Tocilizumab

Tocilizumab is a an Antirheumatic Agent/ Anti-inflammatory agent , belonging to pharmacology class of Interleukin-6 Receptor Antagonist

Tocilizumab can be used in the treatment of COVID-19, hospitalized patients, Cytokine release syndrome, chimeric antigen receptor T-cell therapy-associated, Giant cell arteritis, Polyarticular juvenile idiopathic arthritis, Rheumatoid arthritis, Systemic juvenile idiopathic arthritis, Systemic sclerosis (scleroderma)-associated interstitial lung disease .It is also used to treat Cytokine release syndrome, bi-specific T-cell engaging therapy-associated; Neuromyelitis optica, relapse prevention.

The bioavailability of Tocilizumab is 95% in healthy subjects administered a 70 mg subcutaneous bolus injection. In patients with rheumatoid arthritis (RA) administered a subcutaneous dose of Tocilizumab, the maximum plasma concentration was detected 3 to 7 hours later.The volume of distribution averaged 18.5 L. As a protein-based therapy, Tocilizumab is expected to be metabolized by proteases throughout the body. Tocilizumab is mostly excreted by the kidney; therefore, the risk of toxic reactions may increase in patients with impaired renal function

The common side effects associated with Tocilizumab include Gastrointestinal/diverticular perforation, haematologic effects (e.g. neutropenia, thrombocytopenia), increased hepatic transaminases, total cholesterol, triglycerides.

Tocilizumab is available in the form of Injectable solutions.

The molecule is available in India, USA, Japan, Germany.

Tocilizumab belonging to the Interleukin-6 Receptor Antagonist acts a Antirheumatic Agent/ Anti-inflammatory agent ,

The interleukin-6 (IL-6) receptor is inhibited by tocilizumab. Inflammatory stimuli cause the production of endogenous IL-6, which mediates a range of immune reactions. Acute phase reactant and cytokine production are decreased as a result of tocilizumab's inhibition of IL-6 receptors.

Tocilizumab is available in Injectable solution

IV : Allow diluted solution for infusion to reach room temperature prior to administration; infuse over 60 minutes using a dedicated IV line. Do not infuse other agents through same IV line. Do not administer IV push or IV bolus. If additional doses are necessary for the management of cytokine-release syndrome, the interval between doses should be at least 8 hours. Do not use if opaque particles or discoloration is visible.

Tocilizumab can be used in the treatment of COVID-19, hospitalized patients, Cytokine release syndrome, chimeric antigen receptor T-cell therapy-associated, Giant cell arteritis, Polyarticular juvenile idiopathic arthritis, Rheumatoid arthritis, Systemic juvenile idiopathic arthritis, Systemic sclerosis (scleroderma)-associated interstitial lung disease. It is also used to treat Cytokine release syndrome, bi-specific T-cell engaging therapy-associated; Neuromyelitis optica, relapse prevention.

Tocilizumab is a recombinant, non-glycosylated form of IL-1Ra that competes with and inhibits IL-1 by binding to the IL-1 receptor; therefore, the administration of this drug reduces the inflammatory response in RA patients.

Tocilizumab is approved for use in the following clinical indications

COVID-19, hospitalized patients: Treatment of COVID-19 in adult, hospitalized patients who are receiving systemic glucocorticoids and require supplemental oxygen, noninvasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation.

Cytokine release syndrome, chimeric antigen receptor T-cell therapy-associated: Treatment of chimeric antigen receptor T-cell–induced severe or life-threatening cytokine release syndrome in patients ≥2 years of age.

Giant cell arteritis: Treatment of giant cell arteritis in adult patients.

Polyarticular juvenile idiopathic arthritis: Treatment of active polyarticular juvenile idiopathic arthritis in patients ≥2 years of age.

Rheumatoid arthritis: Treatment of adults with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more disease-modifying antirheumatic drugs.

Systemic juvenile idiopathic arthritis: Treatment of active systemic juvenile idiopathic arthritis in patients ≥2 years of age.

Systemic sclerosis (scleroderma)-associated interstitial lung disease: Indicated to slow the rate of decline in pulmonary function in adult patients with systemic sclerosis (scleroderma)-associated interstitial lung disease.

Although not approved there have been certain off labelled uses documented for toci.lizumab which include:

Cytokine release syndrome, bi-specific T-cell engaging therapy-associated; Neuromyelitis optica, relapse prevention.

COVID-19, hospitalized patients: Note: For use in hospitalized patients with significant oxygen requirements (eg, high-flow oxygen, noninvasive ventilation, mechanical ventilation, or extracorporeal membrane oxygenation) and those with lower but increasing oxygen requirements and evidence of systemic inflammation. Do not initiate if ANC <1,000/mm³, platelets <50,000/mm³, or ALT or AST >10 times ULN.

IV: 8 mg/kg once (maximum dose: 800 mg) as part of an appropriate combination regimen. If clinical signs or symptoms worsen or do not improve, a second dose may be considered ≥8 hours after the first dose.

Cytokine release syndrome:

Bi-specific T-cell engaging therapy-associated (off-label use): Note: Some experts reserve for patients with severe cytokine release syndrome (CRS) who do not respond to initial measures.

IV: 8 mg/kg once (maximum dose: 800 mg [based on chimeric antigen receptor T-cell CRS dosing]); if clinical improvement does not occur within 8 to 24 hours after, up to 3 additional doses may be administered (with at least an 8-hour interval between consecutive doses).

Chimeric antigen receptor T-cell therapy-associated: IV: 8 mg/kg once (maximum dose: 800 mg). May give with or without glucocorticoids; some experts suggest using in combination with a glucocorticoid for grades 3 and 4 CRS. If clinical improvement does not occur after the first dose, up to 3 additional doses may be administered (with at least an 8-hour interval between consecutive doses)

Giant cell arteritis (adjunctive agent):

Note: Do not initiate if ANC is <2,000/mm³, platelets are <100,000/mm³, or if ALT or AST are >1.5 times ULN. If a patient develops a serious infection, interrupt therapy until the infection is controlled.

IV: 6 mg/kg (maximum dose: 600 mg) once every 4 weeks in combination with glucocorticoids ; some experts use 8 mg/kg once every 4 weeks in combination with glucocorticoids (or as monotherapy following discontinuation of glucocorticoids) and do not exceed 800 mg per dose.

SUBQ: 162 mg once every week; based on clinical considerations, may consider 162 mg once every other week; to be administered in combination with glucocorticoids (or as monotherapy following discontinuation of glucocorticoids)

Neuromyelitis optica, relapse prevention (alternative agent) (off-label use):

Note: For long-term therapy to prevent attacks; optimal immunotherapy selection has not been established. Do not initiate if ANC is <2,000/mm³, platelets are <100,000/mm³, or if ALT or AST are >1.5 times ULN. If a patient develops a serious infection, interrupt therapy until the infection is controlled.

IV: 8 mg/kg once every 4 weeks, maximum dose has not been established; some experts do not exceed 800 mg per dose.

Rheumatoid arthritis:

Note: May be administered in combination with methotrexate, another conventional synthetic disease-modifying antirheumatic drug, or as monotherapy if other treatment options are not tolerated . Patients should be under the care of a clinician experienced with use of tocilizumab for this condition. Do not initiate if ANC is <2,000/mm³, platelets are <100,000/mm³, or if ALT or AST are >1.5 times ULN. If a patient develops a serious infection, interrupt therapy until the infection is controlled.

IV: Initial: 4 mg/kg once every 4 weeks; may be increased to 8 mg/kg once every 4 weeks based on clinical response (maximum dose: 800 mg) .

SUBQ:

<100 kg: 162 mg once every other week; may increase to 162 mg once every week based on clinical response.

≥100 kg: 162 mg once every week.

Systemic sclerosis (scleroderma)–associated interstitial lung disease (alternative agent) :

Note: For initial and/or maintenance therapy in patients who cannot take other preferred agents. Do not initiate if ANC is <2,000/mm³, platelets are <100,000/mm³, or if ALT or AST are >1.5 times ULN. If a patient develops a serious infection, interrupt therapy until the infection is controlled.

SUBQ: 162 mg once every week.

Transitioning from IV therapy to SUBQ therapy: Administer the first SUBQ dose instead of the next scheduled IV dose.

• Injectable solution: 80 mg/4 mL (4 mL); 200 mg/10 mL (10 mL); 400 mg/20 mL, 162mg/0.9mL

Injectable solution

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dose Adjustment in Kidney impairment patient:

CrCl ≥30 mL/minute: No dosage adjustment necessary.

CrCl <30 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); however, based on tocilizumab's molecular weight (148 kDa), it is unlikely to be significantly renally eliminated

Dose Adjustment in Hepatic Patients:

ALT or AST >1.5 × ULN: rheumatoid arthritis (RA), giant cell arteritis, or systemic sclerosis (scleroderma)-associated interstitial lung disease (SSc-ILD).

ALT or AST >10 × ULN: COVID-19.

Hepatotoxicity during treatment: RA, giant cell arteritis, and SSc-ILD:

>1 to 3 × ULN: Note: Adjust concomitant disease-modifying antirheumatic drugs (for RA and SSc-ILD) or immunomodulatory agents (for GCA) as appropriate.

For persistent increases >1 to 3 × ULN, adjust dose as follows:

Giant cell arteritis:

IV: Interrupt therapy until ALT/AST have normalized.

SUBQ: Reduce injection frequency to every other week or interrupt therapy until ALT/AST have normalized; resume therapy at every other week, then increase frequency to every week as clinically appropriate.

Rheumatoid arthritis:

IV: Reduce dose to 4 mg/kg or interrupt therapy until ALT/AST have normalized.

SUBQ: Reduce injection frequency to every other week or interrupt therapy until ALT/AST have normalized; resume therapy at every other week, then increase frequency to every week as clinically appropriate.

Systemic sclerosis (scleroderma)-associated interstitial lung disease: SUBQ: Reduce injection frequency to every other week or interrupt therapy until ALT/AST have normalized; resume therapy at every other week, then increase frequency to every week as clinically appropriate.

>3 to 5 × ULN (confirmed with repeat testing): Interrupt until ALT/AST <3 × ULN and follow dosage adjustments recommended for liver enzyme abnormalities >1 to 3 × ULN. For persistent increases >3 × ULN, discontinue.

>5 × ULN: Discontinue.

Dose Adjustment in Pediatric Patients:

COVID-19 (hospitalized patients who are receiving systemic corticosteroids), treatment:

Note: Emergency authorization in pediatric patients for COVID-19 is supported by efficacy data from adult patients and pediatric safety and dosing data extrapolated from other indications very limited pediatric retrospective data are available. Not recommended for use in patients with ANC <1,000/mm³, platelets <50,000/mm³, or in patients with active hepatic disease or hepatic impairment .

Children ≥2 years and Adolescents: Very limited data available:

<30 kg: IV: 12 mg/kg/dose once; if clinical signs or symptoms worsen or do not improve after initial dose, may repeat dose once ≥8 hours after initial dose

≥30 kg: IV: 8 mg/kg/dose once; maximum dose: 800 mg/dose; if clinical signs or symptoms worsen or do not improve after initial dose, may repeat dose once ≥8 hours after initial dose

Cytokine release syndrome (CRS) due to chimeric antigen receptor T-cell therapy; severe or life-threatening:

Children ≥2 years and Adolescents: May be used alone or in combination with corticosteroids.

<30 kg: IV: 12 mg/kg/dose once; if no clinical improvement after initial dose, may repeat dose every 8 hours for up to 3 additional doses.

≥30 kg: IV: 8 mg/kg/dose once; if no clinical improvement after initial dose, may repeat dose every 8 hours for up to 3 additional doses; maximum single dose: 800 mg/dose.

Cytokine release syndrome (CRS) due to bi-specific T-cell engaging therapy, severe or life-threatening: Very limited data available ,optimal dose not established.

Children ≥2 years and Adolescents: IV: 8 mg/kg/dose once; some experts suggest may repeat the dose if clinical improvement does not occur within 24 to 48 hours; dosing based on expert recommendations and a case report of a 7-year-old who received blinatumomab as part of a Phase I clinical trial and developed CRS; a single 8 mg/kg dose of tocilizumab was used (patient weight was not provided) and within 12 hours a significant clinical response was observed; other reports of experience in pediatric patients are lacking.

Polyarticular juvenile idiopathic arthritis (PJIA):

Children ≥2 years and Adolescents: Note: Do not initiate if ANC is <2,000/mm³, platelets are <100,000/mm³, or if ALT or AST are >1.5 times ULN. Dose adjustment should not be made based solely on a single-visit body weight measurement due to fluctuations in body weight. May be used as monotherapy or in combination with methotrexate. Variable routes of administration (IV, SUBQ) and dosing; use precaution to ensure appropriate dose/route.

IV:

<30 kg: 10 mg/kg/dose every 4 weeks.

≥30 kg: 8 mg/kg/dose every 4 weeks; maximum dose: 800 mg/dose.

SUBQ:

<30 kg: 162 mg/dose once every 3 weeks.

≥30 kg: 162 mg/dose once every 2 weeks.

Conversion from IV to SUBQ dosing: Administer the first SUBQ dose instead of the next scheduled IV dose.

Systemic juvenile idiopathic arthritis (SJIA):

Children ≥2 years and Adolescents: Note: Do not initiate if ANC is <2,000/mm³, platelets are <100,000/mm³, or if ALT or AST are >1.5 times ULN. Dose adjustment should not be made based solely on a single-visit body weight measurement due to fluctuations in body weight. May be used as monotherapy or in combination with methotrexate.

IV:

<30 kg: 12 mg/kg/dose every 2 weeks.

≥30 kg: 8 mg/kg/dose every 2 weeks; maximum dose: 800 mg/dose.

SUBQ:

<30 kg: 162 mg/dose once every 2 weeks.

≥30 kg: 162 mg/dose once every week.

Conversion from IV to SUBQ dosing: Administer the first SUBQ dose instead of the next scheduled IV dose.

Tocilizumab may be contraindicated in the following conditions:-

Hypersensitivity to E. coli-derived proteins or Tocilizumab. Neutropenia (absolute neutrophil count <1.5 x 10⁹/L). Severe renal impairment (CrCl <30 mL/min).

The treating physician must closely monitor the patient and keep pharmacovigilance as follows

Concerns related to adverse effects:

• Herpes zoster reactivation: Herpes zoster reactivation has been reported.

• Hyperlipidemia: Therapy is associated with increases in total cholesterol, triglycerides, low-density lipoprotein, and/or high-density lipoprotein.

• Malignancy: Use of tocilizumab may affect defenses against malignancies; impact on the development and course of malignancies is not fully defined; however, malignancies were observed in clinical trials.

Disease-related concerns:

• Demyelinating CNS disease: Use with caution in patients with preexisting or recent onset CNS demyelinating disorders; rare cases of CNS demyelinating disorders (multiple sclerosis and chronic inflammatory demyelinating polyneuropathy) have occurred.

• Hepatic impairment: Use with caution in hepatic impairment; see "Dosage: Hepatic Function Impairment" for additional information.

• Tuberculosis: Consider anti-tuberculosis (TB) treatment in patients with a history of latent or active TB if adequate treatment course cannot be confirmed, and for patients with risk factors for TB despite a negative test.

Concurrent drug therapy issues:

• Biological disease-modifying antirheumatic drugs: Concomitant use with other biological disease-modifying antirheumatic drugs (DMARDs) (eg, tumor necrosis factor blockers, IL-1 receptor blockers, anti-CD20 monoclonal antibodies, selective costimulation modulators) has not been studied and should be avoided due to the increased risk of infection.

There is no sufficient scientific evidence traceable regarding use and safety of Tocilizumab in concurrent use with alcohol.

There is no sufficient scientific evidence traceable regarding use and safety of Tocilizumab in breast milk

There is no sufficient scientific evidence traceable regarding use and safety of Tocilizumab in concurrent use with any particular food.

The adverse reactions related to Tocilizumab can be categorized as

Common Adverse effects: Gastrointestinal/diverticular perforation, hematologic effects (e.g. neutropenia, thrombocytopenia), increased hepatic transaminases, total cholesterol, triglycerides

Less Common Adverse effects: Constipation, diarrhea, nausea, abdominal pain, mouth ulceration, gastritis.

Rare Adverse effects: Cough, dyspnea, nasopharyngitis.

The clinically relevant drug interactions of Tocilizumab is briefly summarized here

May enhance the immunosuppressive effect and increase the risk of infection with other biologic DMARDs, TNF antagonists, IL-1 receptor antagonists, anti-CD20 monoclonal antibodies, selective co-stimulation modulators. May increase metabolism of methylprednisolone, dexamethasone, atorvastatin, Ca channel blockers, theophylline, warfarin, phenprocoumon, phenytoin, ciclosporin, and benzodiazepines. May increase risk of vaccine associated infection; avoid use with live and live attenuated vaccines.

The common side of Tocilizumab include the following

Gastrointestinal/diverticular perforation, hematologic effects (e.g. neutropenia, thrombocytopenia), increased hepatic transaminases, total cholesterol, triglycerides.

Pregnancy

Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Tocilizumab during pregnancy. Physicians are encouraged to register patients and pregnant women are encouraged to register themselves by calling 1-877-311-8972.

Risk Summary

The limited available data with Tocilizumab in pregnant women are not sufficient to determine whether there is a drug-associated risk for major birth defects and miscarriage. Monoclonal antibodies, such as tocilizumab, are actively transported across the placenta during the third trimester of pregnancy and may affect immune response in the in utero exposed infant.

In animal reproduction studies, intravenous administration of tocilizumab to Cynomolgus monkeys during organogenesis caused abortion/embryo-fetal death at doses 1.25 times and higher than the maximum recommended human dose by the intravenous route of 8 mg per kg every 2 to 4 weeks. The literature in animals suggests that inhibition of IL-6 signaling may interfere with cervical ripening and dilatation and myometrial contractile activity leading to potential delays of parturition. Based on the animal data, there may be a potential risk to the fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes.

Clinical Considerations Fetal/Neonatal adverse reactions Monoclonal antibodies are increasingly transported across the placenta as pregnancy progresses, with the largest amount transferred during the third trimester. Risks and benefits should be considered prior to administering live or live-attenuated vaccines to infants exposed to Tocilizumab in utero

Data

Animal Data

An embryo-fetal developmental toxicity study was performed in which pregnant Cynomolgus monkeys were treated intravenously with tocilizumab at daily doses of 2, 10, or 50 mg/ kg during organogenesis from gestation day (GD) 20-50. Although there was no evidence for a teratogenic/dysmorphogenic effect at any dose, tocilizumab produced an increase in the incidence of abortion/embryo-fetal death at doses 1.25 times and higher the MRHD by the intravenous route at maternal intravenous doses of 10 and 50 mg/ kg. Testing of a murine analogue of tocilizumab in mice did not yield any evidence of harm to offspring during the pre- and postnatal development phase when dosed at 50 mg/kg intravenously with treatment every three days from implantation (GD 6) until post-partum day 21 (weaning). There was no evidence for any functional impairment of the development and behavior, learning ability, immune competence and fertility of the offspring. Parturition is associated with significant increases of IL-6 in the cervix and myometrium. The literature suggests that inhibition of IL-6 signaling may interfere with cervical ripening and dilatation and myometrial contractile activity leading to potential delays of parturition. For mice deficient in IL-6 (ll6-/- null mice), parturition was delayed relative to wild-type (ll6+/+) mice. Administration of recombinant IL-6 to ll6-/- null mice restored the normal timing of delivery.

Lactation

Risk Summary No information is available on the presence of tocilizumab in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. Maternal immunoglobulin G (IgG) is present in human milk. If tocilizumab is transferred into human milk, the effects of local exposure in the gastrointestinal tract and potential limited systemic exposure in the infant to tocilizumab are unknown. The lack of clinical data during lactation precludes clear determination of the risk of Tocilizumab to an infant during lactation; therefore the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Tocilizumab and the potential adverse effects on the breastfed child from tocilizumab or from the underlying maternal condition.

Pediatric Use

Tocilizumab by intravenous use is indicated for the treatment of pediatric patients with:

• Active systemic juvenile idiopathic arthritis in patients 2 years of age and older

• Active polyarticular juvenile idiopathic arthritis in patients 2 years of age and older

• Severe or life-threatening CAR T cell-induced cytokine release syndrome (CRS) in patients 2 years of age and older. Safety and effectiveness of Tocilizumab in pediatric patients with conditions other than PJIA, SJIA or CRS have not been established.

Children under the age of two have not been studied. SC administration has not been studied in pediatric patients. Testing of a murine analogue of tocilizumab did not exert toxicity in juvenile mice. In particular, there was no impairment of skeletal growth, immune function and sexual maturation.

Geriatric Use

Of the 2644 patients who received Tocilizumab in Studies I to V [see Clinical Studies (14)], a total of 435 rheumatoid arthritis patients were 65 years of age and older, including 50 patients 75 years and older. Of the 1069 patients who received Tocilizumab-SC in studies SC-I and SC-II there were 295 patients 65 years of age and older, including 41 patients 75 years and older. The frequency of serious infection among Tocilizumab-treated subjects 65 years of age and older was higher than those under the age of 65. As there is a higher incidence of infections in the elderly population in general, caution should be used when treating the elderly. Clinical studies that included Tocilizumab for CRS did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. 8.6 Hepatic Impairment The safety and efficacy of Tocilizumab have not been studied in patients with hepatic impairment, including patients with positive HBV and HCV serology

Renal Impairment

No dose adjustment is required in patients with mild or moderate renal impairment. Tocilizumab has not been studied in patients with severe renal impairment.

There are limited data available on overdoses with Tocilizumab. One case of accidental overdose was reported with intravenous Tocilizumab in which a patient with multiple myeloma received a dose of 40 mg per kg. No adverse drug reactions were observed. No serious adverse drug reactions were observed in healthy volunteers who received single doses of up to 28 mg per kg, although all 5 patients at the highest dose of 28 mg per kg developed dose-limiting neutropenia. In case of an overdose, it is recommended that the patient be monitored for signs and symptoms of adverse reactions. Patients who develop adverse reactions should receive appropriate symptomatic treatment.

Pharmacodynamics:

Tocilizumab is a recombinant humanized monoclonal antibody. It is an antagonist of the interleukin-6 (IL-6) receptor. IL-6 is a pleiotropic pro-inflammatory cytokine that is involved in physiological processes such as T-cell activation, induction of Ig secretion, initiation of hepatic acute phase protein synthesis, and stimulation of hematopoietic precursor cell proliferation and differentiation. It binds specifically to both soluble and membrane-bound receptors (sIL-6R and mIL-6R) and inhibits IL-6-mediated signalling, thereby resulting in a reduction in inflammatory mediator production.

Pharmacokinetics:

1. https://www.uptodate.com/contents/Tocilizumab -drug-information?search=Tocilizumab &source=panel_search_result&selectedTitle=1~148&usage_type=panel&kp_tab=drug_general&display_rank=1#F154338
2. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022352s017lbl.pdf
3. https://www.medicaid.nv.gov/Downloads/provider/Tocilizumab _2015-1215.pdf
4. https://www.mims.com/india/drug/info/Tocilizumab ?type=full&mtype=generic#mechanism-of-action