Tocilizumab - Uses, Mechanism of Action, Precautions, and Side Effects

Overview:

Tocilizumab is an interleukin-6 receptor antagonist used to treat various autoimmune conditions. FDA (Food and Drug Association) approved Tocilizumab on the 8th of January 2010. After being used to treat severely ill patients of COVID-19, the drug was approved by the European Commission in December 2021 and by Health Canada in October 2022 to be used to treat COVID-19 in people on systemic corticosteroids and ventilation.

How Does Tocilizumab Work?

Tocilizumab binds to the soluble and membrane-bound interleukin-6 (IL-6) receptors. It inhibits sIL-6R and mIL-6R-mediated signaling. IL-6 is a pro-inflammatory cytokine produced by T and B cells, monocytes, and fibroblasts. IL-6 is involved in the pathogenesis of inflammatory diseases, osteoporosis, and neoplasia.

Uses of Tocilizumab:

• Rheumatoid arthritis.

• Giant cell arteritis.

• Polyarticular juvenile idiopathic arthritis.

• Systemic juvenile idiopathic arthritis.

• Cytokine release syndrome.

Dosage Restrictions:

1. Route of Administration

Intravenous infusion or subcutaneous injection.

2. Dosage Strengths

Intravenous Infusion: 80 mg/4 mL, 200 mg/10 mL, 400 mg/20 mL.

Subcutaneous Injection: 162 mg/0.9 mL.

3. Dosage Forms

Tocilizumab is a sterile, clear, colorless to pale yellow solution in 20 mg/mL single-dose vials.

Special Considerations:

• Pregnancy- Tocilizumab is transported through the placenta and might affect the immune response in the infant. In addition, inhibition of IL-6 signaling might interfere with cervical dilatation and myometrial contractile activity leading to delays in parturition. A pregnancy exposure registry keeps a tab on the outcomes of pregnant women exposed to Tocilizumab.

• Fetal or Neonatal - Monoclonal antibodies are transported through the placenta during pregnancy, with the largest amount transferred during the third trimester.

• Breastfeeding - Whether Tocilizumab is excreted in breast milk is unknown. The decision to continue or discontinue breastfeeding or the drug during Tocilizumab therapy should be made, keeping in mind the benefit of breastfeeding to the child or the benefit of the drug to the mother.

• Renal Impairment - Mild renal impairment did not impact the pharmacokinetics of Tocilizumab. Therefore, no dosage adjustment of Tocilizumab is required in people with mild to moderate renal impairment.

• Pediatric - The drug's safety in kids below two years of age has not been established.

• Elderly - No dose adjustment is needed for the elderly above 65 years of age.

Warnings and Contraindications:

Tocilizumab is contraindicated in patients with hypersensitivity to the medication.

Warnings and Precautions:

1. Infections

Fatal infections such as bacterial, mycobacterial, fungal, viral, protozoal, or other pathogens have been found in individuals treated with Tocilizumab. The typical serious infections caused by the drug include pneumonia, urinary tract infections, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis, and bacterial arthritis. In addition, opportunistic infections include tuberculosis, cryptococcus, aspergillosis, candidiasis, and pneumocytosis.

2. Gastrointestinal Perforations

In individuals treated with Tocilizumab, gastrointestinal perforations have been reported in certain clinical trials.

3. Neutropenia

Tocilizumab has been associated with increased neutropenia during treatment.

4. Thrombocytopenia

Tocilizumab has been associated with a decrease in the platelet count.

5. Elevated Liver Enzymes

Treatment with Tocilizumab has been associated with increased levels of transaminase, a liver enzyme.

6. Immunosuppression

Tocilizumab has been found to suppress immunity, that might increase the risk of developing certain malignancies.

7. Demyelinating Disorders

The impact of treatment with Tocilizumab on demyelinating disorders is not known, but cases of multiple sclerosis and chronic inflammatory demyelinating polyneuropathy were rarely reported.

8. Active Hepatic Disease and Hepatic Impairment

Treatment with Tocilizumab is not recommended in patients with active hepatic disease or hepatic impairment.

9. Vaccinations

Live vaccines should be avoided concurrently with Tocilizumab as no clinical safety has been established. Data is not available on the effectiveness of vaccination in patients receiving Tocilizumab. It is recommended that all patients, particularly children or the elderly, should be brought with all immunizations in agreement with current immunization guidelines before initiating Tocilizumab therapy.

For Patients:

What Is Rheumatoid Arthritis?

Rheumatoid arthritis (RA) is an autoimmune disease in which the body’s immune system attacks healthy cells by mistake, leading to inflammation. Rheumatoid arthritis primarily attacks the joints.

Why Is Tocilizumab Prescribed?

• Rheumatoid Arthritis: An autoimmune condition in which the body attacks its joints, leading to pain, swelling, and loss of function.

• Giant Cell Arteritis: This condition causes swelling of the blood vessels, especially of the scalp and head, in adults.

• Systemic Sclerosis-associated Interstitial Lung Disease: This, also known as scleroderma-associated interstitial lung disease, is a disease of the lungs leading to scarring of the lungs.

• Polyarticular Juvenile Idiopathic Arthritis: This is a type of childhood arthritis affecting five or more joints leading to pain, function loss, and swelling in kids two years of age or older.

• Systemic Juvenile Idiopathic Arthritis: This condition leads to inflammation in different areas of the body, causing fever, joint pain, swelling, and delays in growth in children two years or older.

• Cytokine Release Syndrome: A life-threatening condition in adults and children of two years of age or older after undergoing immunotherapy.

How Should One Take Tocilizumab?

• Tocilizumab comes as a sterile solution for intravenous or subcutaneous injection.

• For rheumatoid arthritis, it is given intravenously once every four weeks or subcutaneously once every week or alternate weeks.

• For polyarticular juvenile idiopathic arthritis, it is given intravenously once every four weeks or subcutaneously once every two to three weeks.

• To treat giant cell arteritis, it is usually given subcutaneously once every four weeks.

• It is given subcutaneously once a week for systemic sclerosis-associated interstitial lung disease.

• To treat systemic juvenile idiopathic arthritis, it is given intravenously once every two weeks or subcutaneously weekly once.

• The first dose of subcutaneous injection is received at the doctor's clinic.

• The injection needs to be brought to room temperature before injecting.

• The drug can be injected in the front of the thighs or stomach except the naval area two inches around it.

• Do not inject the medication into the skin with bruises, scars, pain, scars, moles, or injury.

• Do not reuse the prefilled syringes, and do not recap the syringes after use.

What Should One Discuss With the Doctor Before Beginning Tocilizumab?

• The doctor should be informed if one is allergic to Tocilizumab, other medications, or the ingredients in the injection.

• The doctor should be informed about certain prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products if one takes them while on Tocilizumab.

• The doctor should be informed in case one has cancer, diverticulitis (small pouches in the lining of the large intestine that can become inflamed), stomach or intestinal ulcers, high cholesterol, or any condition affecting the nervous system such as multiple sclerosis, chronic inflammatory demyelinating polyneuropathy ( a disorder of the immune and nervous systems), or liver disease.

• The doctor should be informed if one is pregnant, plans to become pregnant, or is breastfeeding.

• During any surgery, including dental surgery, the doctor should be informed about one receiving the Tocilizumab injection.

• The doctor should be consulted on whether one should receive any vaccinations before beginning the treatment with Tocilizumab.

Is Tocilizumab Safe?

Tocilizumab might increase the risk of getting certain cancers or infections. Therefore, a proper discussion should be done with the doctor before starting the therapy.

Is Tocilizumab Effective?

Tocilizumab injection might control the symptoms but will not cure them. Therefore, the doctor will monitor the drug's efficacy by adjusting the dosage.

What Side Effects Can One Expect With Tocilizumab?

Tocilizumab may cause common side effects like,

• Headache.

• Itching, redness, pain, or swelling at the injection site.

• Runny nose and sneezing.

Some serious side effects include:

• Swelling of the eyes, face, lips, tongue, throat, arms, feet, ankles, or legs.

• Rashes.

• Flushing.

• Hives.

• Itching.

• Difficulty in breathing or swallowing.

• Chest pain.

• Fever.

• Dizziness.

• Fainting.

• Continuous pain in the stomach.

• Changes in bowel habits.

• Yellowish eyes or skin.

• Pain in the upper right abdominal area.

• Bleeding or bruising.

• Loss of appetite.

• Yellowish brown stools.

• Pale stools.

• Risk of developing certain cancers.

Can One Stop Taking Tocilizumab Without the Doctor's Approval?

Do not stop taking the injection without the doctor's approval.

Are There Any Dietary Restrictions to Consider When Taking Tocilizumab?

Continue with the regular diet unless the doctor recommends otherwise.

How Should One Store Tocilizumab?

The medication should be stored away from light, closed tightly, and out of children's reach. The injection should be stored in the refrigerator. The prefilled syringes should be kept dry.

How Should One Dispose of Tocilizumab?

• The unused medications should be disposed of so that pets, kids, and others cannot take them.

• The injection should not be flushed down the toilet.

• The medicine take-back program should be utilized to dispose of the vials.

What To Do in Case of Overdose?

In case of an overdose, the poison control team or emergency services should be contacted if the person collapses, has a seizure, or has trouble waking up.

For Doctors:

Indications

Tocilizumab is indicated in the following:

• Rheumatoid arthritis.

• Giant cell arteritis.

• Polyarticular juvenile idiopathic arthritis.

• Systemic juvenile idiopathic arthritis.

• Cytokine release syndrome.

What Is the Pharmacology of Tocilizumab?

Description

Tocilizumab is a recombinant anti-human interleukin 6 (IL-6) receptor monoclonal antibody of the immunoglobulin IgG1k (gamma 1, kappa) subclass with a typical H2L2 polypeptide structure. Each light and heavy chain consists of 214 and 448 amino acids. The four polypeptide chains are linked both intra and inter-molecularly.

The intravenous Tocilizumab injection is a sterile, preservative-free solution to be diluted further before intravenous infusion at a concentration of 20 mg/mL. Tocilizumab is a clear, colorless, yellowish liquid with a 6.5 pH.

Subcutaneous Tocilizumab injection is a sterile, clear, colorless, slightly yellowish, preservative-free liquid solution with a pH of 6.0. It is supplied in a 1 mL ready-to-use, single-use prefilled syringe (PFS) and a needle safety device. Single-dose vials of 80 mg/ 4 mL, 200 mg/ 10 mL, or 400 mg/ 20 mL are available for intravenous administration.

Components

1. Active Ingredients

• Tocilizumab.

2. Inactive Ingredients

Intravenous Injection:

• Sucrose.

• Polysorbate 80.

• Disodium phosphate dodecahydrate.

• Sodium dihydrogen phosphate dihydrate.

Subcutaneous Injection:

• L-arginine.

• L-arginine hydrochloride.

• L-methionine.

• L-histidine.

• L-histidine hydrochloride monohydrate.

Clinical Pharmacology:

Mechanism of Action

Tocilizumab is the drug that binds to both the soluble and membrane-bound IL-6 (interleukin 6) receptors (sIL-6R and mIL-6R) and inhibits the IL-6-mediated signaling through these receptors. Interleukin 6 is a pleiotropic pro-inflammatory cytokine produced by different cells, including the T- and B-cells, lymphocytes, monocytes, and fibroblasts. IL-6 has been involved in various physiological processes like T-cell activation, immunoglobulin secretion induction, hepatic acute phase protein synthesis, and the stimulation of hematopoietic precursor cell proliferation and differentiation. IL-6 is also produced by the synovial and endothelial cells leading to the production of IL-6 in the joints of people affected by rheumatoid arthritis.

Pharmacodynamics

Pharmacodynamic changes such as a decrease in rheumatoid factor, erythrocyte sedimentation rate (ESR), serum amyloid A, and an increase in hemoglobin have been observed with doses of 4 mg per kg and 8 mg per kg IV doses or 162 mg weekly dosage.

Pharmacodynamic changes also occurred after Tocilizumab administration leading to a decrease in CRP, ESR, and hemoglobin levels. In healthy individuals, administering 2 to 28 mg per kg intravenously and 81 to 162 mg subcutaneously, the neutrophil counts decreased in 3 to 5 days, but the neutrophils recovered towards the baseline. The relationship between these pharmacodynamic findings and clinical efficiencies has yet to be discovered.

Pharmacokinetics

• Mean Cmax - For 4 mg of Tocilizumab per kg, given every four weeks, the Cmax was 88+_41.4 mcg per mL.

• Median Tmax - 2.8 days after Tocilizumab was administered every week and 4.7 days after Tocilizumab was administered every other week.

[Cmax- Maximum concentration achieved by a drug in the blood, cerebrospinal fluid, or target organ after administration of a dose]

[Tmax- Time taken for a drug to reach maximum concentration after administration of a dose]

• Pharmacokinetic Changes

The pharmacokinetic parameters of Tocilizumab did not change with time. However, a dose-proportional increase in the AUC (area under the curve) and Cmin were observed for 4 and 8 mg/kg doses every four weeks.

A. Distribution:

• Steady-state Plasma Levels - 6.4 liters.

• Time to Approach Steady-state Levels - 10 to 12 weeks.

B. Metabolism

Tocilizumab is metabolized to smaller proteins and amino acids by proteolytic enzymes.

C. Elimination

Tocilizumab, after intravenous administration, gets removed from the circulation in two ways, one through a linear clearance and the other through a concentration-dependent clearance. In rheumatoid arthritis patients, the linear clearance is 9.5 mL/h. At high Tocilizumab concentration, the non-linear clearance pathway is saturated. Therefore, clearance is mainly determined by linear clearance. In rheumatoid arthritis patients, the half-life of Tocilizumab is concentration-dependent. At a steady state following a dose of 8 mg/kg every four weeks, the half-life decreased with decreasing concentrations with dose intervals from 18 days to 6 days.

Special Considerations:

• Hepatic Impairment - No study on the effect of Tocilizumab on people with hepatic impairment was conducted.

• Renal Impairment - Mild renal impairment did not impact the pharmacokinetics of Tocilizumab. Therefore, no dosage adjustment of Tocilizumab is required in people with mild to moderate renal impairment.

• Pregnancy - Monoclonal antibodies, such as Tocilizumab, are transported through the placenta during the third trimester of pregnancy and might affect the immune response in the infant. In addition, inhibition of IL-6 signaling might interfere with the cervical and dilatation and myometrial contractile activity leading to delays of parturition. A pregnancy exposure registry keeps a tab on the outcomes of pregnant women exposed to Tocilizumab.

• Fetal or Neonatal - Monoclonal antibodies are transported through the placenta during pregnancy, with the largest amount transferred during the third trimester.

• Breastfeeding - Whether Tocilizumab is excreted in breast milk is unknown. The decision to continue or discontinue breastfeeding or the drug during Tocilizumab therapy should be made, keeping in mind the benefit of breastfeeding to the child or the benefit of the drug to the mother.

Drug Interactions:

• Acetaminophen - The metabolism of Acetaminophen is increased when combined with Tocilizumab.

• Acyclovir - The metabolism of Acyclovir can be expanded when combined with Tocilizumab.

• Alprazolam - The metabolism of Alprazolam is increased in combination with Tocilizumab.

What Have Clinical Trials Shown Concerning Tocilizumab?

The efficacy and safety of intravenous administration of Tocilizumab in rheumatoid administration were obtained in five randomized, double-blind, multicenter studies in adult patients. Patients had at least eight tender and six swollen joints at baseline. Tocilizumab was given intravenously every four weeks as monotherapy (study I), in combination with methotrexate (studies II and III) or other disease-modifying anti-rheumatic drugs (study IV) in patients with an inadequate response to such drugs, or together with Methotrexate in individuals with an insufficient response to TNF (tumor necrosis factor) antagonists (study V).

Study I assessed patients with moderate to severe rheumatoid arthritis not treated with methotrexate within 24 weeks before randomization or who continued with previous methotrexate treatment due to clinically significant toxic effects or lack of response. The people received 8 mg per kg monotherapy or methotrexate alone. In this study, 67 % of patients were methotrexate-naive, and over 40 % had rheumatoid arthritis in less than two years.

Primary Endpoint - The proportion of Tocilizumab patients who achieved an ACR 20 response in the 24th week.

Study II was a 104-week study with an optional 156-week extension phase that accessed patients with moderate to severely active rheumatoid arthritis who had an inadequate response to methotrexate. Patients received Tocilizumab 8 mg per kg, 4 mg per kg, or placebo every four weeks, combined with methotrexate (10 to 25 mg weekly). Upon completion of 52 weeks, patients received open-label treatment with Tocilizumab 8 mg per kg through 104 weeks or could continue their double-blind treatment if there was an improvement more significant than 70 % in swollen or tender joints. Two pre-specified analyses at week 24 and week 52 were conducted.

Primary Endpoint - It was achieved in the 24th week and was the proportion of patients who achieved an ACR 20 response. At the 52nd and 104th weeks, the primary endpoints were changed from the baseline in the modified total Sharp-Genant score and the area under the curve of the change from the baseline in the HAQ-DI score.

Results

Patients treated with Tocilizumab reported an improvement in all the patient-reported outcomes.

Patient Counseling Information:

1. The patient should be advised to read the FDA (Food and Drug Administration)-approved patient labeling.

2. The patient and guardians of minors with PJIA, SJIA, or CRS should be warned of Tocilizumab's potential benefits and risks.

3. The patients should be informed that Tocilizumab may lower their resistance to infections.

4. The patient should contact their doctor immediately when infection symptoms appear to get a rapid evaluation and prompt treatment.

5. The patients should be informed that some treated with Tocilizumab have had complicacy effects in the stomach and intestines. Therefore, patients should be advised to contact their physician immediately to get appropriate treatment when severe, persistent abdominal pain symptoms appear.

6. The patient should be informed of developing serious allergic reactions, including anaphylaxis, with Tocilizumab administration. They should get immediate medical help on experiencing serious allergic reactions.

Administration Instructions:

1. Tocilizumab is available as a sterile solution for intravenous or subcutaneous injection.

2. Injection Technique

• The first injection should be given with the supervision of a qualified healthcare administration. If a patient or caregiver is to give subcutaneous Tocilizumab, instruct them about the injection techniques and evaluate their ability to inject the drug subcutaneously to ensure proper administration.
• The patients or caregivers should be thoroughly instructed about the technique and proper syringe and needle disposal and cautioned against reusing such items. Before use, the prefilled syringe should be removed from the refrigerator and allowed to come at room temperature for 30 minutes, out of the reach of children. A puncture-resistant container for needles and syringes disposal should be used and kept out of the reach of children.

Complications or Side Effects

Complications or side-effects of Tocilizumab include:

• Injection site reactions.

• Upper respiratory tract infections.

• Nasopharyngitis.

• Constipation.

• Headache.

• Bronchitis.

• Rashes.

• Dizziness.

• Ulcers in the mouth.

• Pain in the upper abdominal area.

• Gastritis.

• Stomatitis.

• Increase in weight.

• Increase in the total bilirubin.

• Leukopenia.

• Edema in the peripheries.

• Cough.

• Dyspnea.

• Conjunctivitis.

• Anaphylaxis.

• Stevens-Johnson syndrome.

• Pancreatitis.

• Hepatitis or jaundice.