Sarilumab - Uses, Precautions, Side Effects, Dosage, and Clinical Trial Results

Overview:

Sarilumab, a human monoclonal antibody developed by Regeneron Pharmaceuticals and Sanofi, is used to treat moderately to severely active rheumatoid arthritis (RA), especially in those whose response to or tolerance for other conventional treatment options has been poor. RA affects multiple joints in the body, and treatment has been a challenge as different patients respond differently. Sarilumab, when administered subcutaneously, has been shown to improve the clinical symptoms of RA.

For rheumatoid arthritis, Sarilumab can be used alone or in combination with other disease-modifying antirheumatic drugs (DMARDs) or Methotrexate. This drug received United States Food and Drug Administration (FDA) approval on 22nd May, 2017 and European Medicines Agency (EMA) approval on 23rd June, 2017. It was also being tested for ankylosing spondylitis, but as it failed to show superior benefits to Methotrexate, Sarilumab has been suspended for this use.

How Does Sarilumab Work?

Sarilumab blocks the cis- and trans-inflammatory signaling cascades of IL-6 (interleukin 6) by binding to membrane-bound and soluble IL-6 receptors. IL-6 is known to activate T and B immune cells and hepatocytes (cells of the liver) to release CRP (C-reactive protein), serum amyloid A, fibrinogen, and other biomarkers of RA activity. IL-6 present in the synovial fluid (fluid present in the joints) mediates the inflammation and joint characteristics of rheumatoid arthritis. Sarilumab's action of inhibiting intra-articular and systemic IL-6 signaling reduces RA symptoms.

Uses:

1) Rheumatoid Arthritis - For moderately to severely active rheumatoid arthritis (RA) in adults who failed to respond to or tolerate more than one disease-modifying antirheumatic drug (DMARDs). Sarilumab can be used alone or in combination with other DMARDs or Methotrexate.

2) Off-Label for Coronavirus Disease 2019 (COVID-19)- The FDA has not approved Sarilumab as a treatment for COVID-19. This drug can be used as part of an investigational protocol for COVID-19 patients.

Dosage:

Injectable solution (prefilled syringe/pen)-

• 150mg/1.14 mL.

• 200mg/1.14 mL.

Warning:

1) Serious Infection Risk - Sarilumab affects the immune system, reducing the body's ability to fight infections. This can lead to serious and fatal infections for some people. Sarilumab can make you susceptible to various bacterial, viral, fungal, and other infectious diseases [including tuberculosis (TB)] that can spread throughout the body, resulting in the need for hospitalization or leading to death. There have been reports of death among people taking Sarilumab due to infections. In case of serious infection, Sarilumab should be stopped. Also, patients should be tested for latent TB (and if positive, treatment for TB should be started).

2) Intestinal Perforation- Intestinal perforation (a tear in the stomach or intestine) is commonly seen in patients taking Sarilumab along with nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, or Methotrexate. Those with diverticulitis (inflammation or infection of the pouches formed in the large intestine) and stomach ulcers are more prone. Warning signs for intestinal perforation are persistent fever and stomach ache.

3) Altered Lab Results- Sarilumab can lower the neutrophil (white blood cells that fight off infections), and platelet (cells that stop bleeding by clotting blood) counts, increase liver enzymes, and alter blood cholesterol levels. These changes can be severe, so blood tests should be done before starting this medicine, 4 weeks to 8 weeks after starting, and every six months.

4) Cancer- Sarilumab can make the user susceptible to certain cancers, as it alters the way the immune system works.

5) Severe Allergic Reactions- Sarilumab can cause severe allergic reactions and make the user feel dizzy and breathless. It can also lead to stomach ache, vomiting, chest pain, and swollen tongue, face, or lips.

Sarilumab is not approved for use in adolescents and children.

For Patients:

Learn About Rheumatoid Arthritis

Rheumatoid arthritis (RA) is an autoimmune condition, meaning the person’s immune system gets affected. Instead of attacking and fighting off infections and foreign bodies, the immune system starts affecting the healthy tissues around your joints, resulting in pain, inflammation, and stiffness. The exact cause behind the immune system acting this way is still not understood. The activation of the immune system results in the following proteins and cells attacking the joints, leading to joint damage.

1. Interleukin-6 (IL-6) - A protein produced by the white blood cells, majorly responsible for joint pain and swelling, morning stiffness, fatigue, and other symptoms of RA.

2. T cell - A type of white blood cell responsible for the functioning of our immune system functioning properly. In patients with RA, these cells identify parts of the body as foreign and attack them.

3. Tumor Necrosis Factor (TNF) - Also an immune system protein responsible for joint symptoms seen in RA, as it promotes inflammation.

Which Body Parts Does Rheumatoid Arthritis Affect?

Joints, especially in the hands, wrists, knees, elbows, and ankles, are mostly affected by rheumatoid arthritis. Many times, multiple joints get affected. It is called polyarthritis when five or more joints are affected or inflamed. Joint swelling results in joint stiffness and difficulty in moving the joints, particularly during the day (typically worse early in the morning).

Most people think RA symptoms are limited to the joints. But, in reality, RA can also damage other parts of the body. Over time, it can affect the eyes, skin, heart, blood vessels, and lungs. This is why it is said that over time, rheumatoid arthritis affects the way the entire body functions.

How Does Rheumatoid Arthritis Affect the Joints?

The body’s immune system attacks the tissue lining the joints (synovium), resulting in swelling or inflammation, which leads to loss of cartilage and bone erosion. The loss in cartilage decreases the space between adjacent bones, making joint movements painful and difficult. As it is a progressive disease, the bones and joints are damaged eventually.

Learn More About Sarilumab

Before Starting Sarilumab

Why and When to Switch to Sarilumab?

Rheumatoid arthritis (RA) affects and changes the body over time, making carrying out day-to-day and easy activities challenging. Doctors usually prescribe corticosteroids and Methotrexate after trying various medicines to achieve pain relief. In case all these options are suddenly ineffective, or your body is unable to tolerate the drugs, a newer treatment might help. This is the right time to talk to your healthcare provider about an IL-6 receptor blocker like Sarilumab. Sarilumab has proven to relieve joint pain, stiffness, and swelling associated with rheumatoid arthritis.

What Differentiates Sarilumab From Other Conventional Medicines?

Sarilumab works on the interleukin-6 (IL-6) receptor, while Methotrexate and DMARDs act on other pathways to reduce inflammation and pain. Sarilumab blocks the production of IL-6 by binding to IL-6 receptors. IL-6 is known to activate T and B immune cells and hepatocytes (cells of the liver) to release CRP (C-reactive protein), serum amyloid A, fibrinogen, and other biomarkers of RA activity. IL-6 in the synovial fluid (fluid present in the joints) mediates the inflammation and joint characteristics of rheumatoid arthritis. Sarilumab's action of inhibiting intra-articular (within the joints) and systemic IL-6 signaling reduces RA symptoms.

What Is the Action of Sarilumab on IL-6 and IL-6 Receptors?

Interleukin-6 or IL-6 is the protein produced by our white blood cells and is responsible for RA symptoms. In patients with RA, this protein is constantly produced in the joints and is carried throughout the body to other organs through blood. IL-6 receptors present on the cell membrane help connect IL-6 to the cells, which triggers the inflammatory response. These receptors present in the blood can also travel to other organs and bind with IL-6, resulting in inflammation. So to stop this inflammation process, the process by which IL-6 binds to IL-6 receptors has to be stopped. Sarilumab, which is an IL-6 receptor blocker, does precisely this.

How Effective Is Sarilumab?

When taken along with Methotrexate, Sarilumab was proven to:

• Provide pain relief in 2 weeks for some patients (although it might take up to three months to be effective in others).

• Reduce joint tenderness and swelling.

• Protect the joints and slow the progression of rheumatoid arthritis.

• Improve the ability to perform everyday activities.

Overall, Sarilumab reduces the symptoms and rate of progression of RA, thus improving the patient's general health.

Things to Tell Physicians Before They Prescribe Sarilumab:

1) History of infections or symptoms like fever, chills, cough, difficulty breathing, unexplained weight loss, painful skin lesions, stomach ache, vomiting, diarrhea, muscle pain, blood in the phlegm, painful urination, frequent urination, feeling more tired than usual, or history of treatment for infections.

2) Recent contact with a tuberculosis patient or a patient under treatment for tuberculosis.

3) History of conditions affecting and weakening the immune system, such as HIV (human immunodeficiency virus) infection, diabetes, etc.

4) History of hepatitis or other liver problems.

5) Recent travel to certain countries with high chances of getting infected with histoplasmosis, blastomycosis, coccidioidomycosis, or other fungal infections.

6) If you are taking medicines for stomach ulcers or diverticulitis.

7) If you are scheduled for or have already received a live vaccine shot.

8) If you are planning for surgery or other medical procedures.

9) If you are already pregnant or planning to start a family, or are breastfeeding.

10) Names of all the prescription and nonprescription medicines and supplements you are taking or have taken in the past. This should include details on medicines for rheumatoid arthritis and those that affect the liver enzymes.

Starting Sarilumab

How to Take Sarilumab?

Sarilumab is available as a pre-filled pen or syringe, which has to be self-injected once every two weeks. Your doctor will advise on taking this medicine alone or with Methotrexate.

Do’s and Don’ts While Using a Pre-Filled Pen:

• Do not forget to carefully read the instructions on using a pre-filled pen before using it.

• Store unused pens in the refrigerator between 36ºF and 46ºF (2ºC and 8ºC).

• If you are carrying it while traveling, keep it in an insulated bag with ice packs.

• Before injecting, warm the pen at room temperature for a minimum of 60 minutes.

• Ensure you use the pen within two weeks after taking it out of its cool environment.

• Avoid using the pen if it is damaged or the cap is detached or damaged.

• Remove the orange cap just before injecting.

• Avoid touching the yellow needle cover.

• Never try to put the orange cap back on the pen.

• Do not reuse, freeze, or heat up the pen.

• Avoid direct sun exposure.

• Never inject through clothes.

Disposing of the Pen Safely:

Expired medicine and used pens need to be disposed of carefully. The right way to do it is to put the pen in a sharps disposal container immediately after use and never throw it along with the household thrash. If you do not have a sharps disposal container, you can use a closed, puncture-resistant, leakproof container made of heavy-duty plastic. Once the container is almost full, follow your community guidelines to dispose of it. Make sure you follow the state or local laws about the disposal of syringes and pens.

Do’s and Don’ts While Using a Pre-Filled Syringe:

• Do not forget to read the instructions on using a pre-filled syringe carefully before using it.

• Check the dosage and name of the medicine.

• Store unused syringes in the refrigerator between 36ºF and 46ºF (2ºC and 8ºC).

• If you are carrying it while traveling, keep it in an insulated bag with ice packs.

• Before injecting, warm up the syringe at room temperature for a minimum of 30 minutes.

• Use the syringe within 14 days after taking it out of the refrigerator or insulated bag

• Avoid using the syringe if it is damaged or the needle is broken.

• Remove the needle cap just before you are ready to inject and not before.

• Avoid touching the needle.

• Never put the cap back on the needle.

• Do not reuse, freeze, or heat the syringe.

• Once out of the refrigerator, avoid storing the needle above 77ºF.

• Avoid direct sun exposure.

• Never inject through clothes.

Disposing of the Syringes Safely:

Expired medicine and used syringes need to be disposed of carefully. The right way is to put the syringe in a sharps disposal container immediately after use and never throw it along with the household thrash. If you do not have a sharps disposal container, you can use a closed, puncture-resistant, leakproof container made of heavy-duty plastic. Once the container is almost full, follow your community guidelines to dispose it of. Make sure you follow the state or local laws about the disposal of syringes and pens.

Things to Do After You Start Taking Sarilumab:

When you start taking Sarilumab, note any changes in feeling or health. Then, immediately inform your treating doctor if you develop any new symptoms or if the symptoms of RA worsen. Your doctor will only be able to monitor the effects of Sarilumab on you if you track the changes and inform them of the same.

Keep Moving:

It is imperative to keep your joints and body moving along with medication. Keeping the joints moving will improve morning stiffness. Always remember to consult your physician before introducing any new exercise routine.

Some things that you can consider are,

• Have a warm shower as soon as you get up or warm up your room to help your joints function properly. You will find it easier to flex the joints.

• Stay active with household chores or anything else the entire day.

• You can also try yoga, gentle stretching, walking, water aerobics, swimming, and other muscle-strengthening exercises to reduce joint stiffness, pain, and other symptoms.

Eat Healthily:

It is crucial to eat a healthy and well-balanced diet. For patients suffering from rheumatoid arthritis, foods that contain high amounts of omega-3 fatty acids help reduce inflammation to a great extent. Also include fatty fish, soy, whole grains, nuts, beets, leafy greens, and other anti-inflammatory food items in your diet. Avoid refined sugars and dairy at all costs.

Look Out for the Side Effects:

For patients who experience side effects of the drug, it is essential to adjust the treatment accordingly. Familiarize yourself with the common and rare side effects of Sarilumab, so you know exactly what to look out for. Remember, Sarilumab can result in some other side effects that are not listed here.

The common side effects include:

• Redness in the injection site.

• Upper respiratory tract infection, resulting in nasal congestion, runny nose, and sore throat.

• Tuberculosis and other infections - Sarilumab affects the immune system’s ability to fight off infections, making you more susceptible to infections, especially tuberculosis (TB). Unchecked, infections can spread throughout the body and result in fatal complications.

Common signs of infections include-

• Fever.

• Chills.

• Profuse sweating.

• Cough.

• Dyspnea or shortness of breath.

• Muscle pains.

• Blood in phlegm.

• Painful and red skin lesions.

• Weight loss.

• Upset stomach, diarrhea, and vomiting.

• Fatigue or tiredness.

• Pain or burning while urinating.

• Frequent urination.

• Increased risk of certain types of cancer.

• Intestinal Perforation - When Sarilumab is taken with nonsteroidal anti-inflammatory drugs (like Aspirin or Ibuprofen), disease-modifying antirheumatic drugs (DMARDs), and corticosteroids, some people might experience small tears in the stomach lining.

• Allergy - Severe allergic reactions are possible. Some signs include dizziness, breathing difficulty, stomach pain, vomiting, chest pain, and swollen tongue, face, or lips.

Get Blood Tests Regularly:

Along with your regular blood tests to check for moderate to severe rheumatoid arthritis, you would also have to get additional blood tests before and after starting Sarilumab. In addition to the blood tests before prescribing the medicine, your doctor will ask you for one after four to eight weeks and then every three months to check the levels of platelets, neutrophils, and liver enzymes, and every six weeks. This is to keep track of your:

• White blood cells (WBC) and platelets - Sarilumab can lower these blood parameters.

• Liver enzymes - They can increase.

• Blood cholesterol - It can also increase.

Any abnormalities in these test reports can result in the doctor asking you to temporarily stop taking the drug or adjust the dosage.

Avoid Self-Medication:

Never take any medicine, including Sarilumab, unless prescribed by a registered healthcare provider. All the blood tests mentioned are mandatory before starting this drug.

Staying on Sarilumab

Tips to Stay on Track:

Some patients see improvement in their symptoms within a few weeks, but it can take months for some. So if you do not see any changes immediately, do not stop taking the drug unless your physician suggests it. If you face any side effects, seek help immediately, so that the dosage can be altered or the drug can be stopped. Do not forget to report infection and allergy symptoms, if any. Also, follow the dosing and treatment schedule set by the physician.

Three points to remember,

1) Missing a dose will impact the treatment outcome, so stick to the schedule.

2) Set goals with the help of your doctor.

3) Follow up regularly with your doctor and let them know how you are doing.

For Doctors

Indication:

Sarilumab is used in adults with unacceptable drug responses or those intolerant to other conventional treatments.

Pharmacology:

Mechanism of Action:

This IL-6 inhibitor binds to IL-6 receptors (both soluble and membrane-bound) and inhibits the receptors' signaling. IL-6, a cytokine with inflammatory action, is produced by T-lymphocytes, B-lymphocytes, monocytes, fibroblasts, and a variety of other cells. The synovial and endothelial cells also produce IL-6, leading to inflammation in the joints and all the other symptoms of rheumatoid arthritis. As Sarilumab binds to these IL-6 receptors, IL-6 production does not take place, reducing inflammation and other symptoms.

Pharmacodynamics:

Treatment with Sarilumab in rheumatoid arthritis patients resulted in:

• Rapid reduction of CRP levels.

• Decrease in absolute neutrophil count.

• Decreases in fibrinogen and serum amyloid A.

• Increases in hemoglobin and serum albumin.

Absorption:

Metabolism:

Similar to endogenous IgG, Sarilumab gets degraded into small peptides and amino acids through the catabolic pathways.

Elimination:

The half-life is ten days for 200 mg and eight days for 150 mg. Monoclonal antibodies like Sarilumab are not excreted through the renal or hepatic pathways.

Warnings and Precautions:

1) Severe Infection Risk - Avoid prescribing this drug for patients with an active infection. Also, patients on Sarilumab are prone to serious infections requiring hospitalization or death. Opportunistic infections in patients taking Sarilumab along with immunosuppressants have been reported. The common infections include-

• Active pulmonary and extrapulmonary tuberculosis. Make sure the patient is tested for latent tuberculosis before starting Sarilumab. If present, treatment with standard antimycobacterial therapy should be started. In patients with a history of latent or active TB or those at risk for developing TB, consider anti-TB therapy before starting Sarilumab.

• Candidiasis, pneumocystis, and other invasive fungal infections.

• Viral or bacterial opportunistic infections.

• Pneumonia and cellulitis are also more commonly seen.

• In case the patient develops symptoms of infection while taking Sarilumab, stop the treatment and control the infection. Consider the risks and benefits of starting treatment with Sarilumab in patients with chronic or recurrent infection.

• In clinical studies, Sarilumab was reported to reactivate herpes zoster and other latent viruses.

2) Abnormal Lab Reports-

The following lab abnormalities were more frequently witnessed in those taking other hepatotoxic drugs, such as Methotrexate, along with Sarilumab-

• Decreased neutrophil count (neutropenia).

• Decreased platelet count (thrombocytopenia).

• Increased transaminase levels.

• Increased LDL (low-density lipoprotein), HDL (high-density lipoprotein), and triglycerides.

It is recommended that doctors check the neutrophil count, platelet count, and liver enzymes before putting the patient on Sarilumab. Also, keep assessing these parameters four to eight weeks after starting the drug and every three months thereafter. Blood cholesterol levels have to be assessed four to eight weeks after the initial dose, and then at every six months.

3) Gastrointestinal (GI) Perforation- Concomitant use of NSAIDs or corticosteroids can lead to GI perforation. Also, GI perforations are primarily reported with the use of Sarilumab in patients with diverticulitis. Look out for any gastrointestinal symptoms reported by the patient.

4) Increased Cancer Risk- Immunosuppressant treatment does increase the risk of certain types of cancer. Even though cancers have been reported in clinical studies, the exact role of Sarilumab here is not fully understood.

5) Hypersensitivity Reactions- 0.3 % of patients in clinical trials had to stop treatment with Sarilumab due to hypersensitivity reactions. The most common allergic reactions reported are-

• Rash in the injection site.

• Skin rash.

• Urticaria or hives.

Inform the patient to get help immediately if they experience allergic symptoms. In case of anaphylaxis or other severe allergic reactions, discontinue Sarilumab.

6) Liver Impairment - As this drug is known to increase transaminase levels, it is not recommended for patients with active liver disease or hepatic impairment.

7) Live Vaccines- Live vaccines should be avoided while the patient is on this drug due to an increased risk of infections. There is no data on the possible secondary transmission of infection from a vaccinated patient taking Sarilumab to others.

Indications and Uses:

Rheumatoid Arthritis - For moderately to severely active rheumatoid arthritis (RA) in adults who failed to respond to or tolerate more than one disease-modifying antirheumatic drug (DMARDs).

Dosage Strength and Forms:

Sarilumab is injected subcutaneously. Injection of the strength 150 mg/1.14 mL or 200 mg/1.14 mL, either pre-filled pen or syringe, is available. The medicine looks colorless to pale yellow.

Dosage and Administration:

Sarilumab is used alone or in combination with Methotrexate (MTX) or other conventional DMARDs. The recommended dosage is 200 mg once every two weeks (subcutaneous injection). For management of neutropenia, thrombocytopenia, and elevated liver enzymes, reduce the dose to 150 mg once every two weeks. See the table below for detailed information.

Considerations for Administration:

Do not prescribe Sarilumab in patients with:

• Absolute neutrophil count (ANC) less than 2000 per mm3.

• Platelets count less than 150,000 per mm3.

• ALT (alanine aminotransferase) or AST (aspartate transaminase) is above 1.5 times the upper limit of normal (ULN).

• An active infection.

Before prescribing Sarilumab, remember to:

• Test patients for latent tuberculosis (TB). Treat TB before starting the IL-6 blocker.

• Never prescribe Sarilumab with any biological DMARDs (TNF antagonists, IL-1R antagonists, antiCD20 monoclonal antibodies, and selective costimulation modulators) because of increased risk of infection due to immunosuppression. There is no data available for the use of Sarilumab with these biological DMARDs.

Contraindications:

Do not prescribe Sarilumab for patients with known hypersensitivity to Sarilumab or the inactive ingredients in the formulation.

Results from Clinical Trials:

Patients in the clinical trials had moderately to severely active rheumatoid arthritis. The safety of Sarilumab, when used along with conventional DMARDs, was evaluated in seven studies, two of which were placebo-controlled and had 2887 patients. The patients were split and given conventional DMARDs along with Sarilumab 200 mg, Sarilumab 150 mg, or a placebo.

The most common side effect seen was infections, and almost 3 % of patients showed:

• Neutropenia.

• Increased ALT.

• Injection site erythema.

• Upper respiratory infections.

• Urinary tract infections.

Premature discontinuation due to side effects occurred in 8 %, 6 %, and 3 % of patients taking 200 mg, 150 mg, and placebo, respectively. Neutropenia was the most common adverse reaction (more than 1 %), resulting in discontinuation.

In another trial with 132 patients, 67 received only Sarilumab 200 mg, and 65 received the 150 mg dosage without additional conventional DMARDs. However, this did not alter the safety profile by much.

Drug Interactions:

Interactions with Other Rheumatoid Arthritis Drugs:

Sarilumab clearance was not affected by Methotrexate (MTX). No data is available for the interactions between this drug and JAK (Janus kinase) inhibitors or biological DMARDs like TNF antagonists.

Interactions with CYP450 Substrates:

Limited studies show interactions between Sarilumab and cytochrome P450 (CYP) enzymes, resulting in increased metabolism of CYP450 substrates drugs like Dexamethasone, oral contraceptives, Lovastatin, Atorvastatin, Diazepam, etc. This will make these drugs less effective, so dose adjustment is essential.

Interactions With Live Vaccines:

Due to the increased risk of infection, ask the patients not to take any live vaccines during treatment with Sarilumab.

Other Specifications:

Sarilumab During Pregnancy

There is not enough data about the effects of Sarilumab on pregnant women. Monoclonal antibodies get transported across the placenta, more in the third trimester, and can affect the immune response in the fetus. So far, animal study data gives no evidence of embryotoxicity or fetal malformations when exposed to Sarilumab in vitro. Sarilumab should be prescribed in pregnancy only if the potential benefits outweigh the potential risks to the unborn baby.

Breastfeeding and Sarilumab:

No information is available on the effects of Sarilumab on breastfed infants, its presence in human milk, or the drug's impact on milk production. Also, the drug is not approved to be used in pediatric patients, so consider the risks and benefits before prescribing Sarilumab for breastfeeding mothers.

Sarilumab in Geriatric Patients:

In clinical trials, 15 % of the patients were over 65, and 1.6 % were above 75 years. No differences in safety and efficacy were observed between the older and younger patients. However, serious infections were common in patients over 65 years of age compared to those under 65. Therefore, be cautious while prescribing Sarilumab to older adults because of the higher susceptibility to fatal infections.