Actemra (Tocilizumab) is a human monoclonal antibody that antagonizes the binding of Interleukin 6 to its receptors blunting the inflammatory response.

Actemra (Tocilizumab) uses:

• Severe or life-threatening Cytokine release syndrome:

  • It is used in the treatment of chimeric antigen receptor (CAR) T-cell induced severe or life-threatening cytokine release syndrome in patients 2 years of age and older.
  • It has also been incorporated in the treatment of severe cytokine storm associated with COVID-19 (Coronavirus) infection in patients who are critically ill.

• Giant cell arteritis:

  • It is used to treat adult patients with giant cell arteritis (GCA).

• Polyarticular juvenile idiopathic arthritis:

  • It is used in the treatment of active polyarticular juvenile idiopathic arthritis (pJIA) in patients 2 years of age and older.

• Rheumatoid arthritis:

  • It is used in the treatment of moderately to severely active rheumatoid arthritis (RA) in adults who have had an inadequate response to one or more disease-modifying antirheumatic drugs (DMARDs)

• Systemic juvenile idiopathic arthritis:

  • It is used in the treatment of active systemic juvenile idiopathic arthritis (SJIA) in patients 2 years of age and older.

• Off Label Use of Tocilizumab in Adults:

  • Severe or life-threatening Cytokine release syndrome due to BiTE (Bi-specific T-cell engagers) therapy.
  • COVID-19 associated cytokine release syndrome.

Actemra (Tocilizumab) dose in Adults

Note:

• In patients with giant cell arteritis (GCA) or rheumatoid arthritis (RA), Tocilizumab treatment should not be initiated if the ANC is less than 2,000/ul, platelets are less than 100,000/ul, or if ALT or AST levels are greater than 1.5 times the ULN.

• Patients with Cytokine storm (cytokine release syndrome) may have cytopenias or elevated liver enzymes due to the underlying disease state. The risks and benefits of the treatment should be evaluated in patients with severe or life-threatening cytokine release syndrome.

Actemra (Tocilizumab) dose in the treatment of severe or life-threatening Cytokine storm (Cytokine release syndrome) due to chimeric antigen receptor-T cell therapy:

Note: A total of 3 doses may be administered at an interval of at least 8 hours interval between consecutive doses if a single dose does not suffice. Tocilizumab may be administered as monotherapy or in combination with corticosteroids.

• Intravenous dose:

  • Patients weighing less than 30 kgs:

    • 12 mg/kg

  • Patients weighing more than 30 kgs:

    • 8 mg/kg

  • The maximum dose is 800 mg per dose

Actemra (Tocilizumab) dose in the treatment of Cytokine storm associated with COVID-19 (Coronavirus) infection:

• A single Intravenous dose of Actemra is recommended. Two additional doses may be administered in patients with persistent hypotension and cytopenias.

  • Patients weighing less than 30 kgs:

    • 12 mg/kg

  • Patients weighing more than 30 kgs:

    • 8 mg/kg

  • The maximum dose is 800 mg per dose

Tocilizumab (Actemra) Dose in the treatment of Giant cell arteritis:

• 162 mg SubQ administered once every week in combination with a tapering course of glucocorticoids.
• Tocilizumab may be administered as monotherapy following discontinuation of glucocorticoids.

Tocilizumab dose in the treatment of Rheumatoid arthritis:

Note:

• • Tocilizumab should not be administered with concomitant biological DMARDs.
  • It may be administered as monotherapy or in combination with methotrexate or other nonbiologic disease-modifying antirheumatic drugs (DMARDs).

• Initial Intravenous dose:

  • 4 mg/kg once every 4 weeks.
  • The dose may be increased to 8 mg/kg once every 4 weeks based on clinical response
  • The maximum single dose is 800 mg.

• SubQ dose:

  • Weight less than 100 kg:

    • 162 mg once every other week.
    • The dose may be increased to 162 mg once every week based on clinical response

  • weight 100 kgs or more:

    • 162 mg once every week

• Switching Actemra from intravenous to SubQ therapy:

  • Administer the first SubQ dose at the time of the next scheduled IV dose.

Actemra (Tocilizumab) Dose in the treatment of severe or life-threatening cytokine release syndrome due to bi-specific T-cell engaging therapy:

• 4 mg/kg intravenously as a single dose.
• The dose may be repeated if clinical improvement does not occur within 24 - 48 hours.

Actemra (Tocilizumab) Dosing adjustment for Actemra toxicity in Adults:

• Neutropenia:

  • ANC >1,000/ul:

    • Maintain dose.

  • ANC 500 to 1,000/ul:

    • Interrupt therapy.
    • When ANC exceeds 1,000/ul, resume intravenous tocilizumab at 4 mg/kg which may later be increased to 8 mg/kg as clinically appropriate or
    • Resume SubQ tocilizumab at every other week dosing (increase the frequency to every week as clinically appropriate).

  • ANC less than 500/ul:

    • Discontinue.

• Thrombocytopenia:

  • Platelets 50,000 to 100,000/ul:

    • Interrupt therapy.
    • When the platelet count exceeds 100,000/ul, resume intravenous tocilizumab at 4 mg/kg that may be increased to 8 mg/kg as clinically appropriate or
    • resume SubQ tocilizumab at every other week dosing (increase frequency to every week as clinically appropriate).

  • Platelets <50,000/ul:

    • Discontinue.

Actemra (Tocilizumab) dose in Childrens

Actemra (Tocilizumab) Dose in the treatment of severe or life-threatening cytokine release syndrome (CRS) due to chimeric antigen receptor T-cell therapy:

• Children older than 2 years and Adolescents:

  • <30 kgs:

    • 12 mg/kg/dose intravenously as a single dose.
    • The dose may be repeated every 8 hours for up to 3 additional doses if no clinical improvement is noted after the initial dose.

  • ≥30 kg:

    • 8 mg/kg/dose intravenously as a single dose
    • The dose may be repeated every 8 hours for up to 3 additional doses if no clinical improvement is noted after the initial dose.
    • The maximum dose is 800 mg/dose.

Actemra Dose in the treatment of severe or life-threatening cytokine release syndrome (CRS) due to bi-specific T-cell engaging therapy: 

• Children ≥2 years and Adolescents:

  • 8 mg/kg/dose intravenously as a single dose.

Actemra (Tocilizumab) Dose in the treatment of Polyarticular juvenile idiopathic arthritis (PJIA):

• Children ≥2 years and Adolescents:

Note:

• Treatment should not be initiated if the ANC is less than 2,000/ul, platelets are less than 100,000/ul or the ALT or AST are greater than 1.5 times the ULN.
• It may be used as monotherapy or in combination with methotrexate.

• Intravenous dose:

  • <30 kg:

    • 10 mg/kg/dose every 4 weeks

  • ≥30 kg:

    • 8 mg/kg/dose every 4 weeks.
    • The maximum dose is 800 mg/dose

• SubQ dose:

  • <30 kg:

    • 162 mg/dose once every 3 weeks

  • ≥30 kg:

    • 162 mg/dose once every 2 weeks

• Switching Actemra from intravenous to SubQ dosing:

  • Administer the first SubQ dose at the time of the next scheduled intravenous dose.

Actemra (Tocilizumab) Dose in the treatment of Systemic juvenile idiopathic arthritis (SJIA):

• Children ≥2 years and Adolescents:

Note:

• Treatment should not be initiated if the ANC is less than 2,000/ul, platelets are less than 100,000/ul or the ALT or AST are greater than 1.5 times the ULN.

• Intravenous dose:

  • <30 kg:

    • 12 mg/kg/dose every 2 weeks

  • ≥30 kg:

    • 8 mg/kg/dose every 2 weeks.
    • The maximum dose is 800 mg/dose

• SubQ dose:

  • <30 kg:

    • 162 mg/dose once every 2 weeks

  • ≥30 kg:

    • 162 mg/dose once every week

Switching Actemra from intravenous to SubQ dosing:

• Administer the first SubQ dose at the time of the next scheduled intravenous dose.

Actemra Dosing adjustment for toxicity in children 2 years of age or older and adolescents:

• Polyarticular and systemic juvenile idiopathic arthritis (SJIA):

  • Non-hematologic toxicity:

    • A reduction in the dose has not been studied, however, treatment interruption is important in patients with liver disease (see the section on "dose in liver disease").
    • For patients who develop any infection, tocilizumab treatment must be interrupted until the resolution of the infection.
    • Those who develop a hypersensitivity reaction to the drug, permanent discontinuation of the treatment is recommended.

  • Hematologic toxicity:

    • Dose reductions in children who develop cytopenias have not been studied.
    • However, as in adults, the following recommendations should be followed:

      • Neutropenia:

        • ANC >1,000/ul:

          • Maintain dose.

        • ANC 500 to 1,000/ul:

          • Interrupt therapy.
          • When ANC exceeds 1,000/ul, resume intravenous tocilizumab at 4 mg/kg which may later be increased to 8 mg/kg as clinically appropriate or
          • Resume SubQ tocilizumab at every other week dosing (increase the frequency to every week as clinically appropriate).

        • ANC less than 500/ul:

          • Discontinue.

      • Thrombocytopenia:

        • Platelets 50,000 to 100,000/ul:

          • Interrupt therapy.
          • When the platelet count exceeds 100,000/ul, resume intravenous tocilizumab at 4 mg/kg that may be increased to 8 mg/kg as clinically appropriate or
          • resume SubQ tocilizumab at every other week dosing (increase frequency to every week as clinically appropriate).

        • Platelets <50,000/ul:

          • Discontinue.

Pregnancy Risk Factor: C

• The placental barrier is usually crossed by most maternal antibodies during the third trimester.
• Studies on animal reproduction have shown that fetal health can be adverse.
• It is possible for the infant's immune system to be affected.
• Before administering any live or live-attenuated vaccinations, it is important to weigh the benefits and risks.

Actemra (Tocilizumab) use during breastfeeding:

• It is unknown if the drug will be excreted into breastmilk.
• Manufacturers recommend that you weigh the risks for the child against the benefits for the mother.

Dose of Tocilizumab (Actemra) in renal disease:

• CrCl of 30 mL/minute or more:

  • Adjustment in the dose is not necessary.

• CrCl of less than 30 mL/minute:

  • The manufacture has not recommended any adjustments in the dose. It has not been studied in these patients.

Actemra dose in liver disease:

• Hepatic impairment prior to treatment initiation:

  • The manufacturer has not recommended an adjustment in the dose.
  • However, treatment with tocilizumab should not be initiated if the ALT or AST is greater than 1.5 times the ULN or the patient has an active hepatic disease.

• Hepatotoxicity during treatment:

  • Rheumatoid arthritis and giant cell arteritis:

    • ALT or AST >1 to 3 times the ULN:

      • Patients who are receiving intravenous therapy with persistent increases of greater than 1 to 3 times the ULN, reduce the dose to 4 mg/kg or interrupt until ALT and AST have normalized.
      • Patients who are receiving SubQ therapy with persistent increases of greater than 1 to 3 times the ULN, reduce the frequency to every other week or interrupt treatment until ALT and AST have normalized.
      • Adjust the dose of concomitant hepatotoxic drugs.

    • ALT or AST 3 to 5 times the ULN (confirmed with repeat testing):

      • The treatment must be interrupted until the ALT or AST is less than 3 times the ULN.
      • For persistent increases of ALT and AST greater than 3 times the ULN, discontinue the treatment.

    • ALT or AST greater than 5 times the ULN:

      • Avoid using it.

Common Side Effects of Actemra (Tocilizumab):

• Endocrine & Metabolic:

  • Increased Serum Cholesterol

• Hepatic:

  • Increased Serum Alanine Aminotransferase
  • Increased Serum Aspartate Aminotransferase

• Local:

  • Injection Site Reaction

• Miscellaneous:

  • Infusion-Related Reaction

Less Common Side Effects of Tocilizumab (Actemra):

• Cardiovascular:

  • Hypertension
  • Peripheral Edema

• Central Nervous System:

  • Headache
  • Dizziness

• Dermatologic:

  • Skin Rash
  • Dermatological Reaction

• Endocrine & Metabolic:

  • Increased LDL Cholesterol
  • Hypothyroidism

• Gastrointestinal:

  • Diarrhea
  • Abdominal Pain
  • Oral Mucosa Ulcer
  • Gastric Ulcer
  • Stomatitis
  • Weight Gain
  • Gastritis

• Hematologic & Oncologic:

  • Neutropenia
  • Thrombocytopenia
  • Leukopenia

• Hepatic:

  • Increased Serum Bilirubin

• Immunologic:

  • Antibody Development

• Infection:

  • Herpes Simplex Infection

• Ophthalmic:

  • Conjunctivitis

• Renal:

  • Nephrolithiasis

• Respiratory:

  • Upper Respiratory Tract Infection
  • Nasopharyngitis
  • Bronchitis
  • Cough
  • Dyspnea

Frequency unknown:

• Infection:

  • Infection
  • Infection Due To An Organism In Genus Pneumocystis
  • Serious Infection
  • Varicella Zoster Infection

• Otic:

  • Otitis Media

Contraindications to Actemra (Tocilizumab):

• Patients who have had an allergic reaction to tocilizumab, or any component of it, should not be treated.
• Active infections

Actemra Warnings & Precautions

• Perforation of the GI:

  • Tocilizumab therapy has been associated with gastrointestinal perforations, especially in patients suffering from diverticulitis.
  • Patients should be checked for any new abdominal symptoms, such as bleeding per rectum or vomiting.

• Hematologic effects

  • It is important to monitor closely as it has been linked to neutropenia and thrombocytopenia.
  • Patients should be closely monitored. Treatment may need to be interrupted, discontinued, or modified depending on the severity and duration of cytopenias.
  • If the ANC is lower than 2000/ul, or the platelet count less than 100,000/ul, treatment should be stopped immediately.
  • If the ANC is below 500/ul, or the platelet count is lower than 50,000/ul, patients with treatment-associated cytopenias must stop taking tocilizumab.

• Hepatic effects

  • Tocilizumab has been linked to liver injury caused by drugs. This could lead to liver transplantation or even death.
  • After treatment with tocilizumab, liver injury can occur for months or even years.
  • This is represented by a marked increase in liver enzymes (more that 5 times the ULN) or mildly elevated liver enzymes, with clinical signs of liver dysfunction.
  • Treatment interruption, discontinuation or modification of intervals may be required for liver injury.
  • Before and during treatment, it is important to monitor the liver functions.
  • Patients who have a baseline ALT/AST that is greater than 1.5 times the upper limits should not be given the treatment. 
  • If the ALT/AST exceeds 5x the ULN, patients who are currently receiving treatment should stop.
  • Patients with symptomatic conditions should be evaluated for liver function.
  • Treatment must be stopped if the ALT/AST or serum bilirubin are greater than 3x the ULN. 
  • These patients should be evaluated by a physician and treated only after the LFTs have stabilized.
  • Patients on concomitant hepatotoxicity drugs such as methotrexate are especially at risk of liver injury.

• Herpes zoster reactivation:

  • It has been reported that Herpes zoster reactivation can be caused by its use. Before initiating treatment, patients should have completed the 4-8 week vaccination schedule.

• Hyperlipidemia:

  • Tocilizumab has been linked to dyslipidemia, which manifests as high total cholesterol, triglycerides and LDL levels, and/or HDL.
  • Patients should be closely monitored for approximately 4-8 weeks following treatment initiation, and as directed subsequently.

• Hypersensitivity

  • Tocilizumab has been linked to severe allergic reactions, including anaphylaxis which can be fatal (especially after intravenous administration).
  • Patients who had never experienced an allergic reaction before were also susceptible to allergic reactions.
  • During the infusion, life-saving medications like epinephrine, glucocorticoids, fluids, and antihistamines should be available for immediate use.
  • SubQ administration can cause hypersensitivity reactions in patients who present with symptoms. Patients should immediately seek medical attention.
  • All patients with an allergic reaction must stop receiving treatment.

• Infections [US Boxed Warning]

  • Tocilizumab treatment can lead to serious infections, which may require hospitalization.
  • These infections can include active tuberculosis and invasive bacterial fungal, viral, or other opportunistic diseases.
  • Patients should be monitored closely for signs and symptoms of infection during and after treatment.
  • Tocilizumab should not be administered to patients if they have an infection.
  • Patients with chronic or recurrent infections, people who have been exposed to tuberculosis, people with underlying medical conditions that could predispose to infection, and patients who live in areas with endemic mycosis or tuberculosis should carefully consider the potential benefits and risks of tocilizumab before starting treatment.
  • Patients receiving tocilizumab therapy may develop serious infections such as pneumonia, urinary tract infection and cellulitis.
  • Tocilizumab should never be given to patients with active infections (including localized ones).

• Malignancy

  • Patients receiving tocilizumab therapy may develop malignancies because their natural defenses are compromised.

• Tuberculosis: [US-Boxed Warning]

  • Tocilizumab has been linked to new infections and reactivation latent tuberculosis.
  • Before and after tocilizumab treatment, all patients should be tested for tuberculosis.
  • Tocilizumab therapy should not be started on patients with latent tuberculosis.
  • Although patients may not be positive for tuberculosis, they may develop active infections. 
  • Patients should be closely monitored, even if they have negative initial results.

• Demyelinating CNS Disease:

  • It has been linked to CNS demyelinating diseases, including chronic inflammatory demyelinating disorder and multiple sclerosis.
  • Tocilizumab should be used with caution in patients with CNS demyelinating diseases, especially those who have recently developed or had a history.
  • Tocilizumab treatment patients should be closely monitored for signs of CNS demyelinating disorders, such as weakness, visual impairment, or sensory impairment.

• Hepatic impairment

  • Patients with liver disease and hepatic impairment should avoid it.
  • Patients with RA or GCA should not receive treatment if their baseline ALT/AST is greater than 1.5x the ULN.

Tocilizumab: Drug Interaction

Monitor:

• All patients should be screened for latent tuberculosis.
• Patients who are treated for RA and GCA should have CBC monitored prior to the treatment, 4 - 8 weeks after initiating the treatment, and every 3 months thereafter.
• Monitor Liver function tests before initiating the treatment, every 4 - 8 weeks after the start of the treatment for the first 6 months, and every three months thereafter.
• Patients with SJIA should have CBC and liver function tests monitored prior to treatment initiation, at the second dose, and every 2 - 4 weeks (or every 4 - 8 weeks in patients with PJIA).
• Lipid profile should be done at baseline, 4 - 8 weeks after treatment initiation, and as clinically indicated thereafter.
• All patients should be monitored for the clinical features of CNS demyelinating disorders such as multiple sclerosis.
• Monitor all patients for the clinical features of infections before, during, and after the treatment.

How to administer Actemra (Tocilizumab)?

Intravenous administration of Actemra:

• It is administered via a dedicated line as a slow intravenous infusion over 60 minutes after dilution (A rapid intravenous bolus administration should be avoided).
• It should not be administered with other agents through the same IV line.
• In patients with cytokine storm (cytokine release syndrome) who require a second dose, an interval of at least 8 hours should elapse.
• The opaque or discolored solutions should not be injected.

SubQ administration of Actemra:

• It is important to note that an opaque or discolored solution should not be injected.
• The injection should not be administered into moles, scars, bruised, tender, or inflamed skin. The site of the injection should be rotated.
• The prefilled syringe should be allowed for at least 30 minutes and the autoinjector for at least 45 minutes prior to the administration.
• It can be administered by the patient or the patient's caregiver after proper training.

How to switch from Intravenous Actemra to SubQ injections?

• The first SubQ dose should be administered at the next scheduled intravenous dose.

Mechanism of action of Tocilizumab (Actemra):

• Tocilizumab, a monoclonal anti-interleukin-6 (IL-6) receptor antagonist, is a monoclonal antibody.
• Inflammatory stimuli can induce IL-6 and other cytokines or chemokines. 
• These chemical mediators mediate many immunological responses.
• Tocilizumab inhibits the IL-6 receptors, which in turn inhibits the inflammatory response and inhibits the production of cytokines.
• Patients with Cytokine Storm [CRS] will experience a four-hour wait for the medication to take effect. 
• The fever and hypotension will resolve in a matter of hours. In about one to three days, blood pressure will stabilize. 
• Cytokine storm management usually requires 1 to 4 doses (with a median of one-dose) of chimeric antigen receptor therapy T-cell therapy.
• SubQ is bioavailable at 80% for patients with Rheumatoid and Giant cell arthritis, 95% for systemic juvenile idiopathic arteritis (SJIA) and 96% for polyarticular juvenile idiopathic arteritis (PJIA) after subQ administration.
• After intravenous administrations of Actemra, half-life elimination is possible
• The half-life of the drug is concentration-dependent. 
• It can last up to 16 days in SJIA for children and teens, and up to 17 in PJIA for adolescents.
•  Adults with Rheumatoid Arthritis have a half-life of 11 to 13 days.

Half-life elimination after SubQ administration:

In children and adolescents, the half-life of the drug is between 14 and 10 days in SJIA. It can also be up to 10 days when administered in PJIA. Adults with RA have a half-life of up to five days if they are administered every other week, and thirteen days if administered weekly. It has a half-life of between 4.2 and 7.9 days if administered every other week to adults with Giant Cell Arteritis, and 18.3 to 18.9 days if administered weekly. It takes time to get their peak serum concentration SubQ administration takes approximately 3 days if administered weekly, and about 4.5 days if administered every other week.

Brand Names of Tocilizumab (International):

• Actemra
• Actemra SC
• RoActemra

Tocilizumab brand names in Pakistan:

• Actemra (Rs. 66000/injection)
• Tocilizumab price and availability in Pakistan is discussed here: Actemra (Tocilizumab) Injection in Pakistan - Cost, Side effects