4.1. Therapeutic indications

Tyenne, in combination with methotrexate (MTX), is indicated for:

• the treatment of severe, active and progressive rheumatoid arthritis (RA) in adults not previously treated with MTX.

• the treatment of moderate to severe active RA in adult patients who have either responded inadequately to, or who were intolerant to, previous therapy with one or more disease-modifying anti-rheumatic drugs (DMARDs) or tumour necrosis factor (TNF) antagonists.

In these patients, Tyenne can be given as monotherapy in case of intolerance to MTX or where continued treatment with MTX is inappropriate.

Tocilizumab has been shown to reduce the rate of progression of joint damage as measured by X-ray and to improve physical function when given in combination with methotrexate.

Tyenne is indicated for the treatment of coronavirus disease 2019 (COVID-19) in adults who are receiving systemic corticosteroids and require supplemental oxygen or mechanical ventilation.

Tyenne is indicated for the treatment of active systemic juvenile idiopathic arthritis (sJIA) in patients 2 years of age and older, who have responded inadequately to previous therapy with NSAIDs and systemic corticosteroids. Tyenne can be given as monotherapy (in case of intolerance to MTX or where treatment with MTX is inappropriate) or in combination with MTX.

Tyenne in combination with methotrexate (MTX) is indicated for the treatment of juvenile idiopathic polyarthritis (pJIA; rheumatoid factor positive or negative and extended oligoarthritis) in patients 2 years of age and older, who have responded inadequately to previous therapy with MTX.

Tyenne can be given as monotherapy in case of intolerance to MTX or where continued treatment with MTX is inappropriate.

Tyenne is indicated for the treatment of chimeric antigen receptor (CAR) T cell-induced severe or life-threatening cytokine release syndrome (CRS) in adults and paediatric patients 2 years of age and older.

4.2. Posology and method of administration

Treatment should be initiated by healthcare professionals experienced in the diagnosis and treatment of RA, COVID-19, sJIA, pJIA or CRS.

All patients treated with Tyenne should be given the Patient Alert Card.

Posology

RA Patients

The recommended posology is 8 mg/kg body weight (BW), given once every four weeks.

For individuals whose body weight is more than 100 kg, doses exceeding 800 mg per infusion are not recommended (see section 5.2).

Doses above 1.2 g have not been evaluated in clinical studies (see section 5.1).

Dose adjustments due to laboratory abnormalities (see section 4.4).

• Liver enzyme abnormalities

Laboratory Value

Action

> 1 to 3 x Upper Limit of Normal (ULN)

Modify the dose of the concomitant MTX if appropriate

For persistent increases in this range, reduce Tyenne dose to 4 mg/kg or interrupt Tyenne until alanine aminotransferase (ALT) or aspartate aminotransferase (AST) have normalized

Restart with 4 mg/kg or 8 mg/kg, as clinically appropriate

> 3 to 5 x ULN

(confirmed by repeat testing, see section 4.4).

Interrupt Tyenne dosing until < 3 x ULN and follow recommendations above for > 1 to 3 x ULN

For persistent increases > 3 x ULN, discontinue Tyenne

> 5 x ULN

Discontinue Tyenne

• Low absolute neutrophil count (ANC)

In patients not previously treated with tocilizumab, initiation is not recommended in patients with an absolute neutrophil count (ANC) below 2 x 109/L.

Laboratory Value (cells x 109/L)

Action

ANC > 1

Maintain dose

ANC 0.5 to 1

Interrupt Tyenne dosing

When ANC increases > 1 x 109/L resume Tyenne at 4 mg/kg and increase to 8 mg/kg as clinically appropriate

ANC < 0.5

Discontinue Tyenne

• Low platelet count

Laboratory Value

(cells x 103/µL)

Action

50X100

Interrupt Tyenne dosing

When platelet count > 100 X 103/L resume Tyenne at 4 mg/kg and increase to 8 mg/kg as clinically appropriate

<50

Discontinue Tyenne

COVID-19 Patients

The recommended posology for treatment of COVID-19 is a single 60-minute intravenous infusion of 8 mg/kg in patients who are receiving systemic corticosteroids and require supplemental oxygen or mechanical ventilation, see section 5.1. If clinical signs or symptoms worsen or do not improve after the first dose, one additional infusion of Tyenne 8 mg/kg may be administered. The interval between the two infusions should be at least 8 hours.

For individuals whose body weight is more than 100 kg, doses exceeding 800 mg per infusion are not recommended (see section 5.2).

Administration of Tyenne is not recommended in patients with COVID-19 who have any of the following laboratory abnormalities:

Laboratory test type

Laboratory value

Action

Liver enzyme

> 10x ULN

Administration of Tyenne is not recommended

Absolute neutrophil count

< 1 x 109 /L

Platelet count

< 50 x 103 /μL

Cytokine Release Syndrome (CRS) (adults and paediatrics)

The recommended posology for treatment of CRS given as a 60-minute intravenous infusion is 8 mg/kg in patients weighing greater than or equal to 30 kg or 12 mg/kg in patients weighing less than 30 kg. Tyenne can be given alone or in combination with corticosteroids.

If no clinical improvement in the signs and symptoms of CRS occurs after the first dose, up to 3 additional doses of Tyenne may be administered. The interval between consecutive doses should be at least 8 hours. Doses exceeding 800 mg per infusion are not recommended in CRS patients.

Patients with severe or life-threatening CRS frequently have cytopenias or elevated ALT or AST due to the underlying malignancy, preceding lymphodepleting chemotherapy or the CRS.Special populations

Paediatric patients

sJIA Patients

The recommended posology in patients above 2 years of age is 8 mg/kg once every 2 weeks in patients weighing greater than or equal to 30 kg or 12 mg/kg once every 2 weeks in patients weighing less than 30 kg. The dose should be calculated based on the patient's body weight at each administration. A change in dose should only be based on a consistent change in the patient's body weight over time.

The safety and efficacy of intravenous tocilizumab in children below 2 years of age has not been established.

Dose interruptions of tocilizumab for the following laboratory abnormalities are recommended in sJIA patients in the tables below. If appropriate, the dose of concomitant MTX and/or other medicines should be modified or dosing stopped and tocilizumab dosing interrupted until the clinical situation has been evaluated. As there are many co-morbid conditions that may affect laboratory values in sJIA, the decision to discontinue Tyenne for a laboratory abnormality should be based upon the medical assessment of the individual patient.

• Liver enzyme abnormalities

Laboratory Value

Action

> 1 to 3 x ULN

Modify the dose of the concomitant MTX if appropriate.

For persistent increases in this range, interrupt Tyenne until ALT/AST have normalized.

> 3 x ULN to 5x ULN

Modify the dose of the concomitant MTX if appropriate.

Interrupt Tyenne dosing until < 3x ULN and follow recommendations above for > 1 to 3x ULN.

> 5x ULN

Discontinue Tyenne.

The decision to discontinue Tyenne in sJIA for a laboratory abnormality should be based on the medical assessment of the individual patient.

• Low absolute neutrophil count (ANC)

Laboratory Value

(cells x 109/ L)

Action

ANC > 1

Maintain dose

ANC 0.5 to 1

Interrupt Tyenne dosing

When ANC increases to > 1 x 109/ L resume Tyenne

ANC < 0.5

Discontinue Tyenne

The decision to discontinue Tyenne in sJIA for a laboratory abnormality should be based on the medical assessment of the individual patient.

• Low platelet count

Laboratory Value

(cells x 103/µL)

Action

50 to 100

Modify the dose of the concomitant MTX if appropriate

Interrupt Tyenne dosing

When platelet count is > 100 x 103/μL resume Tyenne

< 50

Discontinue Tyenne.

The decision to discontinue Tyenne in sJIA for a laboratory abnormality should be based on the medical assessment of the individual patient.

There are insufficient clinical data to assess the impact of a tocilizumab dose reduction in sJIA patients who have experienced laboratory abnormalities.

Available data suggest that clinical improvement is observed within 6 weeks of initiation of treatment with tocilizumab. Continued therapy should be carefully reconsidered in a patient exhibiting no improvement within this timeframe.

pJIA Patients

The recommended posology in patients above 2 years of age is 8 mg/kg once every 4 weeks in patients weighing greater than or equal to 30 kg or 10 mg/kg once every 4 weeks in patients weighing less than 30 kg. The dose should be calculated based on the patient's body weight at each administration. A change in dose should only be based on a consistent change in the patient's body weight over time.

The safety and efficacy of intravenous tocilizumab in children below 2 years of age has not been established.

Dose interruptions of tocilizumab for the following laboratory abnormalities are recommended in pJIA patients in the tables below. If appropriate, the dose of concomitant MTX and/or other medicines should be modified or dosing stopped and tocilizumab dosing interrupted until the clinical situation has been evaluated. As there are many co-morbid conditions that may affect laboratory values in pJIA, the decision to discontinue Tyenne for a laboratory abnormality should be based upon the medical assessment of the individual patient.

• Liver enzyme abnormalities

Laboratory Value

Action

> 1 to 3 x ULN

Modify the dose of the concomitant MTX if appropriate

For persistent increases in this range, interrupt Tyenne until ALT/AST have normalized.

> 3 x ULN to 5x ULN

Modify the dose of the concomitant MTX if appropriate

Interrupt Tyenne dosing until < 3x ULN and follow recommendations above for >1 to 3x ULN

> 5x ULN

Discontinue Tyenne.

The decision to discontinue Tyenne in pJIA for a laboratory abnormality should be based on the medical assessment of the individual patient.

• Low absolute neutrophil count (ANC)

Laboratory Value

(cells x 109/ L )

Action

ANC > 1

Maintain dose

ANC 0.5 to 1

Interrupt Tyenne dosing

When ANC increases to > 1 x 109/ L resume Tyenne

ANC < 0.5

Discontinue Tyenne

The decision to discontinue Tyenne in pJIA for a laboratory abnormality should be based on the medical assessment of the individual patient.

• Low platelet count

Laboratory Value (cells X 103/µL)

Action

50 to 100

Modify the dose of the concomitant MTX if appropriate interrupt Tyenne dosing

When platelet count is >100 X103/µL resume Tyenne

<50

Discontinue Tyenne

The decision to discontinue Tyenne is pJIA for laboratory abnormality should be based on the medical assessment of the individual patient.

Reduction of tocilizumab dose due to laboratory abnormalities has not been studied in pJIA patients.

Available data suggest that clinical improvement is observed within 12 weeks of initiation of treatment with tocilizumab. Continued therapy should be carefully reconsidered in a patient exhibiting no improvement within this timeframe.

Elderly

No dose adjustment is required in elderly patients > 65 years of age.

Renal impairment

No dose adjustment is required in patients with mild renal impairment. Tocilizumab has not been studied in patients with moderate to severe renal impairment (see section 5.2). Renal function should be monitored closely in these patients.

Hepatic impairment

Tocilizumab has not been studied in patients with hepatic impairment. Therefore, no dose recommendations can be made.

Method of administration

After dilution, Tyenne for RA, sJIA, pJIA, CRS and COVID-19 patients should be administered as an intravenous infusion over 1 hour.

RA, sJIA, pJIA, CRS and COVID-19 Patients ≥ 30 kg

Tyenne should be diluted to a final volume of 100 mL with sterile, non-pyrogenic sodium chloride 9 mg/mL (0.9%) or 4.5 mg/mL (0.45%) solution for injection using aseptic technique.

For instructions on dilution of the medicinal product before administration, see section 6.6.

sJIA, pJIA and CRS Patients < 30 kg

Tyenne should be diluted to a final volume of 50 mL with sterile, non-pyrogenic sodium chloride 9 mg/mL (0.9%) or 4.5 mg/mL (0.45%) solution for injection using aseptic technique.

For instructions on dilution of the medicinal product before administration, see section 6.6.

If signs and symptoms of an infusion related reaction occur, slow or stop the infusion and administer appropriate medicine / supportive care immediately, see section 4.4.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Active, severe infections with the exception of COVID-19 (see section 4.4).

4.4. Special warnings and precautions for use

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

RA, pJIA and sJIA Patients

Infections

Serious and sometimes fatal infections have been reported in patients receiving immunosuppressive agents including tocilizumab (see section 4.8, undesirable effects). Tocilizumab treatment must not be initiated in patients with active infections (see section 4.3). Administration of tocilizumab should be interrupted if a patient develops a serious infection until the infection is controlled (see section 4.8). Healthcare professionals should exercise caution when considering the use of tocilizumab in patients with a history of recurring or chronic infections or with underlying conditions (e.g. diverticulitis, diabetes and interstitial lung disease which may predispose patients to infections.

Vigilance for the timely detection of serious infection is recommended for patients receiving biological treatments as signs and symptoms of acute inflammation may be lessened, associated with suppression of the acute phase reaction. The effects of tocilizumab on C-reactive protein (CRP), neutrophils and signs and symptoms of infection should be considered when evaluating a patient for a potential infection. Patients (which includes younger children with sJIA or pJIA who may be less able to communicate their symptoms) and parents/guardians of sJIA or pJIA patients, should be instructed to contact their healthcare professional immediately when any symptoms suggesting infection appear, in order to assure rapid evaluation and appropriate treatment.

Tuberculosis

As recommended for other biological treatments, RA, sJIA and pJIA patients should be screened for latent tuberculosis (TB) infection prior to starting tocilizumab therapy. Patients with latent TB should be treated with standard anti-mycobacterial therapy before initiating tocilizumab. Prescribers are reminded of the risk of false negative tuberculin skin and interferon-gamma TB blood test results, especially in patients who are severely ill or immunocompromised.

Patients should be instructed to seek medical advice if signs/symptoms (e.g., persistent cough, wasting/weight loss, low grade fever) suggestive of a tuberculosis infection occur during or after therapy with tocilizumab.

Viral reactivation

Viral reactivation (e.g. hepatitis B virus) has been reported with biologic therapies for RA. In clinical studies with tocilizumab, patients who screened positive for hepatitis were excluded.

Complications of diverticulitis

Events of diverticular perforations as complications of diverticulitis have been reported uncommonly with tocilizumab in RA patients (see section 4.8). Tocilizumab should be used with caution in patients with previous history of intestinal ulceration or diverticulitis. Patients presenting with symptoms potentially indicative of complicated diverticulitis, such as abdominal pain, haemorrhage and/or unexplained change in bowel habits with fever should be evaluated promptly for early identification of diverticulitis which can be associated with gastrointestinal perforation.

Hypersensitivity reactions

Serious hypersensitivity reactions have been reported in association with infusion of tocilizumab (see section 4.8). Such reactions may be more severe, and potentially fatal in patients who have experienced hypersensitivity reactions during previous infusions even if they have received pretreatment with steroids and antihistamines. Appropriate treatment should be available for immediate use in the event of an anaphylactic reaction during treatment with tocilizumab. If an anaphylactic reaction or other serious hypersensitivity / serious infusion related reaction occurs, administration of tocilizumab should be stopped immediately and tocilizumab should be permanently discontinued.

Active hepatic disease and hepatic impairment

Treatment with tocilizumab, particularly when administered concomitantly with MTX, may be associated with elevations in hepatic transaminases, therefore, caution should be exercised when considering treatment of patients with active hepatic disease or hepatic impairment (see sections 4.2 and 4.8).

Hepatotoxicity

Transient or intermittent mild and moderate elevations of hepatic transaminases have been reported commonly with tocilizumab treatment (see section 4.8). An increased frequency of these elevations was observed when potentially hepatotoxic medicines (e.g. MTX) were used in combination with tocilizumab. When clinically indicated, other liver function tests including bilirubin should be considered.

Serious treatment-induced liver injury, including acute liver failure, hepatitis and jaundice, have been observed with tocilizumab (see section 4.8). Serious hepatic injury occurred between 2 weeks to more than 5 years after initiation of tocilizumab. Cases of liver failure resulting in liver transplantation have been reported. Patients should be advised to immediately seek medical help if they experience signs and symptoms of hepatic injury.

Caution should be exercised when considering initiation of tocilizumab treatment in patients with elevated ALT or AST > 1.5 x ULN. In RA, pJIA and sJIA patients with baseline ALT or AST > 5 x ULN, treatment is not recommended.

In RA, pJIA and sJIA patients, ALT/AST should be monitored every 4 to 8 weeks for the first 6 months of treatment followed by every 12 weeks thereafter. For recommended modifications, including tocilizumab discontinuation, based on transaminases levels see section 4.2. For ALT or AST elevations > 3–5 x ULN, confirmed by repeat testing, tocilizumab treatment should be interrupted.

Haematological abnormalities

Decreases in neutrophil and platelet counts have occurred following treatment with tocilizumab 8 mg/kg in combination with MTX (see section 4.8). There may be an increased risk of neutropenia in patients who have previously been treated with a TNF antagonist.

In patients not previously treated with tocilizumab, initiation is not recommended in patients with an absolute neutrophil count (ANC) below 2 x 109/L. Caution should be exercised when considering initiation of tocilizumab treatment in patients with a low platelet count (i.e. platelet count below 100 x 103/ μL). In RA, sJIA and pJIA patients who develop an ANC < 0.5 x 109/L or a platelet count < 50 x 103/μL, continued treatment is not recommended.

Severe neutropenia may be associated with an increased risk of serious infections, although there has been no clear association between decreases in neutrophils and the occurrence of serious infections in clinical studies with tocilizumab to date.

In RA patients, neutrophils and platelets should be monitored 4 to 8 weeks after start of therapy and thereafter according to standard clinical practice. For recommended dose modifications based on ANC and platelet counts, see section 4.2.

In sJIA and pJIA patients, neutrophils and platelets should be monitored at the time of second infusion and thereafter according to good clinical practice, see section 4.2.

Lipid parameters

Elevations in lipid parameters including total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL) and triglycerides were observed in patients treated with tocilizumab (see section 4.8). In the majority of patients, there was no increase in atherogenic indices, and elevations in total cholesterol responded to treatment with lipid lowering agents.

In sJIA, pJIA and RA patients, assessment of lipid parameters should be performed 4 to 8 weeks following initiation of tocilizumab therapy. Patients should be managed according to local clinical guidelines for management of hyperlipidaemia.

Neurological disorders

Physicians should be vigilant for symptoms potentially indicative of new-onset central demyelinating disorders. The potential for central demyelination with tocilizumab is currently unknown.

Malignancy

The risk of malignancy is increased in patients with RA. Immunomodulatory medicinal products may increase the risk of malignancy.

Vaccinations

Live and live attenuated vaccines should not be given concurrently with tocilizumab as clinical safety has not been established. In a randomized open-label study, adult RA patients treated with tocilizumab and MTX were able to mount an effective response to both the 23-valent pneumococcal polysaccharide and tetanus toxoid vaccines which was comparable to the response seen in patients on MTX only. It is recommended that all patients, particularly sJIA and pJIA patients, be brought up to date with all immunisations in agreement with current immunisation guidelines prior to initiating tocilizumab therapy. The interval between live vaccinations and initiation of tocilizumab therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.

Cardiovascular risk

RA patients have an increased risk for cardiovascular disorders and should have risk factors (e.g. hypertension, hyperlipidaemia) managed as part of usual standard of care.

Combination with TNF antagonists

There is no experience with the use of tocilizumab with TNF antagonists or other biological treatments for RA, sJIA or pJIA patients. Tocilizumab is not recommended for use with other biological agents.

Sodium

This medicinal Product contains 0.24 mg sodium (main component of cooking/table salt) in each mL. This is equivalent to 0.012% of the recommended maximum daily dietary intake of sodium for an adult.

Tyenne is however, diluted in sodium chloride 9 mg/mL (0.9%) or 4.5 mg/mL (0.45%) solution for infusion. This should be taken into consideration for patients on a controlled sodium diet (see section 6.6).

Polysorbate 80

This medicinal product contains 0.8 mg of polysorbate 80 in each 80 mg vial, 2 mg of polysorbate 80 in each 200 mg vial and 4 mg polysorbate 80 in each 400 mg vial, which is equivalent to 0.2 mg/mL. Polysorbates may cause allergic reactions. Patients' known allergies shall be taken into consideration.

COVID-19 Patients

• The efficacy of tocilizumab has not been established in the treatment of COVID-19 patients who do not have elevated CRP levels, see section 5.1

• Tocilizumab should not be administered to COVID-19 patients who are not receiving systemic corticosteroids as an increase in mortality cannot be excluded in this subgroup, see section 5.1.

Infections

In COVID-19 patients, tocilizumab should not be administered if they have any other concurrent severe active infection. Healthcare professionals should exercise caution when considering the use of Tyenne in patients with a history of recurring or chronic infections or with underlying conditions (e.g. diverticulitis, diabetes, and interstitial lung disease) which may predispose patients to infections.

Hepatotoxicity

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 tocilizumab should balance the potential benefit of treating COVID-19 against the potential risks of acute treatment with tocilizumab. In COVID-19 patients with elevated ALT or AST above 10 x ULN, administration of tocilizumab treatment is not recommended. In COVID-19 patients, ALT/AST should be monitored according to current standard clinical practices.

Haematological abnormalities

In COVID-19 patients who develop an ANC < 1 x 109 /L or a platelet count < 50 x 103 /μL, administration of tocilizumab is not recommended. Neutrophil and platelet counts should be monitored according to current standard clinical practices, see section 4.2.

Paediatric population

sJIA Patients

Macrophage activation syndrome (MAS) is a serious life-threatening disorder that may develop in sJIA patients. In clinical studies, tocilizumab has not been studied in patients during an episode of active MAS.

4.5. Interaction with other medicinal products and other forms of interaction

Interaction studies have only been performed in adults.

Concomitant administration of a single dose of 10 mg/kg tocilizumab with 10-25 mg MTX once weekly had no clinically significant effect on MTX exposure.

Population pharmacokinetic analyses did not detect any effect of MTX, non-steroidal anti-inflammatory drugs (NSAIDs) or corticosteroids on tocilizumab clearance.

The expression of hepatic CYP450 enzymes is suppressed by cytokines, such as IL-6, that stimulate chronic inflammation. Thus, CYP450 expression may be reversed when potent cytokine inhibitory therapy, such as tocilizumab, is introduced.

In vitro studies with cultured human hepatocytes demonstrated that IL-6 caused a reduction in CYP1A2, CYP2C9, CYP2C19 and CYP3A4 enzyme expression. Tocilizumab normalises expression of these enzymes.

In a study in RA patients, levels of simvastatin (CYP3A4) were decreased by 57% one week following a single dose of tocilizumab, to the level similar to, or slightly higher than, those observed in healthy subjects.

When starting or stopping therapy with tocilizumab, patients taking medicinal products which are individually adjusted and are metabolised via CYP450 3A4, 1A2 or 2C9 (e.g. methylprednisolone, dexamethasone, (with the possibility for oral glucocorticoid withdrawal syndrome), atorvastatin, calcium channel blockers, theophylline, warfarin, phenprocoumon, phenytoin, ciclosporin, or benzodiazepines) should be monitored as doses may need to be increased to maintain therapeutic effect. Given its long elimination half-life (t1/2), the effect of tocilizumab on CYP450 enzyme activity may persist for several weeks after stopping therapy.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential

Women of childbearing potential must use effective contraception during and up to 3 months after treatment.

Pregnancy

There are no adequate data from the use of tocilizumab in pregnant women. A study in animals has shown an increased risk of spontaneous abortion/embryo-foetal death at a high dose (see section 5.3). The potential risk for humans is unknown.

Tocilizumab should not be used during pregnancy unless clearly necessary.

Breast-feeding

It is unknown whether tocilizumab is excreted in human breast milk. The excretion of tocilizumab in milk has not been studied in animals. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with tocilizumab should be made taking into account the benefit of breast-feeding to the child and the benefit of tocilizumab therapy to the woman.

Fertility

Available non-clinical data do not suggest an effect on fertility under tocilizumab treatment.

4.7. Effects on ability to drive and use machines

Tocilizumab has minor influence on the ability to drive and use machines (see section 4.8, dizziness).

4.8. Undesirable effects

Summary of the safety profile

The most commonly reported ADRs (occurring in ≥ 5% of patients treated with tocilizumab monotherapy or in combination with DMARDs for RA, sJIA, pJIA and CRS) were upper respiratory tract infections, nasopharyngitis, headache, hypertension and increased ALT. The most serious ADRs were serious infections, complications of diverticulitis, and hypersensitivity reactions.

The most commonly reported ADRs (occurring in ≥ 5% of patients treated with tocilizumab for COVID-19) were hepatic transaminases increased, constipation, and urinary tract infection.

ADRs from clinical studies and/or post marketing experience with tocilizumab based on spontaneous case reports, literature cases and cases from non-interventional study programs are listed in Table 1 and in Table 2 by MedDRA system organ class. The corresponding frequency category for each ADR is based on the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10), uncommon (≥ 1/1 000 to < 1/100), rare (> 1/10 000 to < 1/1 000) or very rare (< 1/10 000). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

RA Patients

The safety profile of tocilizumab has been studied in 4 placebo-controlled studies (studies II, III, IV and V), 1 mTX-controlled study (study I) and their extension periods (see section 5.1).

The double-blind controlled period was 6 months in four studies (studies I, III, IV and V) and was up to 2 years in one study (study II). In the double-blind controlled studies, 774 patients received tocilizumab 4 mg/kg in combination with MTX, 1 870 patients received tocilizumab 8 mg/kg in combination with MTX or other DMARDs and 288 patients received tocilizumab 8 mg/kg monotherapy.

The long-term exposure population includes all patients who received at least one dose of tocilizumab either in the double-blind control period or open label extension phase in the studies. Of the 4 009 patients in this population, 3 577 received treatment for at least 6 months, 3 296 for at least one year, 2 806 received treatment for at least 2 years and 1 222 for 3 years.

Table 1: List of ADRs occurring in patients with RA receiving tocilizumab as monotherapy or in combination with MTX or other DMARDs in the double-blind controlled period or during postmarketing experience

MedDRA System Organ Class

Frequency categories with preferred terms

Very common

Common

Uncommon

Rare

Infections and infestations

Upper respiratory tract infections

Cellulitis, Pneumonia, Oral herpes simplex, Herpes zoster

Diverticulitis

Blood and lymphatic system disorders

Leukopenia, Neutropenia, Hypofibrinogenaemia

Immune system disorders

Anaphylaxis (fatal)1, 2 ,3

Endocrine disorders

Hypothyroidism

Metabolism and nutrition disorders

Hypercholesterolaemia*

Hypertriglyceridaemia

Nervous system disorders

Headache, Dizziness

Eye disorders

Conjunctivitis

Vascular disorders

Hypertension

Respiratory, thoracic and mediastinal disorders

Cough, Dyspnoea

Gastrointestinal disorders

Abdominal pain, Mouth ulceration, Gastritis

Stomatitis, Gastric ulcer

Hepatobiliary disorders

Treatment-induced liver injury, Hepatitis, Jaundice, Very rare: Hepatic failure

Skin and subcutaneous tissue disorders

Rash, Pruritus, Urticaria

Stevens-Johnson-Syndrome3

Renal and urinary disorders

Nephrolithiasis

General disorders and administration site conditions

Peripheral oedema, Hypersensitivity reactions

Investigations

Hepatic transaminases increased, Weight increased, Total bilirubin increased*

* Includes elevations collected as part of routine laboratory monitoring (see text below)

1 See section 4.3

2 See section 4.4

3 This adverse reaction was identified through post marketing surveillance but not observed in controlled clinical studies. The frequency category was estimated as the upper limit of the 95% confidence interval calculated on the basis of the total number of patients exposed to TCZ in clinical studies.

Infections

In the 6-month controlled studies the rate of all infections reported with tocilizumab 8 mg/kg plus DMARD treatment was 127 events per 100 patient years compared to 112 events per 100 patient years in the placebo plus DMARD group. In the long-term exposure population, the overall rate of infections with tocilizumab was 108 events per 100 patient years exposure.

In 6-month controlled clinical studies, the rate of serious infections with tocilizumab 8 mg/kg plus DMARDs was 5.3 events per 100 patient years exposure compared to 3.9 events per 100 patient years exposure in the placebo plus DMARD group. In the monotherapy study the rate of serious infections was 3.6 events per 100 patient years of exposure in the tocilizumab group and 1.5 events per 100 patient years of exposure in the MTX group.

In the long-term exposure population, the overall rate of serious infections (bacterial, viral and fungal) was 4.7 events per 100 patient years. Reported serious infections, some with fatal outcome, included active tuberculosis, which may present with intrapulmonary or extrapulmonary disease, invasive pulmonary infections, including candidiasis, aspergillosis, coccidioidomycosis and pneumocystis jirovecii, pneumonia, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis and bacterial arthritis. Cases of opportunistic infections have been reported.

Interstitial Lung Disease

Impaired lung function may increase the risk for developing infections. There have been post-marketing reports of interstitial lung disease (including pneumonitis and pulmonary fibrosis), some of which had fatal outcomes.

Gastrointestinal Perforation

During the 6-month controlled clinical studies, the overall rate of gastrointestinal perforation was 0.26 events per 100 patient years with tocilizumab therapy. In the long-term exposure population the overall rate of gastrointestinal perforation was 0.28 events per 100 patient years. Reports of gastrointestinal perforation on tocilizumab were primarily reported as complications of diverticulitis including generalised purulent peritonitis, lower gastrointestinal perforation, fistulae and abscess.

Infusion Related reactions

In the 6-month controlled studies adverse events associated with infusion (selected events occurring during or within 24 hours of infusion) were reported by 6.9% of patients in the tocilizumab 8 mg/kg plus DMARD group and 5.1% of patients in the placebo plus DMARD group. Events reported during the infusion were primarily episodes of hypertension; events reported within 24 hours of finishing an infusion were headache and skin reactions (rash, urticaria). These events were not treatment limiting.

The rate of anaphylactic reactions (occurring in a total of 8/4 009 patients, 0.2%) was several fold higher with the 4 mg/kg dose, compared to the 8 mg/kg dose. Clinically significant hypersensitivity reactions associated with tocilizumab and requiring treatment discontinuation were reported in a total of 56 out of 4 009 patients (1.4%) treated with tocilizumab during the controlled and open label clinical studies. These reactions were generally observed during the second to fifth infusions of tocilizumab (see section 4.4). Fatal anaphylaxis has been reported after marketing authorisation during treatment with tocilizumab (see section 4.4).

Haematological abnormalities

Neutrophils

In the 6-month controlled studies decreases in neutrophil counts below 1 x 109/L occurred in 3.4% of patients on tocilizumab 8 mg/kg plus DMARDs compared to < 0.1% of patients on placebo plus DMARDs. Approximately half of the patients who developed an ANC < 1 x 109/L did so within 8 weeks after starting therapy. Decreases below 0.5 x 109/L were reported in 0.3% patients receiving tocilizumab 8 mg/kg plus DMARDs. Infections with neutropenia have been reported.

During the double-blind controlled period and with long-term exposure, the pattern and incidence of decreases in neutrophil counts remained consistent with what was seen in the 6-month controlled clinical studies.

Platelets

In the 6-month controlled studies decreases in platelet counts below 100 x 103/μL occurred in 1.7% of patients on tocilizumab 8 mg/kg plus DMARDs compared to < 1% on placebo plus DMARDs. These decreases occurred without associated bleeding events.

During the double-blind controlled period and with long-term exposure, the pattern and incidence of decreases in platelet counts remained consistent with what was seen in the 6-month controlled clinical studies.

Very rare reports of pancytopenia have occurred in the post marketing setting.

Hepatic transaminase elevations

During the 6-month controlled studies transient elevations in ALT/AST > 3 x ULN were observed in 2.1% of patients on tocilizumab 8 mg/kg compared to 4.9% of patients on MTX and in 6.5% of patients who received 8 mg/kg tocilizumab plus DMARDs compared to 1.5% of patients on placebo plus DMARDs.

The addition of potentially hepatotoxic medicines (e.g. MTX) to tocilizumab monotherapy resulted in increased frequency of these elevations. Elevations of ALT/AST > 5 x ULN were observed in 0.7% of tocilizumab monotherapy patients and 1.4% of tocilizumab plus DMARD patients, the majority of whom were discontinued permanently from tocilizumab treatment. During the double-blind controlled period, the incidence of indirect bilirubin greater than the upper limit of normal, collected as a routine laboratory parameter, is 6.2% in patients treated with 8 mg/kg tocilizumab + DMARD. A total of 5.8% of patients experienced an elevation of indirect bilirubin of > 1 to 2 x ULN and 0.4% had an elevation of > 2 x ULN.

During the double-blind controlled period and with long-term exposure, the pattern and incidence of elevation in ALT/AST remained consistent with what was seen in the 6-month controlled clinical studies.

Lipid parameters

During the 6-month controlled studies, increases of lipid parameters such as total cholesterol, triglycerides, LDL cholesterol, and/or HDL cholesterol have been reported commonly. With routine laboratory monitoring it was seen that approximately 24% of patients receiving tocilizumab in clinical studies experienced sustained elevations in total cholesterol ≥ 6.2 mmol/L, with 15% experiencing a sustained increase in LDL to ≥ 4.1 mmol/L. Elevations in lipid parameters responded to treatment with lipid-lowering agents.

During the double-blind controlled period and with long-term exposure, the pattern and incidence of elevations in lipid parameters remained consistent with what was seen in the 6-month controlled studies.

Malignancies

The clinical data are insufficient to assess the potential incidence of malignancy following exposure to tocilizumab. Long-term safety evaluations are ongoing.

Skin Reactions

Rare reports of Stevens-Johnson Syndrome have occurred in the post marketing setting.

Patients with COVID-19

The safety evaluation of tocilizumab in COVID-19 was based on 3 randomized, double-blind, placebo controlled studies (studies ML42528, WA42380, and WA42511). A total of 974 patients were exposed to tocilizumab in these studies. Collection of safety data from RECOVERY was limited and is not presented here.

The following adverse reactions, listed by MedDRA system organ class in Table 2, have been adjudicated from events which occurred in at least 3% of tocilizumab treated patients and more commonly than that in patients on placebo in the pooled safety-evaluable population from clinical studies ML42528, WA42380, and WA42511.

Table 2: List of adverse reactions1 identified from the pooled safety-evaluable population from tocilizumab clinical studies in COVID-19 patients2

MedDRA System Organ Class

Very common

Common

Infections and infestations

Urinary tract infection

Metabolism and nutrition disorders

Hypokalaemia

Psychiatric disorders

Anxiety, Insomnia

Vascular disorders

Hypertension

Gastrointestinal disorders

Constipation, Diarrhoea, Nausea

Hepatobiliary disorders

Hepatic transaminases increased

1 Patients are counted once for each category regardless of the number of reactions

2 Includes adjudicated reactions reported in studies WA42511, WA42380 and ML42528

Description of selected adverse drug reactions

Infections

In the pooled safety-evaluable population from studies ML42528, WA42380, and WA42511, the rates of infection/serious infection events were balanced between COVID-19 patients receiving tocilizumab (30.3%/18.6%, n=974) versus placebo (32.1%/22.8%, n=483).

The safety profile observed in the baseline systemic corticosteroids treatment group was consistent with the safety profile of tocilizumab from the overall population presented in Table 2. In this subgroup, infections and serious infections occurred in 27.8% and 18.1% of patients treated with intravenous tocilizumab and in 30.5% and 22.9% of patients treated with placebo, respectively.

Laboratory Abnormalities

The incidence of laboratory abnormalities was generally similar between patients with COVID-19 who received one or two doses of tocilizumab-IV compared with those who received placebo in the randomized, double-blind, placebo controlled studies with few exceptions. Decreases in platelets and neutrophils and elevations of ALT and AST were more frequent among patients receiving tocilizumab-IV versus placebo (see section 4.2 and 4.4).

sJIA and pJIA Patients

The safety profile of tocilizumab in the pediatric population is summarized in the sections on pJIA and sJIA below. In general, the ADRs in pJIA and sJIA patients were similar in type to those seen in RA patients, see section 4.8.

ADRs in the pJIA and sJIA patients treated with tocilizumab are listed in the Table 3 and presented by MedDRA system organ class. The corresponding frequency category for each ADR is based on the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10) or uncommon (≥ 1/1 000 to < 1/100).

Table 3: List of ADRs occurring in clinical study patients with sJIA or pJIA receiving tocilizumab as monotherapy or in combination with MTX.

MedDRA SOC

Preferred term (PT)

Frequency

Infections and Infestations

Very common

Common

Uncommon

Upper Respiratory Tract Infections

pJIA, sJIA

Nasopharyngitis

pJIA, sJIA

Nervous system disorders

Headache

pJIA

sJIA

Gastrointestinal Disorders

Nausea

pJIA

Diarrhea

pJIA, sJIA

General disorders and administration site conditions

Infusion related reactions

pJIA1, sJIA2

Investigations

Hepatic transaminases increased

pJIA

Decrease in neutrophil count

sJIA

pJIA

Platelet count decreased

sJIA

pJIA

Cholesterol increased

sJIA

pJIA

1. Infusion related reaction events in pJIA patients included but were not limited to headache, nausea and hypotension

2. Infusion related reaction events in sJIA patients included but were not limited to rash, urticaria, diarrhoea, epigastric discomfort, arthralgia and headache

pJIA Patients

The safety profile of intravenous tocilizumab in pJIA has been studied in 188 patients from 2 to 17 years of age. The total patient exposure was 184.4 patient years. The frequency of ADRs in pJIA patients can be found in Table 3. The types of ADRs in pJIA patients were similar to those seen in RA and sJIA patients, see section 4.8. When compared to the adult RA population, events of nasopharyngitis, headache, nausea, and decreased neutrophil count were more frequently reported in the pJIA population. Events of cholesterol increased were less frequently reported in the pJIA population than in the adult RA population.

Infections

The rate of infections in the tocilizumab all exposure population was 163.7 per 100 patient years. The most common events observed were nasopharyngitis and upper respiratory tract infections. The rate of serious infections was numerically higher in patients weighing < 30 kg treated with 10 mg/kg tocilizumab (12.2 per 100 patient years) compared to patients weighing ≥ 30 kg, treated with 8 mg/kg tocilizumab (4.0 per 100 patient years). The incidence of infections leading to dose interruptions was also numerically higher in patients weighing < 30 kg treated with 10 mg/kg tocilizumab (21.4%) compared to patients weighing ≥ 30 kg, treated with 8 mg/kg tocilizumab (7.6%).

Infusion Related Reactions

In pJIA patients, infusion related reactions are defined as all events occurring during or within 24 hours of an infusion. In the tocilizumab all exposure population, 11 patients (5.9%) experienced infusion related reactions during the infusion and 38 patients (20.2%) experienced an event within 24 hours of an infusion. The most common events occurring during infusion were headache, nausea and hypotension and within 24 hours of infusion were dizziness and hypotension. In general, the adverse drug reactions observed during or within 24 hours of an infusion were similar in nature to those seen in RA and sJIA patients, see section 4.8.

No clinically significant hypersensitivity reactions associated with tocilizumab and requiring treatment discontinuation were reported.

Neutrophils

During routine laboratory monitoring in the tocilizumab all exposure population, a decrease in neutrophil count below 1 × 109/L occurred in 3.7% of patients.

Platelets

During routine laboratory monitoring in the tocilizumab all exposure population, 1% of patients had a decrease in platelet count to ≤ 50 × 103/µL without associated bleeding events.

Hepatic transaminase elevations

During routine laboratory monitoring in the tocilizumab all exposure population, elevation in ALT or AST ≥ 3xULN occurred in 3.7% and < 1% of patients, respectively.

Lipid parameters

During routine laboratory monitoring in the intravenous tocilizumab study WA19977 3.4% and 10.4% of patients experienced a post-baseline elevation of their LDL-cholesterol value to ≥ 130 mg/dL and total cholesterol value to ≥ 200 mg/dL at any time during the study treatment, respectively.

sJIA Patients

The safety profile of intravenous tocilizumab in sJIA has been studied in 112 patients from 2 to 17 years of age. In the 12 week double-blind, controlled phase, 75 patients received treatment with tocilizumab (8 mg/kg or 12 mg/kg based upon body weight). After 12 weeks or at the time of switching to tocilizumab, due to disease worsening, patients were treated in the open label extension phase.

In general, the ADRs in sJIA patients were similar in type to those seen in RA patients, see section 4.8. The frequency of ADRs in sJIA patients can be found in Table 3. When compared to the adult RA population, patients with sJIA experienced a higher frequency of nasopharyngitis, decrease in neutrophil counts, hepatic transaminases increased, and diarrhea. Events of cholesterol increased were less frequently reported in the sJIA population than in the adult RA population.

Infections

In the 12 week controlled phase, the rate of all infections in the intravenous tocilizumab group was 344.7 per 100 patient years and 287.0 per 100 patient years in the placebo group. In the open label extension phase (Part II), the overall rate of infections remained similar at 306.6 per 100 patient years.

In the 12 week controlled phase, the rate of serious infections in the intravenous tocilizumab group was 11.5 per 100 patient years. At one year in the open label extension phase the overall rate of serious infections remained stable at 11.3 per 100 patient years. Reported serious infections were similar to those seen in RA patients with the addition of varicella and otitis media.

Infusion Related Reactions

Infusion related reactions are defined as all events occurring during or within 24 hours of an infusion. In the 12 week controlled phase, 4% of patients from the tocilizumab group experienced events occurring during infusion. One event (angioedema) was considered serious and life-threatening, and the patient was discontinued from study treatment.

In the 12 week controlled phase, 16% of patients in the tocilizumab group and 5.4% of patients in the placebo group experienced an event within 24 hours of infusion. In the tocilizumab group, the events included, but were not limited to rash, urticaria, diarrhea, epigastric discomfort, arthralgia and headache. One of these events, urticaria, was considered serious.

Clinically significant hypersensitivity reactions associated with tocilizumab and requiring treatment discontinuation, were reported in 1 out of 112 patients (< 1%) treated with tocilizumab during the controlled and up to and including the open label clinical study.

Neutrophils

During routine laboratory monitoring in the 12 week controlled phase, a decrease in neutrophil counts below 1 x 109/L occurred in 7% of patients in the tocilizumab group, and no decreases in the placebo group.

In the open label extension phase, decreases in neutrophil counts below 1 x 109/L, occurred in 15% of the tocilizumab group.

Platelets

During routine laboratory monitoring in the 12 week controlled phase, 3% of patients in the placebo group and 1% in the tocilizumab group had a decrease in platelet count to ≤ 100 x 103/μL.

In the open label extension phase, decreases in platelet counts below 100 x 103/μL, occurred in 3% of patients in the tocilizumab group, without associated bleeding events.

Hepatic transaminase elevations

During routine laboratory monitoring in the 12 week controlled phase, elevation in ALT or AST ≥ 3 x ULN occurred in 5% and 3% of patients, respectively, in the tocilizumab group, and 0% in the placebo group.

In the open label extension phase, elevation in ALT or AST ≥ 3 x ULN occurred in 12% and 4% of patients, respectively, in the tocilizumab group.

Immunoglobulin G

IgG levels decrease during therapy. A decrease to the lower limit of normal occurred in 15 patients at some point in the study.

Lipid parameters

During routine laboratory monitoring in the 12 week controlled phase (study WA18221), 13.4% and 33.3% of patients experienced a post-baseline elevation of their LDL-cholesterol value to ≥ 130 mg/dL and total cholesterol value to ≥ 200 mg/dL at any time during study treatment, respectively.

In the open label extension phase (study WA18221), 13.2% and 27.7% of patients experienced a post- baseline elevation of their LDL-cholesterol value to ≥ 130 mg/dL and total cholesterol value to ≥ 200 mg/dL at any time during study treatment, respectively.

CRS Patients

The safety of tocilizumab in CRS has been evaluated in a retrospective analysis of data from clinical studies, where 51 patients were treated with intravenous tocilizumab 8 mg/kg (12 mg/kg for patients less than 30 kg) with or without additional high-dose corticosteroids for severe or life-threatening CAR T-cell-induced CRS. A median of 1 dose of tocilizumab (range, 1-4 doses) was administered.

Immunogenicity

Anti-tocilizumab antibodies may develop during tocilizumab treatment. Correlation of antibody development to clinical response or adverse events may be observed.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

There are limited data available on overdose with tocilizumab. One case of accidental overdose was reported in which a patient with multiple myeloma received a single dose of 40 mg/kg. No adverse reactions were observed.

No serious adverse reactions were observed in healthy volunteers who received a single dose of tocilizumab up to 28 mg/kg, although dose limiting neutropenia was observed.

Paediatric population

No case of an overdose in the paediatric population has been observed.