall score for nerve function can range from 0 to 304. Higher scores show worse nerve function.

After 18 months of treatment:

  • The average score in people who received Onpattro decreased by 6 points on the mNIS+7 scale. (This shows better nerve function than before treatment.)
  • The average score in people who received a placebo increased by 28 points. (This shows worse nerve function than before treatment.)

Effectiveness for improving quality of life

In the clinical study, quality of life was assessed using a scale called the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (QoL-DN) scale. This is a questionnaire that asks people to rate the effects of their disease on their daily life. This includes factors such as:

  • nerve symptoms, such as tingling, numbness, pain, and weakness
  • ability to perform daily tasks, such as washing, dressing, and walking
  • steadiness when standing or moving around
  • digestive symptoms, such as diarrhea, constipation, and trouble urinating

The overall score on this scale can range from -4 to 136. Higher scores show more problems with daily activities and a worse quality of life.

After 18 months of treatment:

  • The average score in people who received Onpattro decreased by 6.7 points on the QoL-DN scale. (This shows a better quality of life and fewer problems with daily activities than before treatment.)
  • The average score in people who received a placebo increased by 14.4 points. (This shows a worse quality of life and more problems with daily activities than before treatment.)

Off-label uses for Onpattro

In addition to the uses listed above, Onpattro may be prescribed off-label for other uses. Off-label drug use is when a drug that’s approved for one use is prescribed for a different one that’s not approved. Below is an example of an off-label use for Onpattro.

Onpattro for cardiomyopathy that’s caused by hereditary ATTR amyloidosis

Onpattro is not FDA approved to treat cardiomyopathy (damage to the heart muscle) caused by hATTR amyloidosis. However, it’s sometimes prescribed off-label for this purpose.

A clinical study to test the safety and effectiveness of Onpattro for this use is currently ongoing.

Onpattro and children

Onpattro is not FDA approved for use in children. The drug’s safety and effectiveness in children hasn’t been studied.

The symptoms of hereditary amyloid transthyretin-mediated (hATTR) amyloidosis typically don’t develop until early adulthood. Therefore, people are not usually diagnosed and treated until they are adults.

Onpattro may be taken with other drugs or supplements.

Drugs taken before your Onpattro infusion

Onpattro is given as an intravenous (IV) infusion (an injection into a vein that lasts a certain length of time). You’ll be given a combination of other drugs at least 1 hour before each infusion. These are known as premedications.

The premedications you’ll typically take before Onpattro are:

  • an injection of a corticosteroid, such as dexamethasone
  • two different antihistamine injections, such as famotidine (Pepcid) and diphenhydramine (Benadryl)
  • acetaminophen (Tylenol) to take by mouth

These premedications lower your risk of having a reaction to Onpattro. For more information about infusion reactions, see the “Onpattro side effects” section above.

Vitamin A supplement

During your Onpattro treatment, your doctor will prescribe you a vitamin A supplement. That’s because Onpattro can cause low vitamin A levels in your blood. (See the “Side effect details” section to learn more.)

Be sure to take your supplement exactly as prescribed. Don’t take any extra vitamin A supplements (such as multivitamins that contain vitamin A) in addition to what you’re prescribed.

There are no known interactions between Onpattro and alcohol.

However, drinking alcohol could worsen some of your symptoms of hereditary amyloid transthyretin-mediated (hATTR) amyloidosis. These symptoms may include:

  • fatigue
  • dizziness upon standing up
  • diarrhea
  • sexual problems

If you drink alcohol, talk with your doctor about how much is safe for you to drink during your Onpattro treatment.

There are no known interactions between Onpattro and any other medications, herbs and supplements, or foods.

Onpattro and other medications

No medications have been specifically reported to interact with Onpattro. However, before taking Onpattro, talk with your doctor and pharmacist. Tell them about all prescription, over-the-counter, and other drugs you take. Also tell them about any vitamins, herbs, and supplements you use. Sharing this information can help you avoid potential interactions.

If you have questions about drug interactions that may affect you, ask your doctor or pharmacist.

Onpattro and herbs and supplements

There aren’t any herbs or supplements that have been specifically reported to interact with Onpattro. However, you should still check with your doctor or pharmacist before using any of these products while taking Onpattro.

Onpattro and foods

There aren’t any foods that have been specifically reported to interact with Onpattro. If you have any questions about eating certain foods with Onpattro, talk with your doctor.

As with all medications, the cost of Onpattro can vary. The actual price you’ll pay will depend on your insurance plan, and if applicable, the pharmacy you use. It may also depend on the cost of visits to your clinic or doctor’s office to receive infusions.

It’s important to note that you’ll have to get Onpattro through your doctor’s office or at a specialty pharmacy. This type of pharmacy is authorized to carry specialty medications. These are drugs that may be expensive or may require help from healthcare professionals to be used safely and effectively.

Your insurance plan may require you to get prior authorization before they approve coverage for Onpattro. This means that your doctor and insurance company will need to communicate about your prescription before the insurance company will cover the drug. The insurance company will review the prior authorization request and decide whether the drug will be covered.

If you’re not sure whether you’ll need to get prior authorization for Onpattro, contact your insurance provider.

Financial and insurance assistance

If you need financial support to pay for Onpattro, or if you need help understanding your insurance coverage, help is available.

A program called Alnylam Assist is available for Onpattro. This program provides case managers who will help you find cost assistance for Onpattro. You may be eligible for the Onpattro copay program or patient assistance program. For more information and to find out if you’re eligible for support, call 833-256-2748 or visit the program website.

Generic version

Onpattro is not available in a generic form. A generic drug is an exact copy of the active drug in a brand-name medication. Generics tend to cost less than brand-name drugs.

Onpattro comes as a liquid solution in a single-dose vial. The drug is given as an intravenous (IV) infusion (an injection into a vein that lasts a certain length of time). The IV infusion is usually given at your doctor’s office. However, you may be able to get the injections at home, given to you by a healthcare professional.

Each Onpattro infusion takes about 80 minutes.

At least 1 hour before each infusion, you’ll be given a combination of other drugs. These are known as premedications. They lower your risk of having a reaction to the Onpattro infusion. (For more information about infusion reactions, see the “Onpattro side effects” section above.)

When it’s given

You’ll have your Onpattro infusion once every 3 weeks.

To help make sure you don’t miss an appointment to have your infusion, try setting a reminder in your phone. You can also put your treatment schedule on a calendar.

It’s not known if Onpattro is safe to take during pregnancy. The drug’s use during human pregnancy hasn’t been studied.

Some animal studies of the drug found that it caused fetal harm when given to pregnant females. Other animal studies showed that Onpattro didn’t cause harm. However, animal studies don’t always reflect what will happen in humans.

Onpattro can lower your vitamin A level. Vitamin A supplements are necessary for people taking Onpattro. Vitamin A is needed to help a fetus develop. However, excessive vitamin A can cause congenital anomalies (commonly known as birth defects).

It’s not known if the changes in vitamin A level caused by taking Onpattro and vitamin A supplements will affect the development of a fetus. If you’re pregnant, could become pregnant, or want to plan a pregnancy, talk with your doctor about the possible risks and benefits of Onpattro treatment.

Onpattro pregnancy registry

If you decide to take Onpattro during pregnancy, talk with your doctor about being enrolled in the pregnancy registry for this drug. Pregnancy registries gather information about how certain drugs affect pregnancy. To learn more about the registry, call 877-256-9526 or email alnylampregnancyprogram@iqvia.com.

It’s unknown whether Onpattro is safe to take during pregnancy. If you’re sexually active and you or your partner can become pregnant, talk with your doctor about your birth control needs while you’re using Onpattro.

It’s not known if Onpattro passes into human breast milk or if it can affect milk production.

If you’re currently breastfeeding or plan to breastfeed during your treatment, talk with your doctor about whether Onpattro is right for you.

Here are answers to some frequently asked questions about Onpattro.

Will Onpattro cure my condition?

No, Onpattro won’t cure your condition.

There’s currently no cure for hereditary amyloid transthyretin-mediated (hATTR) amyloidosis. However, Onpattro can help you manage the condition long term and help improve your quality of life.

It relieves symptoms and can slow down the progression (worsening) of hATTR amyloidosis.

Is Onpattro a steroid?

No, Onpattro isn’t a steroid. Steroids (also called corticosteroids) are medications used to reduce inflammation that occurs with a variety of conditions.

Onpattro is a type of drug called an RNA interference therapy (sometimes called a gene silencer). It blocks the effect of the genetic change that causes hATTR amyloidosis. Onpattro reduces the buildup of abnormal proteins that occur with this condition.

Although Onpattro is not a steroid, it’s taken with steroids. Each time you have your Onpattro treatment, you’ll be given a steroid beforehand, along with certain other drugs. This can help lower your risk for having a reaction to the Onpattro infusion. (An infusion is an injection into a vein that lasts a certain length of time.)

Is it safe for older adults to use Onpattro?

Yes, it’s likely safe for older adults to use this drug. In clinical studies of Onpattro, no differences in safety were seen between older adults (ages 65 and older) and younger adults.

If you have questions about whether Onpattro is right for you, talk with your doctor.

Can I take Onpattro if I have problems with my liver or kidneys?

Yes, in most cases you should be able to take Onpattro. However, always check with your doctor.

Onpattro can be used at the usual dosage for people who have mild to moderate kidney problems or mild liver problems. It hasn’t been studied in people with moderate or severe liver problems or those with severe kidney problems.

How will I know if I have a low vitamin A level while I’m taking Onpattro?

Onpattro can cause a low vitamin A level in your blood. Your doctor will prescribe you a vitamin A supplement to help prevent this.

Your doctor likely won’t order blood tests to check the level of vitamin A in your blood. Therefore, you may not know for sure what your vitamin A level is. That’s because the test results wouldn’t reflect vitamin A levels stored in the rest of your body (such as in your liver or fatty tissue). These stores of vitamin A could balance out your body’s overall level of vitamin A. Therefore, the test results likely wouldn’t be helpful.

See your doctor if you develop symptoms of a low vitamin A level. These can include:

Before taking Onpattro, talk with your doctor about your health history. Onpattro may not be right for you if you have certain medical conditions or other factors affecting your health. These include:

Note: For more information about the potential negative effects of Onpattro, see the “Onpattro side effects” section above.

Disclaimer: Medical News Today has made every effort to make certain that all information is factually correct, comprehensive, and up to date. However, this article should not be used as a substitute for the knowledge and expertise of a licensed healthcare professional. You should always consult your doctor or another healthcare professional before taking any medication. The drug information contained herein is subject to change and is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. The absence of warnings or other information for a given drug does not indicate that the drug or drug combination is safe, effective, or appropriate for all patients or all specific uses.

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