TOCILIZUMAB INJ,SOLN

Exclusion Criteria

• Uncontrolled active infection (may start/restart once treatment for the infection is initiated)
• Untreated latent or active tuberculosis infection
• Hepatitis B surface antigen (HBsAg)-positive and not on antiviral prophylaxis (may initiate after starting antiviral prophylaxis)
• Untreated HIV infection (treated, well-controlled, asymptomatic HIV-positive patients may be treated)
• Congenital or acquired immunodeficiency
• Concomitant live or live-attenuated vaccines or administration of inactivated, live, or live-attenuated vaccines less than 2 weeks before initiation
• Concomitant immunosuppressive biologic, immunosuppressive targeted synthetic drug (e.g., tofacitinib or other JAK inhibitors), cyclophosphamide, or alkylating agents
• Active hepatic disease or hepatic impairment
• Baseline absolute neutrophil count (ANC) < 2000/mm3 unless associated with Duffy-null Associated Neutrophil Count
• Baseline platelet count <100,000/mm3
• Baseline ALT and/or AST > 1.5x the upper limit of normal (ULN)

Inclusion Criteria

• Diagnosis of moderate to severe rheumatoid arthritis
• Prescribed and monitored by a VA/VA Community Care rheumatologist or locally-designated expert
• Offered all age-appropriate vaccinations prior to initiating therapy
• Completed tuberculosis (TB) test using tuberculin skin test or interferon-gamma release assay [IGRA]
• Completed hepatitis B screening (HBsAg, total antibody to hepatitis B core antigen [anti-HBc], and antibody to hepatitis B surface antigen [anti-HBs])
• Current or past completion of hepatitis C screening (may initiate while waiting for test results)
• Tumor necrosis factor inhibitor (TNFI) therapy is medically inadvisable, not tolerated, or not adequate (i.e., NO response to ONE TNFI after 3 months, partial response to 3-month trials of TWO TNFIs = total 6 months), or lost response

Additional Inclusion Criteria

• If HBsAg-negative but anti-HBc-positive and consult is deemed indicated: A GI/liver or infectious diseases expert has been consulted for advice on whether to start antiviral prophylaxis or to preemptively monitor for HBV reactivation
• For females who can become pregnant: Counseling provided on potential risks vs benefits of treatment and the use of effective contraception
• For females who are breastfeeding/providing breastmilk to an infant: Counseling provided on potential risks vs benefits of treatment

Laboratory, Screening, & Monitoring Requirements

• Routine rescreening for hepatitis B or hepatitis C is not required for prescription renewals; retesting in high-risk patients should be considered
• Safety of using tocilizumab in patients positive for HBV or HCV is unknown as these patients were excluded from clinical trials

Concomitant Medication & Vaccination Guidelines

• May be used in combination with methotrexate, other nonbiologic disease-modifying antirheumatic drugs (DMARDs), mycophenolate, hydroxychloroquine, or glucocorticoids
• Concomitant use of potent immunosuppressives should generally be avoided
• Vaccinations should be updated before initiation; recombinant zoster vaccine should be completed or at least initiated by the end of the first year of treatment, preferably when dosage is low, disease is stable, or at other times when a robust immune response to vaccination can be expected

Exclusion Criteria

• Uncontrolled active infection (may start/restart once treatment for the infection is initiated)
• Untreated latent or active tuberculosis infection
• Hepatitis B surface antigen (HBsAg)-positive and not on antiviral prophylaxis (may initiate after starting antiviral prophylaxis)
• Untreated HIV infection (treated, well-controlled, asymptomatic HIV-positive patients may be treated)
• Congenital or acquired immunodeficiency
• Concomitant live or live-attenuated vaccines or administration of inactivated, live, or live-attenuated vaccines less than 2 weeks before initiation
• Concomitant immunosuppressive biologic, immunosuppressive targeted synthetic drug (e.g., tofacitinib or other JAK inhibitors), cyclophosphamide, or alkylating agents
• Active hepatic disease or hepatic impairment
• Baseline absolute neutrophil count (ANC) < 2000/mm3 unless associated with Duffy-null Associated Neutrophil Count
• Baseline platelet count <100,000/mm3
• Baseline ALT and/or AST > 1.5x the upper limit of normal (ULN)

Inclusion Criteria: Diagnosis & Disease Characteristics

• Documented active systemic sclerosis (SSc) with laboratory, radiographic, histologic, or other clinical evidence of an inflammatory component
• Diagnosis of SSc-interstitial lung disease (ILD), preferably confirmed by multidisciplinary discussion
• Preferably without WHO functional class 2 to 4 pulmonary arterial hypertension (WHO functional class 1 preferred)
• SSc duration of not more than 5 years from onset of the first non-Raynaud phenomenon manifestation
• Active disease defined as at least one of: disease duration ≤18 months; worsening severity or extent of skin/body involvement; or ≥1 tendon friction rub
• Laboratory evidence of inflammation including elevated acute phase reactants (C-reactive protein [CRP], erythrocyte sedimentation rate [ESR], or platelet count above ULN)

Inclusion Criteria: Treatment History & Disease Progression

• Must meet ONE of the following:
• Progression of clinically evident SSc-ILD during mycophenolate therapy, or mycophenolate is not tolerated/medically inadvisable
• Progression of clinically evident SSc-ILD during cyclophosphamide therapy, or cyclophosphamide is not tolerated/medically inadvisable
• Rapid clinical progression of SSc-ILD even without prior mycophenolate or cyclophosphamide therapy
• Subclinical SSc-ILD (no prior mycophenolate or cyclophosphamide required; objective is to slow/prevent ILD progression)
• Disease progression defined as: ≥10% absolute decrease from baseline in % predicted forced vital capacity (FVC) OR ≥15% absolute decrease from baseline in % predicted diffusing capacity of the lung for carbon monoxide (DLCO) OR progression on high-resolution computed tomography (HRCT)

Inclusion Criteria: Screening, Counseling & Monitoring

• Completed tuberculosis (TB) test using tuberculin skin test or interferon-gamma release assay [IGRA]
• Completed hepatitis B screening (HBsAg, total antibody to hepatitis B core antigen [anti-HBc], and antibody to hepatitis B surface antigen [anti-HBs])
• Current or past completion of hepatitis C screening (may initiate while waiting for test results)
• If HBsAg-negative but anti-HBc-positive and consult indicated: GI/liver or infectious diseases expert consulted for advice on antiviral prophylaxis or preemptive monitoring for HBV reactivation
• Offered all age-appropriate vaccinations prior to initiating therapy
• For females who can become pregnant: Counseling provided on potential risks vs benefits and use of effective contraception
• For females who are breastfeeding/providing breastmilk: Counseling provided on potential risks vs benefits

Prescribing & Administration Requirements

• Prescribed and monitored by a VA/VA Community Care rheumatologist, pulmonologist, or locally designated expert
• May be used in combination with methotrexate, other nonbiologic DMARDs, mycophenolate, hydroxychloroquine, or glucocorticoids
• Concomitant use of potent immunosuppressives should generally be avoided

General Principles & Substitution Guidelines

• Every effort should be made to substitute tocilizumab SC with tocilizumab IV or an agent that has the same mechanism (e.g., sarilumab).
• If an in-class substitution is not feasible, every effort should be made to substitute the targeted therapy (tocilizumab or sarilumab) with other targeted therapies.

Rheumatoid Arthritis (Self-administered SC Alternatives)

• Sarilumab SC, based on availability
• Abatacept SC
• Oral JAK inhibitor (tofacitinib preferred over baricitinib and upadacitinib) with shared decision making as related to recent FDA warnings (mortality, malignancy, MACE, thrombosis)
• Different SC TNFI if patient had a prior loss of initial response (secondary nonresponse) to a TNFI (not if there was primary nonresponse)

Rheumatoid Arthritis (IV Infusion Alternatives)

• Tocilizumab IV, case by case based on site resources/availability of vials
• Abatacept IV
• Rituximab IV
• Infliximab-abda IV if patient had a prior loss of initial response (secondary nonresponse) to a different, non-infliximab TNFI product (not if there was primary nonresponse)

Giant Cell Arteritis (GCA)

• Prioritize patients actively on tocilizumab for GCA for continuation of therapy and available vials as they are obtained.
• If a glucocorticoid-sparing, targeted agent is urgently needed and tocilizumab is not available, off-label use may be considered for:
• Sarilumab SC, based on availability
• Ustekinumab with maintenance of glucocorticoid therapy
• Abatacept

• Uncontrolled, active, severe infection (including undrained abscess); may start/restart once treatment for the infection has been initiated
• Untreated latent or active tuberculosis infection
• Hepatitis B surface antigen (HBsAg)-positive without antiviral prophylaxis; may initiate after starting antiviral prophylaxis
• Untreated HIV infection; treated, well-controlled, asymptomatic HIV-positive patients are eligible
• Concomitant live or live-attenuated vaccines, or administration of inactivated/live/attenuated vaccines <2 weeks before initiation
• Concomitant immunosuppressive biologic, immunosuppressive targeted synthetic drug (e.g., tofacitinib or other JAK inhibitors), cyclophosphamide, or alkylating agents
• Active hepatic disease or hepatic impairment
• Baseline absolute neutrophil count (ANC) < 2000/mm3 (unless associated with Duffy-null Associated Neutrophil Count)
• Baseline platelet count <100,000/mm3
• Baseline ALT and/or AST > 1.5x the upper limit of normal (ULN)
• Inclusion Criteria (All must be met)
• Definite or provisional diagnosis of active giant cell arteritis
• Prescribed and monitored by a VA/VA Community Care rheumatologist or locally designated expert
• Completed tuberculosis (TB) test using tuberculin skin test or interferon-gamma release assay [IGRA]
• Completed hepatitis B screening (HBsAg, total antibody-to-hepatitis-B-core-antigen [anti-HBc], and antibody to hepatitis B surface antigen [anti-HBs])
• Current or past completion of hepatitis C screening; may initiate while awaiting test results
• Initiated concurrently or after glucocorticoid therapy unless medically inadvisable
• Additional Inclusion Criteria (Select if applicable)
• For HBsAg-negative but anti-HBc-positive patients where practitioner deems consult indicated: GI/liver or infectious diseases expert consulted for advice on whether to start antiviral prophylaxis or preemptively monitor for HBV reactivation
• For females who can become pregnant: Counseling provided on potential risks vs benefits of treatment and use of effective contraception
• For females who are breastfeeding/providing breastmilk to an infant: Counseling provided on potential risks vs benefits

Indication & Patient Population

• Hospitalized patients with severe COVID-19
• Positive SARS-CoV-2 direct viral test required
• Must be receiving systemic corticosteroids
• Must require supplemental oxygen, invasive or non-invasive mechanical ventilation, or ECMO

Dosing & Administration Requirements

• Recommended dose: 8 mg/kg (max 800 mg) as a single intravenous infusion for patients weighing ≥30 kg
• One additional dose of 8 mg/kg may be administered at least 8 hours after the first dose if signs and symptoms worsen or do not improve
• Subcutaneous administration is NOT authorized
• Must be diluted in a 100 mL prefilled bag of 0.9% or 0.45% sodium chloride
• Infusion must be administered over 60 minutes
• Must be protected from light after dilution (stored up to 24 hours refrigerated or 4 hours at room temperature)
• Must not be infused concomitantly in the same intravenous line with other drugs

Contraindications

• Known hypersensitivity to tocilizumab
• Active infection (including localized infection)
• ALT or AST greater than 10 times the upper limit of normal
• Absolute neutrophil count (ANC) < 1000/mm³
• Platelet count < 50,000/mm³
• Active hepatic disease or hepatic impairment

Warnings, Precautions & Monitoring

• Serious infections: Do not administer if concurrent active infection exists. Prompt diagnostic workup and antimicrobial therapy required if new infection develops. Weigh risks/benefits in patients with chronic/recurrent infection or history of serious opportunistic infections.
• Gastrointestinal perforation: Use with caution in patients at increased risk; evaluate new abdominal symptoms early for perforation.
• Hepatotoxicity: Monitor AST and ALT per standard practice. Not recommended if transaminases >10x ULN.
• Hypersensitivity reactions: Infuse only by a healthcare professional with appropriate medical support to manage anaphylaxis. Stop and discontinue permanently if anaphylaxis occurs.
• Demyelinating disorders: Monitor for signs/symptoms; exercise caution in patients with pre-existing or recent history.
• Live vaccines: Safety of concurrent use not established.
• Immunomodulation: Avoid in significantly immunosuppressed patients, particularly those with recent or other biologic immunomodulating drugs.
• Laboratory monitoring: Monitor ALT/AST, neutrophils, and platelet counts according to standard practice.

Administrative & EUA Compliance Criteria

• Patient-specific request on PBM EUA portal required (must include patient name, last four of SSN, date of birth, date of positive COVID-19 test)
• Documentation that patient meets all specified criteria is required
• Fact sheet for patients/parents/caregivers must be provided prior to administration (or as soon as practicable if delay endangers life)
• Patient or surrogate decision maker must have option to accept or refuse therapy
• Adverse drug events must be documented per local policy and reported to VA ADERS program
• FDA reporting required: patient-specific information, storage/cold-chain maintenance, lot numbers, administration timing, outcomes, and ADE documentation

Patient Eligibility & Clinical Status

• Laboratory confirmed COVID-19 diagnosis
• Hospitalized for treatment of COVID-19
• Receiving systemic corticosteroids
• Requires supplemental oxygen, non-invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO)

Laboratory Parameters

• Most recent absolute neutrophil count (ANC) > 1000/mm3
• Most recent platelet count > 50,000/mm3
• Most recent AST and ALT < 10 x the upper limit of normal
• Without active hepatic disease or impairment

Contraindications & Precautions

• No known hypersensitivity to tocilizumab (TOCI)
• No ongoing, active infection other than COVID-19

Dosing & Administration

• Dose must be ≤ 800 mg (maximum dose per EUA)
• Recommended dose: 8 mg/kg as a single intravenous infusion over 60 minutes
• One additional dose may be administered at least 8 hours after the initial dose if symptoms worsen or do not improve with the first dose

Documentation & Monitoring Requirements

• Information consistent with the TOCI fact sheet for patients, parents, and caregivers must be communicated prior to administration and documented in the medical record
• If communication delays administration to a degree that would endanger life, information must be provided to the caregiver as soon as feasible after administration (documented in the medical record)
• Patient-specific request on PBM EUA portal required prior to therapy initiation
• Post-administration tracking required: lot numbers administered, package arrival date, total doses given, start/completion dates and times of therapy, and any adverse events
• Any adverse drug events must be documented in accordance with local policy and placed in the VA ADERS program

Exclusion Criteria

• Untreated active hepatitis B infection
• Untreated latent or active tuberculosis infection
• Active, clinically significant infection
• Active hepatic disease or hepatic impairment
• Baseline ALT and/or AST > 1.5 times the upper limit of normal (ULN)
• Baseline Absolute Neutrophil Count (ANC) < 2000/mm3
• Baseline platelet count <100,000/mm3
• Concomitant therapy with another biologic therapy for neuromyelitis optica spectrum disorder (NMOSD)
• Concomitant chronic therapy with intravenous immunoglobulin or plasma exchange (use of these treatments in exacerbations is reasonable)
• Pregnancy

Inclusion Criteria

• Care provided by VA or VA Community Care neurology provider or locally designated expert
• Diagnosis of aquaporin-4 antibody positive NMOSD
• Completed hepatitis B screening (HBsAg, total anti-HBc and anti-HBs) and consult referral for hepatitis B management if either HBsAg or total anti-HBc positive
• All guideline recommended eligible immunizations administered at least 4 weeks prior to the start of treatment for live or live-attenuated vaccines, and whenever possible, at least 2 weeks prior to the start of treatment for inactivated vaccines
• Contraindication, intolerance, or lack of therapeutic response to rituximab

Additional Inclusion Criteria

• For patients who can become pregnant: Counseling provided on potential risks vs benefits of treatment and to inform their provider of a known or suspected pregnancy

Formulation & Dosing Parameters

• Evidenced formulation is the intravenous (IV) infusion; dosing 8mg/kg IV every 4 weeks
• Use in NMOSD is off-label