Adalimumab - Indications, Administration, Mechanism, and Adverse Effects

Overview:

Adalimumab is a high-affinity recombinant anti-TNF (tumor necrosis factor) alpha monoclonal antibody (fully human). It is used to treat various inflammatory conditions such as rheumatoid arthritis, ankylosing spondylitis, and Crohn's disease that are mediated by TNF-alpha. Recombinant DNA technology is applied to produce the monoclonal antibody against TNF-alpha. These are usually administered subcutaneously in the form of injections or prefilled syringes that can be self-administered by the patients. In 2002 the drug was approved for the first time by the FDA to treat rheumatoid arthritis.

Before Adalimumab, FDA had approved two other TNF-alpha inhibitors - Etanercept and Infliximab. With time FDA approved Adalimumab for other conditions such as ankylosing spondylitis (an inflammatory disease that causes the bones of the spine to fuse), Crohn's disease (a type of chronic inflammatory bowel disease), ulcerative colitis (inflammation and sores in the digestive tract), juvenile idiopathic arthritis (joint inflammation in children), hidradenitis suppurativa (a chronic skin condition), plaque psoriasis (immune-mediated skin disease with plaques and scales), psoriatic arthritis (inflammation of the joints along with immune-mediated skin lesions), and uveitis (eye inflammation).

Now, various biosimilar molecules have been developed. In addition, Adalimumab is used to treat other conditions off-label such as Wegener granulomatosis (a rare disease that causes inflammation of the lungs, kidneys, blood vessels, and other body tissues), sarcoidosis (an inflammatory disease with clusters of inflamed tissue in all body parts), pemphigus (a blistering skin disorder), alopecia areata (autoimmune disorder causing patchy hair loss), and multicentric reticulohistiocytosis (proliferation of certain immune cells called histiocytes leading to skin lesions).

What Is Rheumatoid Arthritis?

Rheumatoid arthritis is a chronic autoimmune disorder in which the body's defense mechanism acts against its own cells and tissues, leading to chronic inflammation, especially in the bone joints. The persistent inflammatory condition leads to significant discomfort and can even be life-threatening if not treated. In rheumatoid arthritis, there is marked inflammation of the joints along with swelling of the joints (hyperplasia). Autoantibodies are produced that cause cartilage and bone destruction, and eventually, multiple systems are involved affecting the heart, blood vessels, lungs, and skeletal system. The disorder's risk factors include smoking, genetic factors, silica inhalation, and other inflammatory diseases. Rheumatoid arthritis results in tenderness, pain, stiffness, and swelling in many joints in the body. In addition, it can cause fatigue, weakness, and fever.

What Is Ankylosing Spondylitis?

The chronic inflammatory condition - ankylosing spondylitis, causes the vertebrae (spine) bones to fuse. Due to ankylosing spondylitis, the spine becomes less flexible, leading to a hunched posture. The disease can also affect other bones, such as the ribs leading to difficulty breathing (taking deep breaths becomes difficult). In addition, other parts of the body, such as the eyes, also get inflamed. It starts as stiffness and pain in the lower back and hips(especially worse in the mornings) after periods of inactivity. Fatigue and neck pain may also occur. The symptoms may improve or worsen with time and may even stop at irregular intervals. Treatment can help in reducing the progression of the disease and can reduce the symptoms.

How Does Adalimumab Work?

In ankylosing spondylitis and rheumatoid arthritis, the body's immune system goes into overdrive and increases the levels of inflammatory proteins in the body. Tumor necrosis factor-alpha is an inflammatory protein (cytokine) that is one of the key mediators of inflammation. Numerous studies have demonstrated the role of TNF-alpha in bone loss and joint damage. TNF-alpha stimulates the expression of certain ligands (RANKL) on the defense cells (T and B lymphocytes) and promotes the lymphocytes to differentiate into osteoclast cells (cells that resorb bone), thus increasing bone resorption. In addition, TNF-alpha suppresses bone formation through various signaling pathways. Adalimumab is a TNF inhibitor that targets TNF-alpha and acts by counterbalancing the high TNF levels causing joint inflammation and preventing bone and tissue damage. Thus, Adalimumab is efficient in treating inflammatory disorders such as rheumatoid arthritis and ankylosing spondylitis, as it lowers inflammation and prevents damage to the joints in the long run.

For Doctors:

FDA-approved Indications of Adalimumab:

1. Rheumatoid Arthritis:

   • To reduce the signs and symptoms.

   • To Induce a major clinical response.

   • To inhibit structural damage progression.

   • To improve physical function in adults with moderate to severely active disease.

2. Ankylosing Spondylitis:

   • Indicated for use in adult patients to reduce the severity of the signs and symptoms of the active disease.

3. Crohn's Disease:

   • It is approved for use by the FDA in children six years and older and adults.

   • It treats moderate to severely active Crohn's disease.

4. Ulcerative Colitis:

   • Indicated for use in adults (patients with active disease, moderate to severe ulcerative colitis).

   • Limitations of use - The drug's effectiveness has not been established for patients who were intolerant to or showed a lost response to TNF inhibitors.

5. Juvenile Idiopathic Arthritis:

   • To reduce the symptoms and signs of active disease (moderate to severe polyarticular juvenile idiopathic arthritis).

   • It is to be used above the age of two years.

6. Plaque Psoriasis:

   • It is indicated for use in adults with moderate to severely active disease who require phototherapy or systemic therapy.

   • It is used when other systemic therapies are not indicated or are less appropriate.

7. Psoriatic Arthritis:

   • To reduce the signs and symptoms.

   • To inhibit structural damage progression.

   • To improve physical function in adults with active psoriatic arthritis.

8. Hidradenitis Suppurativa:

   • Indicated for patients aged 12 years and above for treating active disease.

9. Uveitis:

   • Indicated to treat non-infectious uveitis (intermediate, posterior, and panuveitis) in adults.

   • It is indicated for use in pediatric patients two years and above.

The off-label Indications of Adalimumab:

1. Neutrophilic dermatosis – pyoderma gangrenosum, Behcet disease.

2. Multicentric reticulohistiocytosis.

3. Sarcoidosis.

4. Alopecia areata.

5. Pemphigus.

6. Granulomatosis with polyangiitis (Wegener granulomatosis).

Mechanism of Action:

Adalimumab is an anti-TNF alpha monoclonal antibody (high-affinity, fully human, and recombinant immunoglobulin G type). The Adalimumab molecule has a molecular weight of approximately 148 kilodaltons (kDa) and comprises 1330 amino acids. The drug is efficient in treating inflammatory conditions such as various types of arthritis and has an osteogenic action. Adalimumab is a TNF-alpha blocker that inhibits the binding of TNF-alpha to its receptor (both soluble and membrane-bound TNF-alpha).

TNF-alpha is the key inflammatory mediator to activate the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-KB) ligand (RANKL) receptors on osteoblast cells or stromal cells. It also is involved in osteoclast maturation and activation. Thus TNF-alpha increases osteoblastic activity and bone resorption.

Adalimumab is identical to human immunoglobulin (IgG1) in structure as well as function. Adalimumab binds to the soluble and membrane-bound TNF-alpha and specifically inhibits the interaction of TNF-alpha with the cell surface receptors - p55 (TNFR1) and p75 (TNFR2). As a result, it interferes with the inflammatory processes in the body that are cytokine-driven. The drug does not bind to other cytokines, such as interleukins or lymphotoxins. Adalimumab has a high selectivity for TNF-alpha and has a low immunogenic potential. Thus the administration of Adalimumab inhibits or blocks TNF-alpha preventing its activity (thus inhibiting the destruction of cartilage, bone, and other tissues) in rheumatoid arthritis, ankylosing spondylitis, and other inflammatory diseases.

Dosage and Administration:

1. Administration:

Adalimumab is administered as a subcutaneous injection. It can be used at different body sites, such as the lower abdomen and thigh (with rotation of injection sites). Injecting within two inches of the navel must be avoided. The drug should be left at room temperature for 20 minutes before use without removing the cover (to reach room temperature). It should not be injected in areas such as inflamed skin (red and tender), scars, psoriasis plaques, and stretch marks.

The Adalimumab injection is available as a pre-filled pen, glass syringe, or single-use glass vials (in doses of 10 mg, 20 mg, 40 mg, or 80 mg). The pen can be used by the patients to self-administer the drug. However, only healthcare professionals should use the vials to administer Adalimumab.

2. Recommended Dosage of Adalimumab:

Rheumatoid Arthritis, Psoriatic Arthritis, and Ankylosing Spondylitis:

• 40 mg of Adalimumab every other week.

• For patients with rheumatoid arthritis who are not on Methotrexate, increasing the frequency to 40 mg of Adalimumab every week may help.

Adult Crohn's Disease and Ulcerative Colitis:

• An initial dose of 160 mg on day one.

• Second dose (two weeks later or on day 15) of 80 mg.

• 40 mg - maintenance dose injected every other week has to be started on day 29 (two weeks later).

• Adalimumab should be continued for ulcerative colitis patients who show clinical remission by day 57 (eight weeks) of therapy.

Juvenile Idiopathic Arthritis or Pediatric Uveitis:

• 10 mg every other week - for children weighing 10 to 15 kg.

• 20 mg every other week - for children weighing 15 to 30 kg.

• 40 mg every other week - for children weighing greater than 30 kg and adults.

Adult Uveitis and Plaque Psoriasis:

• An initial dose of 80 mg.

• 40 mg - maintenance dose injected every other week has to be started a week after the initial dose.

Hidradenitis Suppurativa:

• An initial dose of 160 mg on day one.

• Second dose (two weeks later or on day 15) of 80 mg.

• Third dose (day 29) and the subsequent doses: 40 mg weekly.

3. Pharmacokinetics:

Following a single subcutaneous dose of 40 mg of Adalimumab, the pharmacokinetics are:

1. Time to peak concentration - 131 (+/- 56) hours.

2. Maximum serum concentration - 4.7 (+/- 1.6) mcg/ml.

3. Absolute bioavailability - 64 %.

4. The volume of distribution - 4.7 to 6 L.

5. Steady-state concentration -

   • With concomitant Methotrexate: 8 to 9 mcg/ml.

   • Without concomitant Methotrexate: 5 mcg/ml.

6. Systemic clearance - 12 milliliters per hour.

7. Route of elimination - removed by opsonization through the reticuloendothelial system.

8. Terminal half-life - two weeks.

Adverse Effects:

1. Common Adverse Effects (Seen in Greater Than 10 Percent):

1. Infections like sinusitis and upper respiratory infections.

2. Reactions at the injection site.

3. Rash.

4. Headaches.

Other Side Effects:

1. Risk of serious infections such as latent tuberculosis reactivation.

2. Infections such as

   • Deep fungal infections.

   • Histoplasmosis.

   • Listeriosis.

   • Pulmonary aspergillosis.

   • Pneumocystis jiroveci pneumonia.

3. Development of antibodies to Adalimumab.

4. Initiation and worsening of congestive heart failure.

5. Elevation of transaminases and creatinine phosphokinase levels.

6. Lupus-like syndrome.

7. Pancytopenia.

8. Lymphoma.

9. Initiation or worsening of neurological disease or multiple sclerosis.

Contraindications:

1. Though no specific contraindications have been listed by the manufacturers; there is very little study on the effects of Adalimumab in children who weigh less than 15 kilograms and are younger than four years of age. Thus healthcare providers must avoid using it in the age group below four years as a precautionary measure.

2. Adalimumab must be avoided in patients with hypersensitivity, congestive cardiac failure, underlying foci of infection, or hepatic dysfunction.

3. Administration of concomitant live vaccines is contraindicated.

4. The risk of serious infections when co-administered with Abatacept and anakinra is significantly increased.

Warnings and Precautions:

A. Serious Infections:

1. Patients treated with Adalimumab are at a greater risk of developing critical infections that can cause hospitalization or death. The risk is higher for patients who take other immunosuppressive drugs, such as corticosteroids or Methotrexate.

2. Adalimumab must be discontinued in case of serious infections or sepsis.

3. The serious infections include:

• Active Tuberculosis (TB): Active TB, including reactivation of latent TB and disseminated or extrapulmonary TB, can occur upon initiating treatment with Adalimumab. To prevent this risk, the patients must be tested for latent TB before and during treatment with Adalimumab. A person with latent TB must be treated before initiating Adalimumab.

• Invasive Fungal Infections: These include candidiasis, histoplasmosis (disseminated), blastomycosis, coccidioidomycosis, aspergillosis, and pneumocystis. Empiric antifungal therapy must be considered in patients who are at risk for serious invasive fungal infections.

• Viral, bacterial, and other infections due to opportunistic pathogens, including Listeria and Legionella.

B. Malignancy:

Fatal malignancies such as lymphoma (hepatosplenic T-cell lymphoma) have been reported in younger patients (children and adolescents). These malignancies are very aggressive and fatal and were seen in patients with Crohn's disease or ulcerative colitis treated with 6-mercaptopurine or azathioprine concomitantly with Adalimumab. However, it is uncertain if they are related.

C. Anaphylaxis or serious hypersensitivity reactions can occur.

D. Hepatitis B Virus Reactivation: Hepatitis B virus (HBV) carriers must be monitored during and after treatment with Adalimumab. If HBV reactivation occurs, Adalimumab must be stopped, and antiviral therapy must be initiated.

E. Exacerbation or new onset of demyelinating disease may occur.

F. Cytopenias and Pancytopenia: The patients must be advised to seek immediate medical attention if the symptoms of cytopenia and pancytopenia develop. Stopping Adalimumab therapy must be considered in such conditions.

G. Worsening or new onset of heart problems such as heart failure may occur.

H. Lupus-like syndromes can develop; Adalimumab therapy must be stopped in such conditions.

Toxicity:

Animal studies and long-term human studies on Adalimumab have not been conducted. As a result, the toxicity profile is not known. In vitro or in vivo studies have demonstrated that it is not mutagenic. It is categorized as a pregnancy category-B drug. There is no evidence of defects or poor pregnancy outcomes due to Adalimumab.

Overdose:

There is no evidence of dose-limiting toxicities in clinical trials. Patients have been administered doses up to 10 mg/kg without any evidence of toxicity. However, the patient must be monitored for adverse reactions in case of overdosage. Appropriate treatment has to be initiated immediately, depending on the symptom.

Drug Interactions:

1. Concomitant use with Methotrexate has been studied. Methotrexate affects Adalimumab clearance, but no dose adjustment is required.

2. There is insufficient information on the drug information with biological products. The risk of serious infections has been observed in the patients who had received treatment with rituximab before Adalimumab therapy. The concomitant use of Adalimumab with other biological products is not recommended.

3. Concomitant use with Abatacept increases the risk of serious infections.

4. Concomitant use of anakinra increases the risk of serious infections.

5. The use of Adalimumab with live vaccines must be avoided.

Use in Specific Population:

1. Pregnancy: The adverse effects of the use of Adalimumab during pregnancy may include low birth weight and preterm delivery. However, the association between the use of Adalimumab and congenital disabilities is not clearly established. In addition, it is known that Adalimumab is transferred actively across the placenta (in the third trimester of pregnancy). This may affect the immune response of the fetus exposed.

2. Lactation: Limited studies indicate Adalimumab is found in human breast milk (at doses of 0.1 % to 1 % of the mother's blood level). So far, no adverse effects have been reported on Adalimumab's effect on the production of milk or on breastfed infants.

3. Pediatric Use: The efficacy and safety of Adalimumab in children (other than pediatric Crohn’s disease, pediatric uveitis, and polyarticular juvenile idiopathic arthritis) have not been established and are largely unknown.

4. Geriatric Use: There is a higher incidence of malignancies and infections in the elderly population. So it is important to use caution when treating elderly patients.

For Patients:

Patient Warning:

1. Adalimumab injection may decrease a person's ability to fight infection. As a result, it increases the chance of developing serious infections, such as severe fungal, bacterial, and viral infections that may spread throughout the patient’s body.

2. In case of serious infections, treatment in a hospital is essential to prevent serious complications and death.

3. Once a person begins treatment, they must look out for symptoms such as the following:

   • Weakness.

   • Sweating.

   • Sore throat.

   • Cough.

   • Coughing up bloody mucus.

   • Fever.

   • Weight loss.

   • Extreme tiredness.

   • Diarrhea.

   • Stomach pain.

   • Warm, red, or painful skin.

   • Painful, difficult, or frequent urination.

   • Other signs of infection.

4. Adalimumab increases the risk of infections such as tuberculosis, and hepatitis B. Asymptomatic latent infections can flare up and become symptomatic and more serious. Thus, it is essential to inform the health care provider about inactive TB infection or hepatitis B infection to prevent serious consequences.

5. Some children and young adults who received Adalimumab have developed life-threatening cancers such as lymphoma (a cancer of the cells that fight infection).

6. Some young adult males who received Adalimumab for conditions such as Crohn's disease (an inflammatory condition in which the body attacks its own digestive tract lining) or ulcerative colitis (sores and swelling in the large intestine) have developed a serious life-threatening cancer hepatosplenic T-cell lymphoma (HSTCL), that can cause death within a short duration.

7. It is important that patients talk to their healthcare provider about the risks of using Adalimumab before initiating therapy.

Why Is Adalimumab Prescribed?

Adalimumab is a tumor necrosis factor (TNF) inhibitor. They act by blocking the action of TNF, an important mediator of inflammation in the body. Adalimumab is used in combination with other medications or alone to relieve the symptoms of certain inflammatory conditions in which the body's immune system attacks the healthy body parts and causes inflammation, pain, swelling, and damage (autoimmune disorders), including the following:

1. Rheumatoid arthritis (an inflammatory condition where a person’s immune system attacks their own tissues, and joints, causing swelling, pain, and loss of function) in adults.

2. Juvenile idiopathic arthritis (an inflammatory condition that may delay growth and development in children above two years of age by causing pain, swelling, and loss of function in the joints and tissues.

3. Crohn's disease (the body attacks the digestive tract lining) in adults and children six years of age and older that has not responded to other medications.

4. Ulcerative colitis (swelling and sores in the large intestine and rectum lining) when other treatments could not be tolerated or did not help in adults and children five years of age and older.

5. Ankylosing spondylitis (inflammation, pain, and joint damage especially in the spine) in adults.

6. Psoriatic arthritis (joint pain, inflammation, swelling, and scales on the skin) in adults.

7. Hidradenitis suppurativa (pimple-like bumps in the skin of the armpits, groin, and anal area skin disease) in children 12 years of age or older and in adults.

8. Uveitis (inflammation and swelling in different areas of the eye) in adults and children older than two years.

9. Chronic plaque psoriasis (red, scaly patches on the skin in some body areas) in adults.

How Should Adalimumab Be Used?

• Adalimumab is usually administered as a subcutaneous injection (injected under the skin). The medication is available as a solution (liquid) that can be injected under the skin.

• The healthcare providers prescribe Adalimumab based on the patient's age and health condition and instruct the patients on how often to use it.

• It is crucial to follow the directions on the prescription label carefully and use Adalimumab injection exactly as the health care provider directs.

• The first dose of the injection is usually administered at the doctor's office or hospital. After that, the medication can be self-administered at home.

Precautions to Be Followed During Injection:

• Adalimumab injections come in prefilled dosing pens, prefilled syringes, and prefilled autoinjectors that should be used only once.

• It is important to inject all the liquid (medicine) in the autoinjector or the prefilled pen or syringe. Even if a little medication is left, one must avoid injecting again.

• Used Adalimumab pens, syringes, and autoinjectors must be disposed of carefully in a puncture-resistant container.

• If the dosing pen or the prefilled syringe has been refrigerated, it must be allowed to warm to room temperature before use.

• Place the pen or syringe on a flat surface for 15 to 30 minutes without removing the needle cap before injecting the medication to ensure that the medication warms to room temperature.

• Patients must avoid warming the medication using hot water, microwave, or any other method.

• It is important to consult with the healthcare provider in case of any doubts about the self-administration of Adalimumab.

Injection Method:

• One can inject the medication Adalimumab anywhere on the front of the thighs or stomach (except the navel and the area two inches around it).

• Using different sites for each injection can help to reduce the chances of injection site redness or soreness.

• Administering each injection at least one inch away from the previously used prevents injection site tenderness.

• One must not inject into scars, stretch marks, and bruised tender, red, or hard skin areas.

• One must check the expiration date before every self-administration and should not use expired medication.

• Patients must not stop the medication without their healthcare provider's consent. One must continue to use Adalimumab even if the symptoms reduce.

What Special Precautions Should One Follow While Using Adalimumab?

Before using Adalimumab injections, the patient must

• Tell their healthcare provider if they are allergic to Adalimumab or any other medications.

• Discuss with their healthcare provider regarding the instructions for use.

• Inform their healthcare provider regarding the medications that they are taking, including prescription and nonprescription medications, nutritional supplements, vitamins, and herbal products.

• Inform their healthcare provider regarding any latent infections or diseases that they might have.

• Inform their healthcare provider if they have undergone any treatments, such as light therapy for psoriasis.

• Inform their doctor if they are pregnant, plan to become pregnant, or are breastfeeding.

• In case of pregnancy, while using Adalimumab, patients must immediately visit their healthcare provider.

• Keep their healthcare provider informed about any surgeries (including dental surgery) that they are undergoing while using Adalimumab.

• Must not receive any vaccinations without talking to their healthcare provider.

• If a child is receiving Adalimumab, the parents must ensure that the child has received all the vaccines necessary for their age before initiating treatment with Adalimumab.

What Should One Do if They Forget a Dose?

If patients forget to inject a dose of Adalimumab, the missed dose must be injected as soon as they remember it. Then, the next dose can be injected on the regularly scheduled day. However, if it is almost time for their next dose, they can skip the missed dose and continue their regular dosing schedule. A double dose should not be used to make up for a missed one.

What Side Effects Can Adalimumab Cause?

Adalimumab injections may cause side effects for some patients. Therefore, it is important to tell their healthcare provider if symptoms are severe or have not gone away. The common side effects include:

• Redness, itching, bruising, pain, or swelling at the injection site.

• Nausea.

• Headache.

• Back pain.

Patients must also be aware of the severe side effects. In such instances, they must immediately seek emergency care. The serious side effects include:

• Numbness or tingling.

• Problems with vision.

• Weakness in legs.

• Chest pain.

• Shortness of breath.

• Swelling (commonly seen in the face, lower legs, feet, and ankles).

• Difficulty breathing.

• Difficulty swallowing.

• Fever and chills.

• Dizziness.

• Sore throat and other infection signs.

• Unusual bleeding or bruising.

• Pale skin.

• Hives.

• Skin lesions such as pus-filled bumps or scaly red rashes.

• Skin rashes in areas sensitive to sunlight (on the arms or cheeks)

• Unexpected new joint pain.

• Itching.

Adults receiving Adalimumab injections may have a greater risk of developing lymphoma, skin cancer, and other types of cancer than normal people. Thus it is important to discuss these risks with their healthcare provider. The patients on Adalimumab must call their healthcare provider in case of unusual health issues while using the injections.

What Should One Know About the Storage and Disposal of Adalimumab?

Adalimumab must be kept in the container it came in, closed tightly.

• It must be stored out of reach of children.

• Adalimumab must be stored in a refrigerator, protected from light.

• Adalimumab injections may be stored at room temperature (77 degrees Fahrenheit) for up to 14 days.

• Adalimumab must not be frozen.

• Dispose of frozen medication or medications stored at room temperature for a longer duration.

• The medications that are not needed should be disposed of with care. Medicine take-back programs can also be used for unused medications.

In Case of an Overdose or Emergency:

The patients must immediately seek medical treatment in case of an overdose with symptoms. They must rush to the emergency departments or call the poison control helplines or the emergency services to get emergency attention. If the patient collapses and has trouble breathing, one must immediately call for emergency medical services.