Nanofix (Human Coagulation Factor IX)
Plasma-derived factor IX concentrate for the treatment and prevention of bleeding in hemophilia B
Quick Facts about Nanofix
Key Takeaways about Nanofix
- Specialized treatment for hemophilia B: Nanofix replaces missing factor IX in patients with Christmas disease, enabling normal blood clotting and preventing or stopping bleeding episodes
- Plasma-derived product: Manufactured from human blood plasma with viral inactivation steps, though a small theoretical risk of pathogen transmission remains
- Inhibitor risk: Patients may develop neutralizing antibodies (inhibitors) against factor IX, which can reduce treatment effectiveness and increase anaphylaxis risk
- Individualized dosing: Dose is calculated based on body weight, desired factor IX level increase, and the clinical situation (type and severity of bleeding)
- Proper storage essential: Store at or below 25°C, do not freeze, protect from light, and use reconstituted solution within 8 hours
What Is Nanofix and What Is It Used For?
Nanofix is a plasma-derived coagulation factor IX concentrate used to treat and prevent bleeding in patients with hemophilia B (Christmas disease). It works by replacing the deficient clotting factor IX in the blood, restoring the body's ability to form blood clots and stop bleeding.
Nanofix belongs to a group of medicines called coagulation factors and contains human coagulation factor IX, a specialized protein that plays a critical role in the blood clotting cascade. In healthy individuals, factor IX works together with other clotting factors to form a stable blood clot when a blood vessel is injured. Patients with hemophilia B have an inherited deficiency of this protein, which means their blood does not clot properly, leading to prolonged or spontaneous bleeding.
Hemophilia B, also known as Christmas disease (named after Stephen Christmas, the first patient described with this condition), is a rare X-linked recessive bleeding disorder affecting approximately 1 in 25,000 to 30,000 male births worldwide. The condition ranges from mild to severe depending on the residual factor IX activity level in the patient's blood. Patients with severe hemophilia B (less than 1% factor IX activity) may experience spontaneous bleeding into joints (hemarthrosis), muscles, and internal organs, while those with mild disease (5-40% activity) typically only bleed excessively after trauma or surgery.
Nanofix is manufactured from pooled human blood plasma by Octapharma. The manufacturing process includes specific viral inactivation and removal steps to minimize the risk of transmitting infectious agents. The product is supplied as a lyophilized (freeze-dried) powder that must be reconstituted with the provided sterile water for injection before intravenous administration.
The primary clinical uses of Nanofix include:
- On-demand treatment: Stopping acute bleeding episodes such as joint bleeds, muscle bleeds, or bleeding following trauma or surgery
- Prophylaxis: Regular preventive treatment to reduce the frequency and severity of bleeding episodes in patients with severe hemophilia B
- Perioperative management: Maintaining adequate factor IX levels before, during, and after surgical procedures to prevent excessive bleeding
Factor IX activity in the blood is measured as a percentage of normal levels or in International Units (IU). One IU of factor IX per kilogram of body weight typically raises the plasma factor IX activity by approximately 1%. Your physician will determine the target factor IX level based on the type and severity of your bleeding episode.
What Should You Know Before Taking Nanofix?
Before using Nanofix, inform your physician about any allergies, history of heparin-induced thrombocytopenia, liver disease, cardiovascular risk factors, or recent surgery. As a plasma-derived product, Nanofix carries specific risks including hypersensitivity reactions, inhibitor development, and a theoretical risk of pathogen transmission.
Contraindications
You must not use Nanofix in the following situations:
- Hypersensitivity: If you are allergic to human coagulation factor IX or to any of the other ingredients in Nanofix, including heparin, sodium chloride, sodium citrate, arginine hydrochloride, or lysine hydrochloride
- Heparin-induced thrombocytopenia type II (HIT type II): If you have a history of HIT type II, a serious condition involving a significant decrease in blood platelet count following exposure to heparin. Platelets are blood cells essential for clot formation, and heparin is an anticoagulant medication. Nanofix contains trace amounts of heparin and must not be used in patients with this condition
As with all intravenously administered protein-containing medicines, hypersensitivity reactions are possible. Nanofix contains trace amounts of other human proteins besides factor IX, as well as heparin. Early signs of allergic reactions include hives, skin rash, chest tightness, wheezing, low blood pressure, and in severe cases, anaphylactic shock. If you experience any of these symptoms, stop the injection immediately and contact your healthcare provider. In the event of anaphylactic shock, standard emergency treatment should be initiated promptly.
Warnings and Precautions
Talk to your doctor or pharmacist before using Nanofix if any of the following apply to you:
Inhibitor development: Patients with hemophilia B can develop inhibitors (neutralizing antibodies) against factor IX. These antibodies are produced by the immune system and can render factor IX replacement therapy ineffective. Importantly, patients who develop inhibitors may have an increased risk of anaphylactic reactions. If you experience an allergic reaction during treatment, you should be tested for the presence of inhibitors. Your physician may therefore decide to administer the first injections of factor IX under medical supervision with appropriate emergency treatment available. After repeated treatment, patients should be monitored for inhibitor development, with levels measured in Bethesda Units (BU) using appropriate biological testing methods.
Thromboembolic risk: Factor IX concentrates can potentially cause thrombosis (blood clots) by promoting coagulation. This risk may be greater with lower-purity products. You should be monitored for signs of thrombosis and consumptive coagulopathy if you have any of the following conditions:
- Signs of fibrinolysis (dissolution of blood clots)
- Disseminated intravascular coagulation (DIC) - widespread clotting within blood vessels
- Liver disease
- Known cardiovascular risk factors
- Recent surgery
- Increased risk of clot formation or DIC
Viral safety: When medicines are manufactured from human blood or plasma, certain measures are taken to prevent the transmission of infections to patients. These include careful selection of blood and plasma donors to exclude those at risk of carrying infections, testing of individual donations and plasma pools for signs of viruses and infections, and inclusion of viral inactivation and removal steps in the manufacturing process. Despite these measures, when medicines prepared from human blood or plasma are administered, the possibility of transmitting an infectious agent cannot be entirely excluded. This also applies to unknown or emerging viruses and other types of infections.
The measures taken are considered effective for enveloped viruses such as HIV, hepatitis B, and hepatitis C, as well as for the non-enveloped hepatitis A virus. The measures may be of limited value against non-enveloped viruses such as parvovirus B19. Parvovirus B19 infection may be serious for pregnant women (fetal infection) and for individuals with compromised immune systems or certain types of anemia (such as sickle cell disease or hemolytic anemia).
Hepatitis vaccination: Your physician may recommend that you consider vaccination against hepatitis A and B if you regularly receive factor IX products derived from human plasma.
When you receive Nanofix, it is recommended that the product name and batch number are recorded to enable traceability of the product used. Keep a record of each infusion, including the batch number, date, and dose administered.
Use in newborns: If Nanofix is given to newborn infants, they should be carefully monitored for signs of disseminated intravascular coagulation (DIC).
Pregnancy and Breastfeeding
There is no clinical experience with the use of factor IX during pregnancy or breastfeeding. Because hemophilia B is an X-linked condition that primarily affects males, the use of factor IX in pregnant or breastfeeding women is extremely rare. Nanofix should only be used during pregnancy and breastfeeding if clearly necessary, and the potential benefits must be carefully weighed against the risks. Always consult your healthcare provider before using any medication during pregnancy or while breastfeeding.
Driving and Using Machines
Nanofix has no known effect on the ability to drive or operate machinery.
Sodium Content
Nanofix contains sodium. Specifically:
- Nanofix 500 IU: Contains up to 69 mg sodium per vial, equivalent to 3.45% of the WHO-recommended maximum daily sodium intake for an adult
- Nanofix 1000 IU: Contains up to 138 mg sodium per vial, equivalent to 6.9% of the WHO-recommended maximum daily sodium intake for an adult
This should be taken into consideration if you are on a controlled sodium diet.
How Does Nanofix Interact with Other Drugs?
No drug interactions have been reported between products containing human coagulation factor IX and other medications. However, always inform your physician about all medicines you are taking, including over-the-counter products and supplements.
Based on available clinical data and the product's mechanism of action, no known interactions exist between Nanofix and other pharmaceutical products. Unlike many oral medications that are metabolized by the liver's cytochrome P450 enzyme system, Nanofix is a protein-based therapy administered intravenously that functions directly within the coagulation cascade. This means it does not compete with other drugs for metabolic pathways.
However, there are certain clinical considerations to keep in mind:
| Drug / Drug Class | Consideration | Clinical Significance |
|---|---|---|
| Heparin and other anticoagulants | Nanofix contains trace amounts of heparin. Concurrent anticoagulant use requires careful monitoring | Monitor coagulation parameters closely |
| Antifibrinolytic agents | Tranexamic acid or aminocaproic acid may be used adjunctively but may increase thrombotic risk | Use with caution; monitor for thrombosis |
| Other factor IX products | Do not mix with other factor concentrates or medicinal products in the same infusion set | Administer separately |
| Activated prothrombin complex concentrates (aPCC) | May be used in patients with inhibitors; however, concurrent use with factor IX increases thrombotic risk | Not to be used simultaneously |
It is essential to inform your healthcare provider about all medications you are currently taking, have recently taken, or might take, including prescription medicines, over-the-counter drugs, and herbal supplements. While no formal drug interactions have been identified, comprehensive disclosure allows your medical team to make the best treatment decisions for your care.
What Is the Correct Dosage of Nanofix?
Nanofix dosing is individualized based on body weight, the desired increase in factor IX activity, the location and severity of bleeding, and the patient's clinical response. The standard formula is: Required IU = body weight (kg) x desired factor IX increase (%) x 0.8. Injection rate should not exceed 2-3 ml per minute.
Always use Nanofix exactly as your physician has instructed. Treatment should be initiated and supervised by a physician experienced in the treatment of hemophilia. The dose and duration of replacement therapy depend on the severity of factor IX deficiency, the location and extent of bleeding, and your clinical condition.
Dose Calculation
The dose of factor IX is expressed in International Units (IU). Factor IX activity in plasma is expressed either as a percentage (relative to normal human plasma) or in IU (relative to an international standard for factor IX in plasma). One IU of factor IX activity corresponds to the amount of factor IX in one milliliter of normal human blood plasma.
The required dose is calculated using the following formula:
Required IU = Body weight (kg) x Desired factor IX increase (%) x 0.8
For example, a 70 kg patient requiring a 50% increase in factor IX activity would need: 70 x 50 x 0.8 = 2,800 IU
Adults
| Type of Bleeding | Target Factor IX Level | Typical Dose Range | Duration |
|---|---|---|---|
| Minor bleeding (early joint bleed, minor muscle bleed) | 20-40% | 20-40 IU/kg | 1-2 days; repeat every 24 hours as needed |
| Moderate bleeding (muscle bleed, oral cavity, hemarthrosis) | 30-60% | 30-60 IU/kg | 2-7 days or until adequate healing |
| Major bleeding (life- or limb-threatening, intracranial) | 60-100% | 60-80 IU/kg | 7-14 days or until adequate healing |
| Surgery (major) | 80-100% (pre- and post-operative) | 60-80 IU/kg | Until adequate wound healing (7-14 days) |
Long-Term Prophylaxis
For the prevention of bleeding in patients with severe hemophilia B, the usual prophylactic dose is 20 to 40 IU per kg body weight, administered twice weekly. The dose should be adjusted based on the individual patient's response. In some cases, particularly in younger patients, shorter dosing intervals or higher doses may be necessary to maintain adequate trough levels of factor IX activity.
Children
In clinical studies involving children under 6 years of age, the average dose per treatment day was approximately 40 IU per kg body weight. Children may require higher doses or more frequent dosing than adults due to differences in pharmacokinetics (faster clearance of factor IX). Dosing in children should be based on clinical response and measured factor IX levels, with careful monitoring by a pediatric hematologist.
Missed Dose
If you are on a prophylactic regimen and miss a scheduled dose, administer the missed dose as soon as you remember. Do not double the dose to make up for a missed injection. Contact your hemophilia treatment center for guidance on adjusting your prophylactic schedule if you frequently miss doses.
Overdose
No symptoms of overdose have been reported with human coagulation factor IX. However, the recommended dose should not be exceeded. Excessive doses may theoretically increase the risk of thromboembolic complications. If you suspect an overdose, contact your physician or hemophilia treatment center immediately for monitoring and appropriate management.
Nanofix is administered intravenously after reconstitution with the provided solvent. The injection rate should not exceed 2-3 ml per minute. As a precaution, your pulse should be monitored before and during injection. If the pulse rate increases significantly, reduce the injection speed or temporarily stop the administration. Use only the infusion equipment provided with the product.
What Are the Side Effects of Nanofix?
Like all medicines, Nanofix can cause side effects, although not everybody gets them. The most significant risks include hypersensitivity reactions (including anaphylaxis), inhibitor development, thromboembolic events, and heparin-induced thrombocytopenia. Most side effects are rare to very rare in frequency.
Hypersensitivity or allergic reactions have been observed in patients treated with factor IX-containing products. These reactions can range from mild symptoms such as skin rash and hives to severe, life-threatening anaphylaxis. Patients who develop inhibitors against factor IX are at particular risk for anaphylactic reactions. If you experience any allergic symptoms, stop the infusion immediately and seek medical attention.
Hypersensitivity Reactions
- Hives (urticaria) and skin rash
- Chest tightness and wheezing
- Low blood pressure (hypotension)
- Nausea and vomiting
- Burning or stinging at injection site
- Headache and dizziness
- Drowsiness and restlessness
- Heart palpitations
- Tingling sensations
- Chills and flushing
Severe Allergic Reactions
- Anaphylaxis (severe systemic allergic reaction that may include shock)
- Angioedema (involuntary blood vessel spasms with facial, mouth, and throat swelling)
- Fever
Thromboembolic Complications
- Heart attack (myocardial infarction)
- Disseminated intravascular coagulation (DIC)
- Deep vein thrombosis (venous thrombosis)
- Pulmonary embolism (blood clots in the lungs)
Immune-Related Complications
- Inhibitor development (neutralizing antibodies against factor IX)
- Nephrotic syndrome (severe kidney disorder, reported in patients with inhibitors undergoing immune tolerance induction)
- Heparin-induced thrombocytopenia type II (sudden decrease in platelet count)
Inhibitor development: Patients with hemophilia B may develop neutralizing antibodies (inhibitors) against factor IX. If this occurs, the treatment may not work as expected, and your bleeding episodes may not be adequately controlled. In a clinical study of 25 children with hemophilia B, including six previously untreated patients, no inhibitors were detected, and injection tolerability was rated as "very good" or "good."
Heparin-induced thrombocytopenia (HIT type II): Nanofix contains heparin, which can cause a sudden decrease in platelet count to below 100,000 per microliter or to below 50% of the baseline count. In patients not previously sensitized to heparin, this decrease may occur 6 to 14 days after the start of treatment. In patients with prior heparin sensitivity, the change may develop within hours. Symptoms associated with HIT type II may include:
- Arterial and venous thrombosis
- Vessel occlusion due to embolism
- Consumptive coagulopathy
- Skin necrosis at the injection site
- Petechiae (pinpoint-sized bleeding spots)
- Purplish bruising
- Tar-like stools (indicating gastrointestinal bleeding)
If you observe any of these allergic or thrombocytopenic reactions, discontinue the injection of Nanofix immediately and do not use products containing heparin in the future. Due to this potential effect on platelets, your physician should monitor your platelet count, especially at the beginning of treatment.
Thromboembolic events are more commonly associated with lower-purity factor IX products and occur rarely with high-purity products such as Nanofix. Nevertheless, patients with predisposing risk factors should be closely monitored.
How Should You Store Nanofix?
Store Nanofix at or below 25°C (77°F). Do not freeze. Keep the vials in the outer carton to protect from light. After reconstitution, use immediately or within 8 hours at room temperature. Do not use if the solution is cloudy or contains undissolved particles.
Proper storage of Nanofix is essential to maintain the potency and safety of the medication. The following storage guidelines should be strictly followed:
- Temperature: Store at or below 25°C (77°F). Do not expose to excessive heat
- Freezing: Do not freeze Nanofix under any circumstances, as freezing can damage the protein structure and reduce effectiveness
- Light protection: Keep the vials in the original outer carton to protect from light, as factor IX is sensitive to light exposure
- Expiry date: Do not use Nanofix after the expiry date printed on the label and carton. The expiry date refers to the last day of the stated month
- After reconstitution: The reconstituted solution should ideally be used immediately. If not used immediately, it must be used within 8 hours when stored at room temperature (25°C)
- Single use only: Use the reconstituted solution on one occasion only. Discard any unused solution
- Visual inspection: Before administration, visually inspect the reconstituted solution. The solution should be clear or slightly opalescent. Do not use if it is cloudy, contains particles, or if the powder has not fully dissolved
- Keep out of reach: Store this medicine out of the sight and reach of children
Unused medicine and waste material should be disposed of in accordance with local requirements. Do not dispose of medicines via household waste or wastewater. Ask your pharmacist how to dispose of medicines you no longer use to help protect the environment.
What Does Nanofix Contain?
The active substance in Nanofix is human coagulation factor IX, derived from pooled human blood plasma. Each vial contains either 500 IU or 1000 IU of factor IX. The inactive ingredients include heparin, sodium chloride, sodium citrate, arginine hydrochloride, and lysine hydrochloride.
Active Ingredient
The active substance is human coagulation factor IX, purified from human blood plasma. The specific activity of Nanofix is approximately 100 IU per mg of protein, indicating a high-purity preparation. The potency (IU) is determined using a one-stage clotting assay according to the European Pharmacopoeia, calibrated against the World Health Organization (WHO) international standard.
Inactive Ingredients (Excipients)
- Heparin - trace amounts (anticoagulant used in manufacturing)
- Sodium chloride - isotonicity agent
- Sodium citrate - buffer/stabilizer
- Arginine hydrochloride - stabilizer
- Lysine hydrochloride - stabilizer
Presentation and Pack Sizes
Nanofix is supplied as a combination package consisting of two cartons held together with plastic film:
- Nanofix 500 IU: One vial of powder (nominally 500 IU factor IX) + one vial of solvent (5 ml water for injections). After reconstitution, contains approximately 100 IU/ml
- Nanofix 1000 IU: One vial of powder (nominally 1000 IU factor IX) + one vial of solvent (10 ml water for injections). After reconstitution, contains approximately 100 IU/ml
Each package also includes: 1 transfer set, 1 infusion set, 1 disposable syringe, and 2 alcohol swabs for disinfection.
How Do You Prepare and Administer Nanofix?
Nanofix must be reconstituted by dissolving the powder in the provided solvent using the enclosed transfer set. The reconstituted solution is then drawn into a syringe and injected slowly into a vein at a rate not exceeding 2-3 ml per minute.
Follow these instructions carefully for safe reconstitution and administration. Maintain sterility throughout the procedure. Only use the infusion equipment provided with the product, as using other injection or infusion sets may increase risks and lead to treatment failure.
Reconstitution Steps
- Allow to reach room temperature: Do not use the product immediately after removing from storage. Allow both the solvent and powder vials to reach room temperature in their unopened vials
- Clean vial stoppers: Remove the caps from both vials and wipe the rubber stoppers with the provided alcohol swabs
- Attach transfer set to solvent: Place the solvent vial on a flat surface and hold it steady. Take the transfer set, turn it upside down, and attach the blue end to the solvent vial. Press firmly until it clicks into place. Do not twist while connecting
- Connect to powder vial: Place the powder vial on a flat surface. Take the solvent vial with the attached transfer set and turn it upside down. Attach the white end to the powder vial's stopper and press firmly until it clicks. The liquid will flow automatically into the powder vial
- Dissolve: Gently rotate the powder vial with both vials connected until the powder is fully dissolved (usually within 10 minutes at room temperature). Some foaming may occur. Separate the transfer set into two parts to allow foam to dissipate
- Discard solvent vial: Dispose of the empty solvent vial with the blue part of the transfer set still attached
Injection Steps
- Draw up solution: Attach the syringe to the white part of the transfer set. Turn the vial upside down and draw the solution into the syringe. The solution should be clear or slightly opalescent
- Remove syringe: Hold the syringe plunger (pointing downward) and detach the syringe from the transfer set
- Prepare injection site: Clean the chosen injection site with an alcohol swab
- Attach infusion set: Connect the provided infusion set to the syringe
- Insert needle: Insert the needle into the selected vein. If you used a tourniquet, release it before starting the injection
- Inject slowly: Inject the solution slowly into the vein at a rate not exceeding 2-3 ml per minute. Blood must not enter the syringe due to the risk of clot formation
As a safety precaution, take your pulse before and during the injection. If your pulse rate increases noticeably, reduce the injection rate or temporarily stop the administration.
If you need more than one vial of Nanofix powder for a single treatment, the same needle and syringe may be used. However, the transfer set is for single use only.
Frequently Asked Questions about Nanofix
Nanofix is used for the treatment and prevention of bleeding in patients with hemophilia B (Christmas disease), an inherited bleeding disorder caused by a deficiency of clotting factor IX. It can be used both for on-demand treatment of acute bleeding episodes and for regular prophylactic treatment to reduce bleeding frequency. It is also used to manage bleeding during and after surgical procedures in hemophilia B patients.
Nanofix is a plasma-derived factor IX product, meaning it is manufactured from pooled human blood plasma. Recombinant factor IX products, by contrast, are produced using genetically engineered cell lines and do not contain human plasma. While both types effectively replace missing factor IX, plasma-derived products carry a theoretical risk of pathogen transmission despite extensive viral safety measures. Recombinant products eliminate this plasma-related risk but may have different pharmacokinetic profiles. Your hematologist will recommend the most appropriate product based on your individual needs.
Yes, after proper training at your hemophilia treatment center, you can learn to reconstitute and administer Nanofix at home. Home treatment allows for faster treatment of bleeding episodes and makes regular prophylaxis more convenient. However, the first several infusions should always be given under medical supervision to monitor for potential allergic reactions. Your healthcare team will provide detailed instructions and ensure you are confident in the technique before starting home treatment.
If your bleeding does not stop after receiving the correct dose of Nanofix, or if the expected factor IX activity level is not achieved, contact your physician immediately. This may indicate that you have developed inhibitors (neutralizing antibodies) against factor IX. Your doctor will test your blood plasma for the presence of inhibitors. If inhibitors are confirmed, alternative treatment approaches may be necessary, which your hematologist will discuss with you.
There is limited clinical experience with factor IX use during pregnancy and breastfeeding. Since hemophilia B primarily affects males, the situation rarely arises. If factor IX replacement is needed during pregnancy, it should only be used when the expected benefit justifies the potential risk. Your obstetrician and hematologist should work together to develop an appropriate treatment plan. Always discuss any medication use with your healthcare team during pregnancy.
After reconstitution, Nanofix should ideally be used immediately. If immediate use is not possible, the reconstituted solution may be stored at room temperature (up to 25°C) for a maximum of 8 hours. Do not refrigerate or freeze the reconstituted solution. Always inspect the solution before use - it should be clear or slightly opalescent. Discard any unused portion; do not save reconstituted Nanofix for later use.
References
This article is based on the following evidence-based medical sources. All information has been reviewed according to international medical standards and follows the GRADE evidence framework.
- European Medicines Agency (EMA). Summary of Product Characteristics: Human Coagulation Factor IX Products. Available at: www.ema.europa.eu
- Srivastava A, Santagostino E, Dougall A, et al. WFH Guidelines for the Management of Hemophilia, 3rd edition. Haemophilia. 2020;26(Suppl 6):1-158. doi:10.1111/hae.14046
- World Health Organization (WHO). WHO Model List of Essential Medicines - 23rd List. 2023. Available at: www.who.int
- Mannucci PM, Tuddenham EG. The hemophilias - from royal genes to gene therapy. N Engl J Med. 2001;344(23):1773-1779. doi:10.1056/NEJM200106073442307
- Bolton-Maggs PH, Pasi KJ. Haemophilias A and B. Lancet. 2003;361(9371):1801-1809. doi:10.1016/S0140-6736(03)13405-8
- Peyvandi F, Garagiola I, Young G. The past and future of haemophilia: diagnosis, treatments, and its complications. Lancet. 2016;388(10040):187-197. doi:10.1016/S0140-6736(15)01123-X
- British National Formulary (BNF). Factor IX Fraction, Dried. National Institute for Health and Care Excellence (NICE). Available at: bnf.nice.org.uk
- Octapharma. Nanofix Summary of Product Characteristics. Octapharma Pharmazeutika Produktionsges.m.b.H, Vienna, Austria.
About the Medical Editorial Team
This article has been written and reviewed by the iMedic Medical Editorial Team, which includes licensed specialist physicians in hematology, internal medicine, and pharmacology. Our editorial process follows international medical guidelines and the GRADE evidence framework to ensure the highest quality of medical information.
Content developed by medical professionals with expertise in hematology and coagulation disorders, based on approved product information and international clinical guidelines (WFH, EMA, WHO).
All content independently reviewed by the iMedic Medical Review Board. Evidence level: 1A (based on systematic reviews and meta-analyses of randomized controlled trials).
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