Tofidence

4) . 3 Recommended Dosage for Giant Cell Arteritis Recommended Intravenous Dosage Regimen: The recommended dosage of TOFIDENCE for adult patients given as a 60-minute single intravenous drip infusion is 6 mg per kg every 4 weeks in combination with tapering course of glucocorticoids.

TOFIDENCE can be used alone following discontinuation of glucocorticoids. 8) ]. 3) ]. When transitioning from intravenous therapy with TOFIDENCE to subcutaneous therapy with another tocilizumab product, administer the first subcutaneous dose instead of the next scheduled intravenous dose.

4 Recommended Dosage for Polyarticular Juvenile Idiopathic Arthritis TOFIDENCE may be used as an intravenous infusion alone or in combination with methotrexate. Do not change dose based solely on a single visit body weight measurement, as weight may fluctuate.

Recommended Intravenous Dosage Regimen:

The recommended dosage of TOFIDENCE for PJIA patients given once every 4 weeks as a 60-minute single intravenous drip infusion is: Recommended Intravenous PJIA Dosage Every 4 Weeks Patients less than 30 kg weight 10 mg per kg Patients at or above 30 kg weight 8 mg per kg When transitioning from intravenous therapy with TOFIDENCE to subcutaneous therapy with another tocilizumab product, administer the first subcutaneous dose instead of the next scheduled intravenous dose.

8) ]. 5 Recommended Dosage for Systemic Juvenile Idiopathic Arthritis TOFIDENCE may be used as an intravenous infusion or in combination with methotrexate. Do not change a dose based solely on a single visit body weight measurement, as weight may fluctuate.

Recommended Intravenous Dosage Regimen:

The recommended dose of TOFIDENCE for SJIA patients given once every 2 weeks as a 60-minute single intravenous drip infusion is: Recommended Intravenous SJIA Dosage Every 2 Weeks Patients less than 30 kg weight 12 mg per kg Patients at or above 30 kg weight 8 mg per kg When transitioning from intravenous therapy with TOFIDENCE to subcutaneous therapy with another tocilizumab product, administer the first subcutaneous dose instead of the next scheduled intravenous dose.

8) ]. 6 Coronavirus Disease 2019 (COVID-19) Administer TOFIDENCE by intravenous infusion only. The recommended dosage of TOFIDENCE for treatment of adult patients with COVID-19 is 8 mg per kg administered as a single 60-minute intravenous infusion.

If clinical signs or symptoms worsen or do not improve after the first dose, one additional infusion of TOFIDENCE may be administered at least 8 hours after the initial infusion. Doses exceeding 800 mg per infusion are not recommended in patients with COVID-19.

7 Preparation and Administration Instructions for Intravenous Infusion TOFIDENCE for intravenous infusion should be diluted by a healthcare professional using aseptic technique as follows: Use a sterile needle and syringe to prepare TOFIDENCE.

9% Sodium Chloride Injection, USP, and then follow steps 1 and 2 below. Patients at or above 30 kg weight: use a 100 mL infusion bag or bottle, and then follow steps 1 and 2 below. Step 1. 5) ]. 6 mL/kg Step 2. 9% Sodium Chloride Injection, USP infusion bag or bottle.

To mix the solution, gently invert the bag to avoid foaming. 9% Sodium Chloride Injection, USP may be stored refrigerated at 36°F to 46°F (2°C to 8°C) for up to 24 hours or room temperature at 68°F to 77°F (20°C to 25°C) for up to 12 hours and should be protected from light.

TOFIDENCE solutions do not contain preservatives; therefore, unused product remaining in the vials should not be used. Allow the fully diluted TOFIDENCE solution to reach room temperature prior to infusion. The infusion should be administered over 60 minutes, and must be administered with an infusion set.

Do not administer as an intravenous push or bolus. TOFIDENCE should not be infused concomitantly in the same intravenous line with other drugs. No physical or biochemical compatibility studies have been conducted to evaluate the co-administration of TOFIDENCE with other drugs.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If particulates and discolorations are noted, the product should not be used.

Fully diluted TOFIDENCE solutions are compatible with infusion bags and/or infusion sets with the following materials: polypropylene, polyethylene, polyolefin, polyvinyl chloride, polyethersulfone, polyurethane, nylon and stainless steel.

8 Dosage Modifications due to Serious Infections or Laboratory Abnormalities Serious Infections Hold TOFIDENCE treatment if a patient develops a serious infection until the infection is controlled. 4) ] Lab Value Recommendation for RA Recommendation for GCA Greater than 1 to 3× ULN Dose modify concomitant DMARDs if appropriate.

For persistent increases in this range:

For patients receiving intravenous TOFIDENCE, reduce dose to 4 mg per kg or hold TOFIDENCE until ALT or AST have normalized. Dose modify immunomodulatory agents if appropriate For persistent increases in this range: For patients receiving intravenous TOFIDENCE, hold TOFIDENCE until ALT or AST have normalized.

Greater than 3 to 5× ULN (confirmed by repeat testing) Hold TOFIDENCE dosing until less than 3× ULN and follow recommendations above for greater than 1 to 3× ULN. For persistent increases greater than 3× ULN, discontinue TOFIDENCE. Hold TOFIDENCE dosing until less than 3× ULN and follow recommendations above for greater than 1 to 3× ULN.

For persistent increases greater than 3× ULN, discontinue TOFIDENCE. Greater than 5× ULN Discontinue TOFIDENCE. Discontinue TOFIDENCE. 4) ] Lab Value (cells per mm 3 ) Recommendation for RA Recommendation for GCA ANC greater than 1000 Maintain dose.

Maintain dose. ANC 500 to 1000 Hold TOFIDENCE dosing.

When ANC greater than 1000 cells per mm 3:

For patients receiving intravenous TOFIDENCE, resume TOFIDENCE at 4 mg per kg and increase to 8 mg per kg as clinically appropriate. Hold TOFIDENCE dosing.

When ANC greater than 1000 cells per mm 3 :

For patients receiving intravenous TOFIDENCE, resume TOFIDENCE at 6 mg per kg. ANC less than 500 Discontinue TOFIDENCE. Discontinue TOFIDENCE. 4) ] Lab Value (cells per mm 3 ) Recommendation for RA Recommendation for GCA 50,000 to 100,000 Hold TOFIDENCE dosing.

When platelet count is greater than 100,000 cells per mm 3 :

For patients receiving intravenous TOFIDENCE, resume TOFIDENCE at 4 mg per kg and increase to 8 mg per kg as clinically appropriate.

Hold TOFIDENCE dosing When platelet count is greater than 100,000 cells per mm 3 :

For patients receiving intravenous TOFIDENCE, resume TOFIDENCE at 6 mg per kg. Less than 50,000 Discontinue TOFIDENCE. Discontinue TOFIDENCE. Polyarticular and Systemic Juvenile Idiopathic Arthritis Dose reduction of tocilizumab products has not been studied in the PJIA and SJIA populations.

Dose interruptions of TOFIDENCE are recommended for liver enzyme abnormalities, low neutrophil counts, and low platelet counts in patients with PJIA and SJIA at levels similar to what is outlined above for patients with RA and GCA.

If appropriate, dose modify or stop concomitant methotrexate and/or other medications and hold TOFIDENCE dosing until the clinical situation has been evaluated. In PJIA and SJIA the decision to discontinue TOFIDENCE for a laboratory abnormality should be based upon the medical assessment of the individual patient.

Overall Infections In the 24 week, controlled clinical studies, the rate of infections in the tocilizumab-IV monotherapy group was 119 events per 100 patient-years and was similar in the methotrexate monotherapy group. The rate of infections in the 4 mg per kg and 8 mg per kg tocilizumab-IV plus DMARD group was 133 and 127 events per 100 patient-years, respectively, compared to 112 events per 100 patient-years in the placebo plus DMARD group.

The most commonly reported infections (5% to 8% of patients) were upper respiratory tract infections and nasopharyngitis. The overall rate of infections with tocilizumab-IV in the all exposure population remained consistent with rates in the controlled periods of the studies.

5 per 100 patient-years in the methotrexate group. 9 events per 100 patient-years in the placebo plus DMARD group. In the all-exposure population, the overall rate of serious infections remained consistent with rates in the controlled periods of the studies.

The most common serious infections included pneumonia, urinary tract infection, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis and bacterial arthritis. 1) ]. 1) ]. 26 events per 100 patient-years with tocilizumab-IV therapy.

In the all-exposure population, the overall rate of gastrointestinal perforation remained consistent with rates in the controlled periods of the studies. Reports of gastrointestinal perforation were primarily reported as complications of diverticulitis including generalized purulent peritonitis, lower GI perforation, fistula and abscess.

2) ]. The relative contribution of these concomitant medications versus tocilizumab-IV to the development of GI perforations is not known. Infusion Reactions In the 24 week, controlled clinical studies, adverse events associated with the infusion (occurring during or within 24 hours of the start of infusion) were reported in 8% and 7% of patients in the 4 mg per kg and 8 mg per kg tocilizumab-IV plus DMARD group, respectively, compared to 5% of patients in the placebo plus DMARD group.

The most frequently reported event on the 4 mg per kg and 8 mg per kg dose during the infusion was hypertension (1% for both doses), while the most frequently reported event occurring within 24 hours of finishing an infusion were headache (1% for both doses) and skin reactions (1% for both doses), including rash, pruritus and urticaria.

These events were not treatment limiting. 2% (8 out of 4009) in the all-exposure population. These reactions were generally observed during the second to fourth infusion of tocilizumab-IV. 6) ]. 1% of patients in the placebo plus DMARD group.

Approximately half of the instances of ANC below 1000 per mm 3 occurred within 8 weeks of starting therapy. 1% of patients in the placebo plus DMARD group. There was no clear relationship between decreases in neutrophils below 1000 per mm 3 and the occurrence of serious infections.

4) ]. 5% of patients on placebo plus DMARD, without associated bleeding events. 4) ]. Elevated Liver Enzymes Liver enzyme abnormalities are summarized in Table 1. 8) ]. 4) ]. Table 1 Incidence of Liver Enzyme Abnormalities in the 24 Week Controlled Period of Studies I to V For a description of these studies, see Section 14, Clinical Studies.

3 In the all-exposure population, the elevations in ALT and AST remained consistent with what was seen in the 24 week, controlled clinical trials. 2% patients, respectively. One serious event of drug induced hepatitis with hyperbilirubinemia was reported in association with tocilizumab.

Lipids Elevations in lipid parameters (total cholesterol, LDL, HDL, triglycerides) were first assessed at 6 weeks following initiation of tocilizumab-IV in the controlled 24 week clinical trials. Increases were observed at this time point and remained stable thereafter.

Increases in triglycerides to levels above 500 mg per dL were rarely observed. Changes in other lipid parameters from baseline to week 24 were evaluated and are summarized below: Mean LDL increased by 13 mg per dL in the tocilizumab 4 mg per kg+DMARD arm, 20 mg per dL in the tocilizumab 8 mg per kg+DMARD, and 25 mg per dL in tocilizumab 8 mg per kg monotherapy.

Mean HDL increased by 3 mg per dL in the tocilizumab 4 mg per kg+DMARD arm, 5 mg per dL in the tocilizumab 8 mg per kg+DMARD, and 4 mg per dL in tocilizumab 8 mg per kg monotherapy. 26 in tocilizumab 8 mg per kg monotherapy. ApoB/ApoA1 ratios were essentially unchanged in tocilizumab-treated patients.

Elevated lipids responded to lipid lowering agents. In the all-exposure population, the elevations in lipid parameters remained consistent with what was seen in the 24 week, controlled clinical trials. Immunogenicity The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay.

Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of tocilizumab or of other tocilizumab products.

In the 24 week, controlled clinical studies, a total of 2876 patients have been tested for anti-tocilizumab antibodies. Forty-six patients (2%) developed positive anti-tocilizumab antibodies, of whom 5 had an associated, medically significant, hypersensitivity reaction leading to withdrawal.

Thirty patients (1%) developed neutralizing antibodies. Malignancies During the 24 week, controlled period of the studies, 15 malignancies were diagnosed in patients receiving tocilizumab-IV, compared to 8 malignancies in patients in the control groups.

37 events per 100 patient-years). 5) ]. Other Adverse Reactions Adverse reactions occurring in 2% or more of patients on 4 or 8 mg per kg tocilizumab-IV plus DMARD and at least 1% greater than that observed in patients on placebo plus DMARD are summarized in Table 2 .

2 Clinical Trials Experience in Giant Cell Arteritis Patients Treated with Intravenous Tocilizumab (Tocilizumab-IV) The safety of tocilizumab-IV was studied in an open label PK-PD and safety study in 24 patients with GCA who were in remission on tocilizumab-IV at time of enrollment.

Patients received tocilizumab 7 mg/kg every 4 weeks for 20 weeks, followed by 6 mg/kg every 4 weeks for 20 weeks. 5 years. The safety of tocilizumab by another route of administration has been studied in one Phase III study with 251 GCA patients.

5 patient years during the 12-month double blind, placebo-controlled phase of the study. The overall safety profile observed was generally consistent with the known safety profile of tocilizumab. There was an overall higher incidence of infections in GCA patients relative to RA patients.

The overall safety profile observed for tocilizumab administered intravenously in GCA patients was consistent with the known safety profile of tocilizumab. 3 Clinical Trials Experience in Polyarticular Juvenile Idiopathic Arthritis Patients Treated with Intravenous Tocilizumab (Tocilizumab-IV) The safety of tocilizumab-IV was studied in 188 pediatric patients 2 to 17 years of age with PJIA who had an inadequate clinical response or were intolerant to methotrexate.

4 patient years. At baseline, approximately half of the patients were taking oral corticosteroids and almost 80% were taking methotrexate. 4) ]. 7 per 100 patient years. The most common events observed were nasopharyngitis and upper respiratory tract infections.

0 per 100 patient years). The incidence of infections leading to dose interruptions was also numerically higher in patients weighing less than 30 kg treated with 10 mg/kg tocilizumab (21%) compared to patients weighing at or above 30 kg, treated with 8 mg/kg tocilizumab (8%).

Infusion Reactions In PJIA patients, infusion-related reactions are defined as all events occurring during or within 24 hours of an infusion. 2%) experienced an event within 24 hours of an infusion. The most common events occurring during infusion were headache, nausea and hypotension, and occurring within 24 hours of infusion were dizziness and hypotension.

4) ]. No clinically significant hypersensitivity reactions associated with tocilizumab and requiring treatment discontinuation were reported. Immunogenicity One patient, in the 10 mg/kg less than 30 kg group, developed positive anti-tocilizumab antibodies without developing a hypersensitivity reaction and subsequently withdrew from the study.

7% of patients. There was no clear relationship between decreases in neutrophils below 1 × 10 9 per L and the occurrence of serious infections. Thrombocytopenia During routine laboratory monitoring in the tocilizumab-IV all exposure population, 1% of patients had a decrease in platelet count at or less than 50,000 per mm 3 without associated bleeding events.

Elevated Liver Enzymes During routine laboratory monitoring in the tocilizumab-IV all exposure population, elevation in ALT or AST at or greater than 3 × ULN occurred in 4% and less than 1% of patients, respectively. 5%). 4 Clinical Trials Experience in Systemic Juvenile Idiopathic Arthritis Patients Treated with Intravenous Tocilizumab (Tocilizumab-IV) The data described below reflect exposure to tocilizumab-IV in one randomized, double-blind, placebo-controlled trial of 112 pediatric patients with SJIA 2 to 17 years of age who had an inadequate clinical response to nonsteroidal anti-inflammatory drugs (NSAIDs) or corticosteroids due to toxicity or lack of efficacy.

3 mg/kg/day corticosteroids or more, and almost 70% were taking methotrexate. The trial included a 12 week controlled phase followed by an open-label extension. In the 12 week double-blind, controlled portion of the clinical study 75 patients received treatment with tocilizumab-IV (8 or 12 mg per kg based upon body weight).

After 12 weeks or at the time of escape, due to disease worsening, patients were treated with tocilizumab-IV in the open-label extension phase. The most common adverse events (at least 5%) seen in tocilizumab-IV treated patients in the 12 week controlled portion of the study were: upper respiratory tract infection, headache, nasopharyngitis and diarrhea.

Infections In the 12 week controlled phase, the rate of all infections in the tocilizumab-IV group was 345 per 100 patient-years and 287 per 100 patient-years in the placebo group. In the open label extension over an average duration of 73 weeks of treatment, the overall rate of infections was 304 per 100 patient-years.

5 per 100 patient years. 4 per 100 patient years. The most commonly reported serious infections included pneumonia, gastroenteritis, varicella, and otitis media. Macrophage Activation Syndrome In the 12 week controlled study, no patient in any treatment group experienced macrophage activation syndrome (MAS) while on assigned treatment; 3 per 112 (3%) developed MAS during open-label treatment with tocilizumab-IV.

One patient in the placebo group escaped to tocilizumab-IV 12 mg per kg at Week 2 due to severe disease activity, and ultimately developed MAS at Day 70. Two additional patients developed MAS during the long-term extension. All 3 patients had tocilizumab-IV dose interrupted (2 patients) or discontinued (1 patient) for the MAS event, received treatment, and the MAS resolved without sequelae.

Based on a limited number of cases, the incidence of MAS does not appear to be elevated in the tocilizumab-IV SJIA clinical development experience; however no definitive conclusions can be made. Infusion Reactions Patients were not premedicated, however most patients were on concomitant corticosteroids as part of their background treatment for SJIA.

Infusion related reactions were defined as all events occurring during or within 24 hours after an infusion. In the 12 week controlled phase, 4% of tocilizumab-IV and 0% of placebo treated patients experienced events occurring during infusion.

One event (angioedema) was considered serious and life-threatening, and the patient was discontinued from study treatment. Within 24 hours after infusion, 16% of patients in the tocilizumab-IV treatment group and 5% of patients in the placebo group experienced an event.

In the tocilizumab-IV group the events included rash, urticaria, diarrhea, epigastric discomfort, arthralgia and headache. One of these events, urticaria, was considered serious. 6) ]. Immunogenicity All 112 patients were tested for anti-tocilizumab antibodies at baseline.

Two patients developed positive anti-tocilizumab antibodies: one of these patients experienced serious adverse events of urticaria and angioedema consistent with an anaphylactic reaction which led to withdrawal; the other patient developed macrophage activation syndrome while on escape therapy and was discontinued from the study.

Laboratory Abnormalities Neutropenia During routine monitoring in the 12 week controlled phase, a decrease in neutrophil below 1 × 10 9 per L occurred in 7% of patients in the tocilizumab-IV group, and in no patients in the placebo group.

In the open label extension over an average duration of 73 weeks of treatment, a decreased neutrophil count occurred in 17% of the tocilizumab-IV group. There was no clear relationship between decrease in neutrophils below 1 × 10 9 per L and the occurrence of serious infections.

Thrombocytopenia During routine monitoring in the 12 week controlled phase, 1% of patients in the tocilizumab-IV group and 3% in the placebo group had a decrease in platelet count to no more than 100,000 per mm 3 . In the open label extension over an average duration of 73 weeks of treatment, decreased platelet count occurred in 4% of patients in the tocilizumab-IV group, with no associated bleeding.

Elevated Liver Enzymes During routine laboratory monitoring in the 12 week controlled phase, elevation in ALT or AST at or above 3× ULN occurred in 5% and 3% of patients, respectively in the tocilizumab-IV group and in 0% of placebo patients.

In the open label extension over an average duration of 73 weeks of treatment, the elevation in ALT or AST at or above 3× ULN occurred in 13% and 5% of tocilizumab-IV treated patients, respectively. 5% of the tocilizumab-IV group and in 0% of placebo patients.

9% of patients in the tocilizumab-IV group and 0% of the placebo group. In the open label extension study over an average duration of 73 weeks of treatment, the pattern and incidence of elevations in lipid parameters remained consistent with the 12 week controlled study data.

5 Clinical Trials Experience in COVID-19 Patients Treated with Intravenous Tocilizumab (Tocilizumab-IV) The safety of tocilizumab in hospitalized COVID-19 patients was evaluated in a pooled safety population that includes patients enrolled in EMPACTA, COVACTA, AND REMDACTA.

The analysis of adverse reactions included a total of 974 patients exposed to tocilizumab. Patients received a single, 60-minute infusion of intravenous tocilizumab 8 mg/kg (maximum dose of 800 mg). If clinical signs or symptoms worsened or did not improve, one additional dose of tocilizumab 8 mg/kg could be administered between 8- 24 hours after the initial dose.

Adverse reactions summarized in Table 3 occurred in at least 3% of tocilizumab -treated patients and more commonly than in patients on placebo in the pooled safety population. Table 3 Adverse Reactions Patients are counted once for each category regardless of the number of reactions Identified From the Pooled COVID-19 Safety Population Adverse Reaction Tocilizumab 8mg per kg Placebo N = 974 (%) N = 483 (%) Hepatic Transaminases increased 10% 8% Constipation 9% 8% Urinary tract infection 5% 4% Hypertension 4% 1% Hypokalaemia 4% 3% Anxiety 4% 2% Diarrhea 4% 2% Insomnia 4% 3% Nausea 3% 2% In the pooled safety population, the rates of infection/serious infection events were 30%/19% in patients receiving tocilizumab versus 32%/23% receiving placebo.

5% of patients who received placebo. 5% of patients who received placebo. 9% of patients who received placebo. 6 Postmarketing Experience The following adverse reactions have been identified during post-approval use of tocilizumab products.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. 3) ]

1) , and Patient Counseling Information (17) ]. Hold TOFIDENCE if a patient develops a serious infection, an opportunistic infection, or sepsis. A patient who develops a new infection during treatment with TOFIDENCE should undergo a prompt and complete diagnostic workup appropriate for an immunocompromised patient, initiate appropriate antimicrobial therapy, and closely monitor the patient.

COVID-19 In patients with COVID-19, monitor for signs and symptoms of new infections during and after treatment with TOFIDENCE. There is limited information regarding the use of tocilizumab products in patients with COVID-19 and concomitant active serious infections.

The risks and benefits of treatment with TOFIDENCE in COVID-19 patients with other concurrent infections should be considered. Tuberculosis Evaluate patients for tuberculosis risk factors and test for latent infection prior to initiating TOFIDENCE.

In patients with COVID-19, testing for latent infection is not necessary prior to initiating treatment with TOFIDENCE. Consider anti-tuberculosis therapy prior to initiation of TOFIDENCE in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but having risk factors for tuberculosis infection.

Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision whether initiating anti-tuberculosis therapy is appropriate for an individual patient. Closely monitor patients for the development of signs and symptoms of tuberculosis including patients who tested negative for latent tuberculosis infection prior to initiating therapy.

1%. Patients with latent tuberculosis should be treated with standard antimycobacterial therapy before initiating TOFIDENCE. Viral Reactivation Viral reactivation has been reported with immunosuppressive biologic therapies and cases of herpes zoster exacerbation were observed in clinical studies with tocilizumab.

No cases of Hepatitis B reactivation were observed in the trials; however patients who screened positive for hepatitis were excluded. 2 Gastrointestinal Perforations Events of gastrointestinal perforation have been reported in clinical trials, primarily as complications of diverticulitis in patients treated with tocilizumab.

Use TOFIDENCE with caution in patients who may be at increased risk for gastrointestinal perforation. 1) ]. 3 Hepatotoxicity Serious cases of hepatic injury have been observed in patients taking intravenous tocilizumab products. Some of these cases have resulted in liver transplant or death.

Time to onset for cases ranged from months to years after treatment initiation with tocilizumab products. While most cases presented with marked elevations of transaminases (> 5 times ULN), some cases presented with signs or symptoms of liver dysfunction and only mildly elevated transaminases.

4) ]. , MTX) were used in combination with tocilizumab. For RA and GCA patients, obtain a liver test panel (serum alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, and total bilirubin) before initiating TOFIDENCE, every 4 to 8 weeks after start of therapy for the first 6 months of treatment and every 3 months thereafter.

5× ULN. In patients who develop elevated ALT or AST greater than 5× ULN, discontinue TOFIDENCE. 8) ]. Patients hospitalized with COVID-19 may have elevated ALT or AST levels. Multi-organ failure with involvement of the liver is recognized as a complication of severe COVID-19.

The decision to administer TOFIDENCE should balance the potential benefit of treating COVID-19 against the potential risks of acute treatment with TOFIDENCE. It is not recommended to initiate TOFIDENCE treatment in COVID-19 patients with elevated ALT or AST above 10 × ULN.

Monitor ALT and AST during treatment. Measure liver tests promptly in patients who report symptoms that may indicate liver injury, such as fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. , ALT greater than three times the upper limit of the reference range, serum total bilirubin greater than two times the upper limit of the reference range), TOFIDENCE treatment should be interrupted and investigation done to establish the probable cause.

TOFIDENCE should only be restarted in patients with another explanation for the liver test abnormalities after normalization of the liver tests. A similar pattern of liver enzyme elevation is noted with tocilizumab products treatment in the PJIA and SJIA populations.

Monitor liver test panel at the time of the second administration and thereafter every 4 to 8 weeks for PJIA and every 2 to 4 weeks for SJIA. 4 Changes in Laboratory Parameters Patients with Rheumatoid Arthritis, Giant Cell Arteritis and Coronavirus Disease 2019 Neutropenia Treatment with tocilizumab products was associated with a higher incidence of neutropenia.

Infections have been uncommonly reported in association with treatment-related neutropenia in long-term extension studies and postmarketing clinical experience. , absolute neutrophil count (ANC) less than 2000 per mm 3 . In patients who develop an absolute neutrophil count less than 500 per mm 3 treatment is not recommended.

2) ]. 8) . – It is not recommended to initiate TOFIDENCE treatment in COVID-19 patients with an ANC less than 1000 per mm 3 . Neutrophils should be monitored. Thrombocytopenia Treatment with tocilizumab products was associated with a reduction in platelet counts.

1) ]. – It is not recommended to initiate TOFIDENCE treatment in RA and GCA patients with a platelet count below 100,000 per mm 3 . In patients who develop a platelet count less than 50,000 per mm 3 treatment is not recommended. – Monitor platelets 4 to 8 weeks after start of therapy and every 3 months thereafter.

8) . – In COVID-19 patients with a platelet count less than 50,000 per mm 3 , treatment is not recommended. Platelets should be monitored. 3 Hepatotoxicity. 8) . 1) ]. – Assess lipid parameters approximately 4 to 8 weeks following initiation of TOFIDENCE therapy.

, National Cholesterol Educational Program (NCEP)] for the management of hyperlipidemia. Patients with Polyarticular and Systemic Juvenile Idiopathic Arthritis A similar pattern of liver enzyme elevation, low neutrophil count, low platelet count and lipid elevations is noted with tocilizumab products treatment in the PJIA and SJIA populations.

Monitor neutrophils, platelets, ALT and AST at the time of the second administration and thereafter every 4 to 8 weeks for PJIA and every 2 to 4 weeks for SJIA. 8) ]. 1) ]. TOFIDENCE is an immunosuppressant, and treatment with immunosuppressants may result in an increased risk of malignancies.

6 Hypersensitivity Reactions, Including Anaphylaxis Hypersensitivity reactions, including anaphylaxis, have been reported in association with tocilizumab products and anaphylactic events with a fatal outcome have been reported with intravenous infusion of tocilizumab products.

2% (8 out of 4009) of patients in the intravenous all-exposure RA population. 9%) experienced hypersensitivity reactions that required treatment discontinuation. In the PJIA controlled trial with intravenous tocilizumab 0 out of 188 patients (0%) in the tocilizumab all-exposure population experienced hypersensitivity reactions that required treatment discontinuation.

Reactions that required treatment discontinuation included generalized erythema, rash, and urticaria. In the postmarketing setting, events of hypersensitivity reactions, including anaphylaxis and death have occurred in patients treated with a range of doses of intravenous tocilizumab products, with or without concomitant therapies.

Events have occurred in patients who received premedication. 6) ]. In addition, serious cutaneous reactions, including Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), have been reported in patients with autoinflammatory conditions treated with tocilizumab products.

TOFIDENCE for intravenous use should only be infused by a healthcare professional with appropriate medical support to manage anaphylaxis. If a hypersensitivity reaction occurs, immediately discontinue TOFIDENCE, treat promptly and monitor until signs and symptoms resolve.

7 Demyelinating Disorders The impact of treatment with tocilizumab products on demyelinating disorders is not known, but multiple sclerosis and chronic inflammatory demyelinating polyneuropathy were reported rarely in RA clinical studies.

Monitor patients for signs and symptoms potentially indicative of demyelinating disorders. Prescribers should exercise caution in considering the use of TOFIDENCE in patients with preexisting or recent onset demyelinating disorders.

6) ]. 9 Vaccinations Avoid use of live vaccines concurrently with TOFIDENCE as clinical safety has not been established. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving tocilizumab products.

No data are available on the effectiveness of vaccination in patients receiving tocilizumab products. Because IL-6 inhibition may interfere with the normal immune response to new antigens, it is recommended that all patients, particularly pediatric or elderly patients, if possible, be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating TOFIDENCE therapy.

The interval between live vaccinations and initiation of TOFIDENCE therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.