Actemra

Anti-Rheumatic Monoclonal Antibodies
Interleukin-6 (IL-6) Inhibitors

 
COVID-19 per the Emergency Use Authorization (EUA):
NOTE: Tocilizumab is not FDA-approved to treat coronavirus disease 2019 (COVID-19) in pediatric patients; however, the FDA has issued an EUA which allows for the drug to be used to treat COVID-19 in hospitalized pediatric patients (2 to 17 years) who are receiving systemic corticosteroids and require supplemental oxygen, mechanical ventilation (invasive or noninvasive), or extracorporeal membrane oxygenation (ECMO). Under the EUA, healthcare providers are required to communicate to the patient, parent, or caregiver information consistent with the "Fact Sheet for Patients, Parents and Caregivers" prior to the patient receiving treatment. If provision of this information delays treatment to the degree that would endanger the lives of patients, then the information must be provided as soon as practical following tocilizumab administration. NOTE: Under the EUA, healthcare providers are required to report all medication errors and serious adverse events potentially related to tocilizumab therapy within 7 calendar days from the healthcare provider's awareness of the event.

Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Tocilizumab is a clear and colorless to pale yellow liquid.
The prefilled syringe and the autoinjector are ONLY for subcutaneous injection use.
The vial is ONLY for use in preparing an intravenous infusion.

Administer intravenous infusions under the supervision of a qualified health professional. Have appropriate medical treatment available for immediate use in the event of a serious hypersensitivity reaction.
The drug must be diluted as an infusion prior to use. Do not administer as an intravenous push or bolus.
 
Infusion Preparation
Compatible infusion solutions for preparation: 0.9% Sodium Chloride Injection or 0.45% Sodium Chloride Injection.
A sterile needle and syringe should be utilized to prepare the solution.
Utilize a 50 mL infusion bag or bottle for patients who weigh less than 30 kg. Utilize a 100 mL infusion bag or bottle for patients who weigh at least 30 kg.
From a 50 mL or 100 mL infusion bag or bottle, withdraw a volume of the 0.9% Sodium Chloride Injection or 0.45% Sodium Chloride Injection equal to the volume of the tocilizumab solution required for the patient's dose.
Each tocilizumab vial contains a 20 mg/mL solution.
For a 4 mg/kg dose, 0.2 mL/kg of tocilizumab is needed.
For a 6 mg/kg dose, 0.3 mL/kg is needed.
For an 8 mg/kg dose, 0.4 mL/kg is needed.
For a 10 mg/kg dose, 0.5 mL/kg is needed.
For a 12 mg/kg dose, 0.6 mL/kg is needed.
Withdraw the amount of tocilizumab for intravenous infusion from the vial(s) and slowly add to the infusion bag or bottle.
Gently invert the bag to mix and to avoid foaming.
Fully diluted tocilizumab solutions are compatible with polypropylene, polyethylene, and polyvinyl chloride infusion bags and polypropylene, polyethylene, and glass infusion bottles.
Storage: The fully diluted tocilizumab solutions for infusion using 0.9% Sodium Chloride Injection may be stored at 2 to 8 degrees C (36 to 46 degrees F) or room temperature for up to 24 hours and should be protected from light. The fully diluted tocilizumab solutions for infusion using 0.45% Sodium Chloride Injection may be stored at 2 to 8 degrees C (36 to 46 degrees F) for up to 24 hours or at room temperature for up to 4 hours and should be protected from light. Do not freeze.
Do not use any unused product remaining in vials; tocilizumab does not contain preservatives.
 
Intravenous Infusion Administration
Prior to infusion, allow the fully diluted tocilizumab infusion to reach room temperature.
Administer as an intravenous infusion over 60 minutes with an infusion set.
Do not infuse tocilizumab concomitantly in the same intravenous line with other drugs. No physical or biochemical compatibility studies have been conducted to evaluate the coadministration of tocilizumab with other drugs.

General information
Administer the first injection of tocilizumab under the supervision of a qualified health professional. Have appropriate medical treatment available for immediate use in the event of a serious hypersensitivity reaction.
Assess the suitability of the patient for home use after the first dose. Patients should inform their provider before administering the next dose if they experience any symptoms of an allergic reaction. Patients should seek immediate medical attention if they develop symptoms of serious allergic reactions.
After the first dose, the subcutaneous injection may subsequently be given by the patient or patient's caregiver after proper training in injection technique, and a healthcare practitioner determines that it is appropriate.
Pediatric patients may self-inject with the prefilled syringe or autoinjector if both the healthcare practitioner and the parent/legal guardian determines it is appropriate.[38283]
 
Prefilled Syringe:
Remove the prefilled syringe from the refrigerator and allow it to sit at room temperature outside of the carton for 30 minutes. Do not warm tocilizumab in any other way.
Pick an injection site such as the front of a thigh, the outer area of an upper arm, or the abdomen except for the 2-inch area around the navel. Do not inject into moles, scars, or areas where the skin is tender, bruised, red, hard, or not intact.
Rotate injection sites with each injection. Inject at least 1 inch from the last area injected.
Remove the needle cap immediately before injection, and gently pinch a cleaned area of skin. Using a dart-like motion, insert the needle at a 45-degree or 90-degree angle. Release the pinched skin, and gently push the plunger all the way down to inject the full amount in the prefilled syringe (0.9 mL), which provides 162 mg of tocilizumab.
The prefilled syringe is for single-use only, as it does not have a preservative.
Remove the needle from the skin while continuing the depress the plunger. After the needle is completely removed, release the plunger, which will allow the needle-shield to protect the needle. Do not rub the injection site.
Dispose of needles and syringes in an FDA-cleared sharps disposal container right away after use.[38283]
 
Autoinjector:
Remove the autoinjector from the refrigerator and allow it to sit at room temperature outside of the carton for 45 minutes. Do not warm tocilizumab in any other way.
Do not use the autoinjector if it has been dropped or appears damaged.
Pick an injection site such as the front of a thigh, the outer area of an upper arm, or the abdomen except for the 2-inch area around the navel. Do not inject into moles, scars, or areas where the skin is tender, bruised, red, hard, or not intact.
Do not auto inject through clothing.
Rotate injection sites with each injection. Inject at least 1 inch from the last area injected.
Remove the needle cap immediately before injection, and gently pinch a cleaned area of skin. Place the needle-shield at a 90-degree angle against the pinched skin.
Unlock the green activation button by firmly pressing the autoinjector against the pinched skin, then press the green button to start the injection. Continue to hold the autoinjector firmly against the pinched skin until the purple indicator stops moving and the full dose administered; the complete injection may take up to 10 seconds.
Release the green button and lift the autoinjector off the skin at a 90-degree angle.
The autoinjector is for single-use only, as it does not have a preservative. Dispose of needles and syringes in an FDA-cleared sharps disposal container right away after use.[38283]

anaphylactic shock / Rapid / 0.1-0.9
anaphylactoid reactions / Rapid / 0.1-0.9
GI perforation / Delayed / Incidence not known
hepatic failure / Delayed / Incidence not known
hepatotoxicity / Delayed / Incidence not known
new primary malignancy / Delayed / Incidence not known
angioedema / Rapid / Incidence not known
Stevens-Johnson syndrome / Delayed / Incidence not known
macrophage activation syndrome / Delayed / Incidence not known
pancreatitis / Delayed / Incidence not known
optic neuritis / Delayed / Incidence not known
visual impairment / Early / Incidence not known

elevated hepatic enzymes / Delayed / 2.2-48.0
neutropenia / Delayed / 0-25.9
infusion-related reactions / Rapid / 4.0-20.2
hyperlipidemia / Delayed / 0-19.6
constipation / Delayed / 9.0-9.0
hypertension / Early / 4.0-6.0
thrombocytopenia / Delayed / 1.0-4.0
hypokalemia / Delayed / 4.0-4.0
oral ulceration / Delayed / 1.0-2.0
gastritis / Delayed / 1.0-2.0
dyspnea / Early / 0-2.0
antibody formation / Delayed / 0.9-1.8
candidiasis / Delayed / Incidence not known
hepatitis / Delayed / Incidence not known
jaundice / Delayed / Incidence not known
hypercholesterolemia / Delayed / Incidence not known
hypertriglyceridemia / Delayed / Incidence not known
hypotension / Rapid / Incidence not known
peripheral neuropathy / Delayed / Incidence not known

injection site reaction / Rapid / 7.1-41.2
infection / Delayed / 3.0-8.0
pharyngitis / Delayed / 4.0-7.0
headache / Early / 5.0-7.0
rash / Early / 2.0-4.0
insomnia / Early / 4.0-4.0
anxiety / Delayed / 4.0-4.0
abdominal pain / Early / 2.0-3.0
dizziness / Early / 2.0-3.0
nausea / Early / 3.0-3.0
cough / Delayed / 0-2.0
urticaria / Rapid / Incidence not known
arthralgia / Delayed / Incidence not known
pruritus / Rapid / Incidence not known
diarrhea / Early / Incidence not known
fatigue / Early / Incidence not known
weakness / Early / Incidence not known

Patients who receive tocilizumab are at increased risk for developing serious infections that may lead to hospitalization or death. Infections include active tuberculosis and invasive fungal infections including candidiasis, aspergillosis, and pneumocystis. Bacterial, viral, and other infections due to opportunistic pathogens have been reported. Most patients who developed serious infections were taking concomitant immunosuppressives such as methotrexate or corticosteroids. Cases of severe and disseminated strongyloidiasis have been reported following use of tocilizumab in combination with corticosteroids to treat patients with coronavirus disease 2019 (COVID-19). The National Institutes of Health (NIH) COVID-19 treatment guidelines recommend administering ivermectin as prophylactic treatment before giving tocilizumab with a corticosteroid to patients from strongyloidiasis endemic areas. Patients who have surgery while taking tocilizumab may be at greater risk for postoperative infections. Patients with an invasive fungal infection may present with disseminated disease, and tuberculosis may present as pulmonary or extrapulmonary disease. Evaluate patients for tuberculosis risk factors before starting tocilizumab. Also, test patients for latent tuberculosis before and during tocilizumab receipt. In patients with COVID-19, testing for latent infection is not necessary prior to initiation of treatment with tocilizumab. Initiate treatment for latent infection before tocilizumab use. Consider anti-tuberculosis therapy prior to tocilizumab initiation for 2 patient groups: patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed and patients with a negative test for latent tuberculosis but with 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. Carefully consider the risks and benefits of tocilizumab before initiating therapy in patients with chronic or recurrent infection, who have been exposed to tuberculosis, with a history of a serious or opportunistic infection, with underlying conditions that may predispose them to infection (e.g., patients with advanced or uncontrolled diabetes mellitus, human immunodeficiency virus (HIV) infection, or immunosuppression), or who have resided or traveled in areas of endemic tuberculosis or endemic mycoses. Tocilizumab initiation is not recommended for patients with an absolute neutrophil count (ANC) less than 2,000 cells/mm3, tocilizumab discontinuation is advised for an ANC less than 500 cells/mm3, and tocilizumab interruption is advised for an ANC between 500 cells/mm3 and 1,000 cells/mm3. For treatment of COVID-19, tocilizumab treatment is not recommended in patients with an ANC less than 1,000 cells/mm3, however, the NIH COVID-19 guidelines recommend caution if the ANC is less than 500 cells/mm3. Closely monitor patients for the development of signs and symptoms of infection during and after tocilizumab treatment; signs and symptoms of acute inflammation may be lessened due to suppression of the acute phase reactants. Consider the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to taking tocilizumab. Do not administer tocilizumab to a patient with an active infection including localized infections. If a serious infection such as sepsis or influenza or an opportunistic infection develops, interrupt tocilizumab receipt until the infection is controlled. If a new infection develops during tocilizumab receipt, complete a prompt and complete diagnostic workup appropriate for an immunocompromised patient, initiate appropriate antimicrobial therapy, and closely monitor the patient.

Actemra

Rx

Humanized IL-6 receptor-inhibiting monoclonal antibody
Used in adults for moderate to severe rheumatoid arthritis (RA), giant cell arteritis (temporal arteritis), systemic sclerosis-associated interstitial lung disease, cytokine release syndrome, and COVID-19; used in pediatric patients 2 years and older with active juvenile idiopathic arthritis (JIA) or cytokine release syndrome; EUA for COVID-19 in pediatric patients 2 years and older
Boxed warning in label regarding risk for serious infections

8 mg/kg (Max: 800 mg/dose) via a single intravenous infusion. If clinical signs or symptoms worsen or do not improve after the first dose, 1 additional dose may be administered at least 8 hours after the initial infusion. Administer tocilizumab in combination with a systemic corticosteroid. The National Institutes of Health (NIH) COVID-19 treatment guidelines recommend tocilizumab in combination with dexamethasone (with or without remdesivir) to treat hospitalized adults requiring supplemental oxygen, IF the patient is exhibiting signs of systemic inflammation and rapidly increasing oxygen needs while on dexamethasone. The NIH also recommends use of tocilizumab plus dexamethasone to treat patients on high-flow oxygen, noninvasive ventilation, mechanical ventilation, or ECMO.

8 mg/kg (Max: 800 mg/dose) via a single intravenous infusion. If clinical signs or symptoms worsen or do not improve after the first dose, 1 additional dose may be administered at least 8 hours after the initial infusion. The Emergency Use Authorization requires tocilizumab to be given in combination with a systemic corticosteroid. The NIH COVID-19 treatment guidelines recommend consideration of the addition of tocilizumab for hospitalized patients requiring high-flow oxygen, noninvasive ventilation, mechanical ventilation, or ECMO who do not have rapid (e.g., within 24 hours) improvement in oxygenation after initiation of dexamethasone. Remdesivir may be added for patients requiring high-flow oxygen or noninvasive ventilation.

12 mg/kg via a single intravenous infusion. If clinical signs or symptoms worsen or do not improve after the first dose, 1 additional dose may be administered at least 8 hours after the initial infusion. The Emergency Use Authorization requires tocilizumab to be given in combination with a systemic corticosteroid. The NIH COVID-19 treatment guidelines recommend consideration of the addition of tocilizumab for hospitalized patients requiring high-flow oxygen, noninvasive ventilation, mechanical ventilation, or ECMO who do not have rapid (e.g., within 24 hours) improvement in oxygenation after initiation of dexamethasone. Remdesivir may be added for patients requiring high-flow oxygen or noninvasive ventilation.

8 mg/kg/dose IV every 4 weeks; administer over 1 hour. Do not change dose based solely on a single visit body weight measurement, as weight may fluctuate. May use as monotherapy or in combination with methotrexate.

10 mg/kg/dose IV every 4 weeks; administer over 1 hour. Do not change dose based solely on a single visit body weight measurement, as weight may fluctuate. May use as monotherapy or in combination with methotrexate.

162 mg/dose subcutaneously every 2 weeks. When transitioning from IV to subcutaneous administration, administer the first subcutaneous dose instead of the next scheduled IV dose. Do not change dose based solely on a single visit body weight measurement, as weight may fluctuate. May use as monotherapy or in combination with methotrexate.

162 mg/dose subcutaneously every 3 weeks. When transitioning from IV to subcutaneous administration, administer the first subcutaneous dose instead of the next scheduled IV dose. Do not change dose based solely on a single visit body weight measurement, as weight may fluctuate. May use as monotherapy or in combination with methotrexate.

4 mg/kg/dose IV every 4 weeks. May increase the dose to 8 mg/kg/dose IV every 4 weeks if needed; doses more than 800 mg are not recommended. May use as monotherapy or concomitantly with methotrexate or other non-biologic DMARDs. Avoid concurrent use with biological DMARDs such as tumor necrosis factor (TNF) modifiers, anakinra, rituximab, ofatumumab, and abatacept.

162 mg subcutaneously every other week as monotherapy or concomitantly with methotrexate or other non-biologic DMARDs. May increase the dose to 162 mg subcutaneously once weekly based on clinical response. If transitioning from IV tocilizumab, give the first subcutaneous dose instead of the next scheduled IV dose.

162 mg subcutaneously once weekly as monotherapy or concomitantly with methotrexate or other non-biologic DMARDs. If transitioning from IV tocilizumab, give the first subcutaneous dose instead of the next scheduled IV dose.

8 mg/kg/dose IV every 2 weeks; administer over 1 hour. Do not change dose based solely on a single visit body weight measurement, as weight may fluctuate. May use as monotherapy or in combination with methotrexate.

12 mg/kg/dose IV every 2 weeks; administer over 1 hour. Do not change dose based solely on a single visit body weight measurement, as weight may fluctuate. May use as monotherapy or in combination with methotrexate.[38283]

162 mg/dose subcutaneously every week. When transitioning from IV to subcutaneous administration, administer the first subcutaneous dose instead of the next scheduled IV dose. Do not change dose based solely on a single visit body weight measurement, as weight may fluctuate. May use as monotherapy or in combination with methotrexate.

162 mg/dose subcutaneously every 2 weeks. When transitioning from IV to subcutaneous administration, administer the first subcutaneous dose instead of the next scheduled IV dose. Do not change dose based solely on a single visit body weight measurement, as weight may fluctuate. May use as monotherapy or in combination with methotrexate.[38283]

8 mg/kg IV over 60 minutes for one dose, alone or in combination with corticosteroids. If no clinical improvement in the signs and symptoms of CRS occur after the first dose, up to 3 additional doses of tocilizumab may be administered at least 8 hours apart; doses exceeding 800 mg are not recommended. Only the intravenous route should be used for the treatment of CRS; subcutaneous administration is not approved for this use. In a retrospective analysis of pooled outcome data from clinical trials of CAR T-cell therapies for hematologic malignancies, 69% of patients with a first episode of CRS who were treated with tocilizumab achieved a response, defined as resolution (lack of fever and off vasopressors for at least 24 hours) within 14 days of the first dose of tocilizumab, less than 2 doses of tocilizumab administered, and no additional treatment beyond tocilizumab and corticosteroids. This was confirmed in a second study using an independent cohort that included 14 patients with CAR T cell-induced CRS.

12 mg/kg IV infusion over 60 minutes for one dose, alone or in combination with corticosteroids. If no clinical improvement in the signs and symptoms of CRS occur after the first dose, up to 3 additional doses of tocilizumab may be administered at least 8 hours apart; doses exceeding 800 mg are not recommended. Only the IV route should be used for the treatment of CRS; subcutaneous administration is not approved for this use. In a retrospective analysis of pooled outcome data from clinical trials of CAR T-cell therapies for hematologic malignancies, 69% of patients with a first episode of CRS who were treated with tocilizumab achieved a response, defined as resolution (lack of fever and off vasopressors for at least 24 hours) within 14 days of the first dose of tocilizumab, less than 2 doses of tocilizumab administered, and no additional treatment beyond tocilizumab and corticosteroids. This was confirmed in a second study using an independent cohort that included 14 patients with CAR T cell-induced CRS.

162 mg subcutaneously once weekly. Therapy interruption may be needed for management of dose-related laboratory abnormalities including elevated liver enzymes, neutropenia, and thrombocytopenia.

6 mg/kg IV infusion over 1 hour every 4 weeks in combination with a tapering course of glucocorticoids. Doses greater than 600 mg per infusion not recommended. Tocilizumab may be used alone following discontinuation of glucocorticoids.

162 mg subcutaneously once weekly, in combination with a tapering course of glucocorticoids, is the recommended dose. A dose of 162 mg subcutaneously once every other week, in combination with a tapering course of glucocorticoids, may be prescribed based on clinical considerations. Tocilizumab may be used alone following discontinuation of glucocorticoids. If transitioning from IV tocilizumab, give the first subcutaneous dose instead of the next scheduled IV dose.

8 mg/kg IV once monthly.

162 mg subcutaneously once weekly.

†Indicates off-label use

Prior to treatment initiation
For COVID-19 patients, it is recommended tocilizumab not be initiated if ALT or AST are greater than 10-times the upper limit of normal (ULN); however, the National Institutes of Health (NIH) COVID-19 guidelines recommend caution in patients with an ALT greater than 5-times the ULN. For all other patients, do not initiate treatment with tocilizumab if active liver disease or hepatic impairment is present, or if baseline AST or ALT is more than 1.5-times the ULN. Although, patients with severe or life-threatening cytokine release syndrome (CRS) frequently have elevated ALT or AST; the decision to administer tocilizumab should take into account the potential benefit of treating the CRS versus the risks of short-term treatment with tocilizumab.[38283]
 
Hepatic enzyme elevations that occur during treatment
Adult Patients with rheumatoid arthritis or systemic sclerosis-associated interstitial lung disease with hepatic impairment[38283]
AST and/or ALT of more than 1 times and up to 3 times the ULN:
Dose modify concomitant DMARDs (RA, SSc-ILD) or immunomodulatory agents, if appropriate.
For persistent increases in this range:
Intravenous dosing: For persistent increases in this range, reduce IV tocilizumab dose to 4 mg/kg every 4 weeks or hold tocilizumab dosing until AST and/or ALT have normalized.
Subcutaneous dosing: Reduce subcutaneous dosing interval to every other week or hold tocilizumab dosing until AST and/or ALT have normalized. Once ALT and/or AST have normalized, resume subcutaneous injection at every other week dosing and increase to once weekly as clinically appropriate.
AST and/or ALT more than 3 times and up to 5 times the ULN:
Interrupt tocilizumab dosing until AST and/or ALT is less than 3 times the ULN and then follow dosing recommendations for AST and/or ALT more than 1 to 3 times ULN.
For persistent increases of more than 3 times the ULN, discontinue tocilizumab.
AST and/or ALT greater than 5 times the ULN: Discontinue tocilizumab.
 
Adult Patients with giant cell arteritis with hepatic impairment[38283]
AST and/or ALT of more than 1 times and up to 3 times the ULN:
Dose modify concomitant immunomodulatory agents, if appropriate.
For persistent increases in this range:
Intravenous dosing: For persistent increases in this range, hold IV tocilizumab dosing until AST and/or ALT have normalized.
Subcutaneous dosing: Reduce subcutaneous dosing interval to every other week or hold tocilizumab dosing until AST and/or ALT have normalized. Once ALT and/or AST have normalized, resume subcutaneous injection at every other week dosing and increase to once weekly as clinically appropriate.
AST and/or ALT more than 3 times and up to 5 times the ULN:
Interrupt tocilizumab dosing until AST and/or ALT is less than 3 times the ULN and then follow dosing recommendations for AST and/or ALT more than 1 to 3 times ULN.
For persistent increases of more than 3 times the ULN, discontinue tocilizumab.
AST and/or ALT greater than 5 times the ULN: Discontinue tocilizumab.
 
-Pediatric Patients with hepatic impairment[38283]
Tocilizumab dose reduction has not been studied in the systemic juvenile idiopathic arthritis (SJIA) or polyarticular juvenile idiopathic arthritis (PJIA) population. Tocilizumab dose interruptions are recommended for liver enzyme abnormalities in patients with SJIA or PJIA at levels similar to what is outlined for adult patients with rheumatoid arthritis and giant cell arteritis. If appropriate, adjust or stop concomitant DMARDs and hold tocilizumab dosing until the clinical situation has been evaluated. In SJIA and PJIA, base the decision to discontinue tocilizumab upon the medical assessment of the individual patient and the laboratory abnormality involved.

CrCl 30 mL/minute or more: No dosage adjustment is needed.
CrCl less than 30 mL/minute: Tocilizumab has not been studied in patients with severe renal impairment.

Abatacept: (Major) Avoid the concomitant use of tocilizumab with biological DMARDs, including selective costimulation modulators such as abatacept; coadministration has not been studied and may result in additive immunosuppression and increased risk of infection.
Acetaminophen; Chlorpheniramine; Dextromethorphan: (Minor) Concomitant use of tocilizumab and dextromethorphan may lead to a decrease in the efficacy of dextromethorphan; clinical significance of this interaction is not known or established. Inhibition of IL-6 signaling by tocilizumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. This effect on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. A 5% decrease in dextromethorphan exposure and a 29% decrease in its metabolite, dextrorphan was noted 1 week after a single tocilizumab infusion. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Dextromethorphan is a CYP2D6 substrate.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Minor) Concomitant use of tocilizumab and dextromethorphan may lead to a decrease in the efficacy of dextromethorphan; clinical significance of this interaction is not known or established. Inhibition of IL-6 signaling by tocilizumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. This effect on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. A 5% decrease in dextromethorphan exposure and a 29% decrease in its metabolite, dextrorphan was noted 1 week after a single tocilizumab infusion. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Dextromethorphan is a CYP2D6 substrate.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Minor) Concomitant use of tocilizumab and dextromethorphan may lead to a decrease in the efficacy of dextromethorphan; clinical significance of this interaction is not known or established. Inhibition of IL-6 signaling by tocilizumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. This effect on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. A 5% decrease in dextromethorphan exposure and a 29% decrease in its metabolite, dextrorphan was noted 1 week after a single tocilizumab infusion. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Dextromethorphan is a CYP2D6 substrate.
Acetaminophen; Dextromethorphan: (Minor) Concomitant use of tocilizumab and dextromethorphan may lead to a decrease in the efficacy of dextromethorphan; clinical significance of this interaction is not known or established. Inhibition of IL-6 signaling by tocilizumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. This effect on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. A 5% decrease in dextromethorphan exposure and a 29% decrease in its metabolite, dextrorphan was noted 1 week after a single tocilizumab infusion. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Dextromethorphan is a CYP2D6 substrate.
Acetaminophen; Dextromethorphan; Doxylamine: (Minor) Concomitant use of tocilizumab and dextromethorphan may lead to a decrease in the efficacy of dextromethorphan; clinical significance of this interaction is not known or established. Inhibition of IL-6 signaling by tocilizumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. This effect on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. A 5% decrease in dextromethorphan exposure and a 29% decrease in its metabolite, dextrorphan was noted 1 week after a single tocilizumab infusion. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Dextromethorphan is a CYP2D6 substrate.
Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Minor) Concomitant use of tocilizumab and dextromethorphan may lead to a decrease in the efficacy of dextromethorphan; clinical significance of this interaction is not known or established. Inhibition of IL-6 signaling by tocilizumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. This effect on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. A 5% decrease in dextromethorphan exposure and a 29% decrease in its metabolite, dextrorphan was noted 1 week after a single tocilizumab infusion. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Dextromethorphan is a CYP2D6 substrate.
Acetaminophen; Dextromethorphan; Guaifenesin; Pseudoephedrine: (Minor) Concomitant use of tocilizumab and dextromethorphan may lead to a decrease in the efficacy of dextromethorphan; clinical significance of this interaction is not known or established. Inhibition of IL-6 signaling by tocilizumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. This effect on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. A 5% decrease in dextromethorphan exposure and a 29% decrease in its metabolite, dextrorphan was noted 1 week after a single tocilizumab infusion. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Dextromethorphan is a CYP2D6 substrate.
Acetaminophen; Dextromethorphan; Phenylephrine: (Minor) Concomitant use of tocilizumab and dextromethorphan may lead to a decrease in the efficacy of dextromethorphan; clinical significance of this interaction is not known or established. Inhibition of IL-6 signaling by tocilizumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. This effect on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. A 5% decrease in dextromethorphan exposure and a 29% decrease in its metabolite, dextrorphan was noted 1 week after a single tocilizumab infusion. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Dextromethorphan is a CYP2D6 substrate.
Acetaminophen; Dextromethorphan; Pseudoephedrine: (Minor) Concomitant use of tocilizumab and dextromethorphan may lead to a decrease in the efficacy of dextromethorphan; clinical significance of this interaction is not known or established. Inhibition of IL-6 signaling by tocilizumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. This effect on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. A 5% decrease in dextromethorphan exposure and a 29% decrease in its metabolite, dextrorphan was noted 1 week after a single tocilizumab infusion. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Dextromethorphan is a CYP2D6 substrate.
Alfentanil: (Moderate) Monitor for evidence of reduced effect if alfentanil coadministration with tocilizumab is necessary; alfentanil dosage adjustment may be needed. Inhibition of IL-6 signaling by tocilizumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as alfentanil, may have fluctuations in drug levels and therapeutic effect when tocilizumab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Alfentanil is a CYP3A4 substrate and narrow therapeutic index drug.
Amlodipine; Atorvastatin: (Moderate) Utilize caution with concomitant use of tocilizumab and CYP3A4 substrate drugs, such as atorvastatin, where a decrease in effectiveness is undesirable. Monitor lipid panels and adjust therapy as indicated. Inhibition of IL-6 signaling by tocilizumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. This effect on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. A 57% decrease in the exposure of another "statin" was noted 1 week after a single tocilizumab dose. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Atorvastatin is a CYP3A4 substrate.
Amoxicillin; Clarithromycin; Omeprazole: (Minor) Concomitant use of tocilizumab and omeprazole may lead to a decrease in the efficacy of omeprazole. Inhibition of IL-6 signaling by tocilizumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. This effect on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. A 12 to 28% decrease in omeprazole exposure occurred 1 week after a single tocilizumab dose. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Omeprazole is a substrate of both CYP2C19 and CYP3A4.
Anakinra: (Major) Avoid the concomitant use of tocilizumab with biological DMARDs, including interleukin-1 receptor antagonists such as anakinra; coadministration has not been studied and may result in additive immunosuppression and increased risk of infection.
Apixaban: (Moderate) Monitor for a decrease in efficacy of apixaban if used with tocilizumab. Until more data are available, consider using an anticoagulant without dependence on CYP450 enzymes for metabolism (e.g., heparins, edoxaban). The formation of CYP450 enzymes may be suppressed by increased concentrations of cytokines such as IL-6 during chronic inflammation. It is expected that the activity of CYP450 enzymes could increase to normal concentrations during treatment with an IL-6 antagonist such as tocilizumab; these effects on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes [including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4]. Apixaban is a substrate for CYP3A4.
Aspirin, ASA; Omeprazole: (Minor) Concomitant use of tocilizumab and omeprazole may lead to a decrease in the efficacy of omeprazole. Inhibition of IL-6 signaling by tocilizumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. This effect on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. A 12 to 28% decrease in omeprazole exposure occurred 1 week after a single tocilizumab dose. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Omeprazole is a substrate of both CYP2C19 and CYP3A4.
Atorvastatin: (Moderate) Utilize caution with concomitant use of tocilizumab and CYP3A4 substrate drugs, such as atorvastatin, where a decrease in effectiveness is undesirable. Monitor lipid panels and adjust therapy as indicated. Inhibition of IL-6 signaling by tocilizumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. This effect on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. A 57% decrease in the exposure of another "statin" was noted 1 week after a single tocilizumab dose. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Atorvastatin is a CYP3A4 substrate.
Atorvastatin; Ezetimibe: (Moderate) Utilize caution with concomitant use of tocilizumab and CYP3A4 substrate drugs, such as atorvastatin, where a decrease in effectiveness is undesirable. Monitor lipid panels and adjust therapy as indicated. Inhibition of IL-6 signaling by tocilizumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. This effect on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. A 57% decrease in the exposure of another "statin" was noted 1 week after a single tocilizumab dose. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Atorvastatin is a CYP3A4 substrate.
Bacillus Calmette-Guerin Vaccine, BCG: (Major) Avoid concurrent use of live vaccines during treatment with tocilizumab due to potentially increased risk of infections; clinical safety of live vaccines during tocilizumab treatment has not been established. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving tocilizumab. The interval between live vaccinations and initiation of tocilizumab therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.
Baricitinib: (Major) Avoid the concomitant use of tocilizumab with other biological DMARDs such as baricitinib; coadministration has not been studied and may result in additive immunosuppression and increased risk of infection.
Basiliximab: (Major) Avoid using tocilizumab with immunosuppressive biological agents such as basilixumab because of the possibility of increased immunosuppression and increased risk of infection. The concurrent use of tocilizumab with other biological agents has not been studied. Most patients taking tocilizumab who developed serious infections were taking concomitant immunosuppressives.
Brompheniramine; Dextromethorphan; Phenylephrine: (Minor) Concomitant use of tocilizumab and dextromethorphan may lead to a decrease in the efficacy of dextromethorphan; clinical significance of this interaction is not known or established. Inhibition of IL-6 signaling by tocilizumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. This effect on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. A 5% decrease in dextromethorphan exposure and a 29% decrease in its metabolite, dextrorphan was noted 1 week after a single tocilizumab infusion. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Dextromethorphan is a CYP2D6 substrate.
Brompheniramine; Pseudoephedrine; Dextromethorphan: (Minor) Concomitant use of tocilizumab and dextromethorphan may lead to a decrease in the efficacy of dextromethorphan; clinical significance of this interaction is not known or established. Inhibition of IL-6 signaling by tocilizumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. This effect on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. A 5% decrease in dextromethorphan exposure and a 29% decrease in its metabolite, dextrorphan was noted 1 week after a single tocilizumab infusion. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Dextromethorphan is a CYP2D6 substrate.
Canakinumab: (Major) Avoid using tocilizumab with other biological DMARDs including interleukin-1 receptor antagonists such as canakinumab; coadministration has not been studied and may result in additive immunosuppression and increased risk of infection.
Carbamazepine: (Moderate) Monitor carbamazepine concentrations and watch for decreased efficacy of carbamazepine if coadministration with tocilizumab is necessary; adjust carbamazepine dosage as necessary. Inhibition of IL-6 signaling by tocilizumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as carbamazepine, may have fluctuations in drug levels and therapeutic effect when tocilizumab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Carbamazepine is a substrate of both CYP1A2 and CYP3A4 and narrow therapeutic index drug.
Chlorpheniramine; Dextromethorphan: (Minor) Concomitant use of tocilizumab and dextromethorphan may lead to a decrease in the efficacy of dextromethorphan; clinical significance of this interaction is not known or established. Inhibition of IL-6 signaling by tocilizumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. This effect on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. A 5% decrease in dextromethorphan exposure and a 29% decrease in its metabolite, dextrorphan was noted 1 week after a single tocilizumab infusion. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Dextromethorphan is a CYP2D6 substrate.
Chlorpheniramine; Dextromethorphan; Phenylephrine: (Minor) Concomitant use of tocilizumab and dextromethorphan may lead to a decrease in the efficacy of dextromethorphan; clinical significance of this interaction is not known or established. Inhibition of IL-6 signaling by tocilizumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. This effect on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. A 5% decrease in dextromethorphan exposure and a 29% decrease in its metabolite, dextrorphan was noted 1 week after a single tocilizumab infusion. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Dextromethorphan is a CYP2D6 substrate.
Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Minor) Concomitant use of tocilizumab and dextromethorphan may lead to a decrease in the efficacy of dextromethorphan; clinical significance of this interaction is not known or established. Inhibition of IL-6 signaling by tocilizumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. This effect on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. A 5% decrease in dextromethorphan exposure and a 29% decrease in its metabolite, dextrorphan was noted 1 week after a single tocilizumab infusion. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Dextromethorphan is a CYP2D6 substrate.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Cisapride: (Moderate) Monitor for decreased efficacy of cisapride if coadministration with tocilizumab is necessary. Inhibition of IL-6 signaling by tocilizumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as cisapride, may have fluctuations in drug levels and therapeutic effect when tocilizumab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Cisapride is a CYP3A4 substrate and narrow therapeutic index drug.
Cyclosporine: (Moderate) Monitor cyclosporine levels and adjust the dose of cyclosporine as appropriate if coadministration with tocilizumab is necessary. Inhibition of IL-6 signaling by tocilizumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as cyclosporine, may have fluctuations in drug levels and therapeutic effect when tocilizumab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Cyclosporine is a CYP3A4 substrate and narrow therapeutic index drug.
Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Minor) Concomitant use of tocilizumab and dextromethorphan may lead to a decrease in the efficacy of dextromethorphan; clinical significance of this interaction is not known or established. Inhibition of IL-6 signaling by tocilizumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. This effect on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. A 5% decrease in dextromethorphan exposure and a 29% decrease in its metabolite, dextrorphan was noted 1 week after a single tocilizumab infusion. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Dextromethorphan is a CYP2D6 substrate.
Dextromethorphan: (Minor) Concomitant use of tocilizumab and dextromethorphan may lead to a decrease in the efficacy of dextromethorphan; clinical significance of this interaction is not known or established. Inhibition of IL-6 signaling by tocilizumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. This effect on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. A 5% decrease in dextromethorphan exposure and a 29% decrease in its metabolite, dextrorphan was noted 1 week after a single tocilizumab infusion. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Dextromethorphan is a CYP2D6 substrate.
Dextromethorphan; Bupropion: (Minor) Concomitant use of tocilizumab and dextromethorphan may lead to a decrease in the efficacy of dextromethorphan; clinical significance of this interaction is not known or established. Inhibition of IL-6 signaling by tocilizumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. This effect on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. A 5% decrease in dextromethorphan exposure and a 29% decrease in its metabolite, dextrorphan was noted 1 week after a single tocilizumab infusion. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Dextromethorphan is a CYP2D6 substrate.
Dextromethorphan; Diphenhydramine; Phenylephrine: (Minor) Concomitant use of tocilizumab and dextromethorphan may lead to a decrease in the efficacy of dextromethorphan; clinical significance of this interaction is not known or established. Inhibition of IL-6 signaling by tocilizumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. This effect on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. A 5% decrease in dextromethorphan exposure and a 29% decrease in its metabolite, dextrorphan was noted 1 week after a single tocilizumab infusion. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Dextromethorphan is a CYP2D6 substrate.
Dextromethorphan; Guaifenesin: (Minor) Concomitant use of tocilizumab and dextromethorphan may lead to a decrease in the efficacy of dextromethorphan; clinical significance of this interaction is not known or established. Inhibition of IL-6 signaling by tocilizumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. This effect on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. A 5% decrease in dextromethorphan exposure and a 29% decrease in its metabolite, dextrorphan was noted 1 week after a single tocilizumab infusion. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Dextromethorphan is a CYP2D6 substrate.
Dextromethorphan; Guaifenesin; Phenylephrine: (Minor) Concomitant use of tocilizumab and dextromethorphan may lead to a decrease in the efficacy of dextromethorphan; clinical significance of this interaction is not known or established. Inhibition of IL-6 signaling by tocilizumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. This effect on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. A 5% decrease in dextromethorphan exposure and a 29% decrease in its metabolite, dextrorphan was noted 1 week after a single tocilizumab infusion. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Dextromethorphan is a CYP2D6 substrate.
Dextromethorphan; Guaifenesin; Potassium Guaiacolsulfonate: (Minor) Concomitant use of tocilizumab and dextromethorphan may lead to a decrease in the efficacy of dextromethorphan; clinical significance of this interaction is not known or established. Inhibition of IL-6 signaling by tocilizumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. This effect on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. A 5% decrease in dextromethorphan exposure and a 29% decrease in its metabolite, dextrorphan was noted 1 week after a single tocilizumab infusion. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Dextromethorphan is a CYP2D6 substrate.
Dextromethorphan; Guaifenesin; Pseudoephedrine: (Minor) Concomitant use of tocilizumab and dextromethorphan may lead to a decrease in the efficacy of dextromethorphan; clinical significance of this interaction is not known or established. Inhibition of IL-6 signaling by tocilizumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. This effect on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. A 5% decrease in dextromethorphan exposure and a 29% decrease in its metabolite, dextrorphan was noted 1 week after a single tocilizumab infusion. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Dextromethorphan is a CYP2D6 substrate.
Dextromethorphan; Quinidine: (Moderate) Monitor quinidine levels and adjust the dose of quinidine as appropriate if coadministration with tocilizumab is necessary. Inhibition of IL-6 signaling by tocilizumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as quinidine, may have fluctuations in drug levels and therapeutic effect when tocilizumab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Quinidine is a CYP3A4 substrate and narrow therapeutic index drug. (Minor) Concomitant use of tocilizumab and dextromethorphan may lead to a decrease in the efficacy of dextromethorphan; clinical significance of this interaction is not known or established. Inhibition of IL-6 signaling by tocilizumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. This effect on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. A 5% decrease in dextromethorphan exposure and a 29% decrease in its metabolite, dextrorphan was noted 1 week after a single tocilizumab infusion. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Dextromethorphan is a CYP2D6 substrate.
Ethosuximide: (Moderate) Monitor for reduced efficacy of ethosuximide, monitor drug concentrations, and adjust the dose of ethosuximide as appropriate if coadministration with tocilizumab is necessary. Inhibition of IL-6 signaling by tocilizumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as ethosuximide, may have fluctuations in drug levels and therapeutic effect when tocilizumab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Ethosuximide is a CYP3A4 substrate and narrow therapeutic index drug.
Everolimus: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate if treatment with tocilizumab is initiated for a patient on chronic everolimus therapy. The dose of everolimus may need to be increased. Everolimus is a sensitive CYP3A4 substrate. During chronic inflammation, increased levels of certain cytokines can decrease the formation of CYP450 enzymes. Thus, the formation of CYP3A4 could be normalized during tocilizumab administration. This effect on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. The addition of tocilizumab to everolimus therapy may increase the metabolism of everolimus and decrease everolimus blood concentrations.
Ezetimibe; Simvastatin: (Moderate) Utilize caution with concomitant use of tocilizumab and CYP3A4 substrate drugs, such as simvastatin, where a decrease in effectiveness is undesirable. Monitor lipid panels and adjust therapy as indicated. Inhibition of IL-6 signaling by tocilizumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. This effect on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. A 57% decrease in simvastatin exposure was noted 1 week after a single tocilizumab dose. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Simvastatin is a CYP3A4 substrate.
Fentanyl: (Moderate) Monitor for evidence of reduced pain control or opioid withdrawal if fentanyl coadministration with tocilizumab is necessary; fentanyl dosage adjustment may be needed. Inhibition of IL-6 signaling by sarilumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as fentanyl, may have fluctuations in drug levels and therapeutic effect when sarilumab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping sarilumab. In vitro, sarilumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Fentanyl is a CYP3A4 substrate and narrow therapeutic index drug.
Fosphenytoin: (Moderate) Monitor drug concentrations and watch for decreased efficacy of fosphenytoin if use with tocilizumab is necessary; adjust fosphenytoin dosage as necessary. Inhibition of IL-6 signaling by tocilizumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as fosphenytoin, may have fluctuations in drug levels and therapeutic effect when tocilizumab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Fosphenytoin is a substrate of both CYP2C9 and CYP2C19 and narrow therapeutic index drug.
Hydrocortisone: (Moderate) Closely observe patients for signs of infection. Most patients taking tocilizumab who developed serious infections were taking concomitant immunosuppressives such as systemic corticosteroids.
Intranasal Influenza Vaccine: (Major) Avoid concurrent use of live vaccines during treatment with tocilizumab due to potentially increased risk of infections; clinical safety of live vaccines during tocilizumab treatment has not been established. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving tocilizumab. The interval between live vaccinations and initiation of tocilizumab therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.
Live Vaccines: (Major) Avoid concurrent use of live vaccines during treatment with tocilizumab due to potentially increased risk of infections; clinical safety of live vaccines during tocilizumab treatment has not been established. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving tocilizumab. The interval between live vaccinations and initiation of tocilizumab therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.
Lovastatin: (Moderate) Utilize caution with concomitant use of tocilizumab and CYP3A4 substrate drugs, such as lovastatin, where a decrease in effectiveness is undesirable. Monitor lipid panels and adjust therapy as indicated. Inhibition of IL-6 signaling by tocilizumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. This effect on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. A 57% decrease in the exposure of another "statin" was noted 1 week after a single tocilizumab dose. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Lovastatin is a CYP3A4 substrate.
Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (Major) Avoid concurrent use of live vaccines during treatment with tocilizumab due to potentially increased risk of infections; clinical safety of live vaccines during tocilizumab treatment has not been established. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving tocilizumab. The interval between live vaccinations and initiation of tocilizumab therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.
Measles/Mumps/Rubella Vaccines, MMR: (Major) Avoid concurrent use of live vaccines during treatment with tocilizumab due to potentially increased risk of infections; clinical safety of live vaccines during tocilizumab treatment has not been established. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving tocilizumab. The interval between live vaccinations and initiation of tocilizumab therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.
Niacin; Simvastatin: (Moderate) Utilize caution with concomitant use of tocilizumab and CYP3A4 substrate drugs, such as simvastatin, where a decrease in effectiveness is undesirable. Monitor lipid panels and adjust therapy as indicated. Inhibition of IL-6 signaling by tocilizumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. This effect on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. A 57% decrease in simvastatin exposure was noted 1 week after a single tocilizumab dose. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Simvastatin is a CYP3A4 substrate.
Ofatumumab: (Major) Avoid the concomitant use of ofatumumab and tocilizumab; coadministration has not been studied and may result in additive immunosuppression and an increased risk of infection.
Omeprazole: (Minor) Concomitant use of tocilizumab and omeprazole may lead to a decrease in the efficacy of omeprazole. Inhibition of IL-6 signaling by tocilizumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. This effect on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. A 12 to 28% decrease in omeprazole exposure occurred 1 week after a single tocilizumab dose. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Omeprazole is a substrate of both CYP2C19 and CYP3A4.
Omeprazole; Amoxicillin; Rifabutin: (Minor) Concomitant use of tocilizumab and omeprazole may lead to a decrease in the efficacy of omeprazole. Inhibition of IL-6 signaling by tocilizumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. This effect on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. A 12 to 28% decrease in omeprazole exposure occurred 1 week after a single tocilizumab dose. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Omeprazole is a substrate of both CYP2C19 and CYP3A4.
Omeprazole; Sodium Bicarbonate: (Minor) Concomitant use of tocilizumab and omeprazole may lead to a decrease in the efficacy of omeprazole. Inhibition of IL-6 signaling by tocilizumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. This effect on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. A 12 to 28% decrease in omeprazole exposure occurred 1 week after a single tocilizumab dose. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Omeprazole is a substrate of both CYP2C19 and CYP3A4.
Oral Contraceptives: (Moderate) Utilize caution with concomitant use of tocilizumab and CYP3A4 substrate drugs, such as combined hormonal oral contraceptives, where a decrease in effectiveness is undesirable. Inhibition of IL-6 signaling by tocilizumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. This effect on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4.
Phenytoin: (Moderate) Monitor phenytoin concentrations and watch for decreased efficacy of phenytoin if coadministration with tocilizumab is necessary; adjust phenytoin dosage as necessary. Inhibition of IL-6 signaling by tocilizumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as phenytoin, may have fluctuations in drug levels and therapeutic effect when tocilizumab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Phenytoin is a substrate of both CYP2C9 and CYP2C19 and narrow therapeutic index drug.
Pimozide: (Moderate) Monitor for an altered patient response to pimozide if coadministration with tocilizumab is necessary. Inhibition of IL-6 signaling by tocilizumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as pimozide, may have fluctuations in drug levels and therapeutic effect when tocilizumab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Pimozide is a substrate of both CYP2D6 and CYP3A4 and narrow therapeutic index drug.
Promethazine; Dextromethorphan: (Minor) Concomitant use of tocilizumab and dextromethorphan may lead to a decrease in the efficacy of dextromethorphan; clinical significance of this interaction is not known or established. Inhibition of IL-6 signaling by tocilizumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. This effect on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. A 5% decrease in dextromethorphan exposure and a 29% decrease in its metabolite, dextrorphan was noted 1 week after a single tocilizumab infusion. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Dextromethorphan is a CYP2D6 substrate.
Quinidine: (Moderate) Monitor quinidine levels and adjust the dose of quinidine as appropriate if coadministration with tocilizumab is necessary. Inhibition of IL-6 signaling by tocilizumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as quinidine, may have fluctuations in drug levels and therapeutic effect when tocilizumab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Quinidine is a CYP3A4 substrate and narrow therapeutic index drug.
Rituximab: (Major) Avoid the concomitant use of rituximab and tocilizumab; coadministration has not been studied and may result in additive immunosuppression and an increased risk of infection.
Rituximab; Hyaluronidase: (Major) Avoid the concomitant use of rituximab and tocilizumab; coadministration has not been studied and may result in additive immunosuppression and an increased risk of infection.
Rivaroxaban: (Moderate) Monitor for a decrease in efficacy of rivaroxaban if used with tocilizumab. Until more data are available, consider using an anticoagulant without dependence on CYP450 enzymes for metabolism (e.g., heparins, edoxaban). The formation of CYP450 enzymes may be suppressed by increased concentrations of cytokines such as IL-6 during chronic inflammation. It is expected that the activity of CYP450 enzymes could increase to normal concentrations during treatment with an IL-6 antagonist such as tocilizumab; these effects on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes [including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4]. Rivaroxaban is a substrate for CYP3A4/5.
Rotavirus Vaccine: (Major) Avoid concurrent use of live vaccines during treatment with tocilizumab due to potentially increased risk of infections; clinical safety of live vaccines during tocilizumab treatment has not been established. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving tocilizumab. The interval between live vaccinations and initiation of tocilizumab therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.
Sarilumab: (Major) Avoid using sarilumab with other biological DMARDs, such as tocilizumab; coadministration has not been studied and may result in additive immunosuppression and increased risk of infection.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Secukinumab: (Major) Avoid using tocilizumab with other biological DMARDs, such as secukinumab; coadministration has not been studied and may result in additive immunosuppression and increased risk of infection.
Simvastatin: (Moderate) Utilize caution with concomitant use of tocilizumab and CYP3A4 substrate drugs, such as simvastatin, where a decrease in effectiveness is undesirable. Monitor lipid panels and adjust therapy as indicated. Inhibition of IL-6 signaling by tocilizumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. This effect on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. A 57% decrease in simvastatin exposure was noted 1 week after a single tocilizumab dose. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Simvastatin is a CYP3A4 substrate.
Smallpox and Monkeypox Vaccine, Live, Nonreplicating: (Major) Avoid concurrent use of live vaccines during treatment with tocilizumab due to potentially increased risk of infections; clinical safety of live vaccines during tocilizumab treatment has not been established. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving tocilizumab. The interval between live vaccinations and initiation of tocilizumab therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.
Smallpox Vaccine, Vaccinia Vaccine: (Major) Avoid concurrent use of live vaccines during treatment with tocilizumab due to potentially increased risk of infections; clinical safety of live vaccines during tocilizumab treatment has not been established. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving tocilizumab. The interval between live vaccinations and initiation of tocilizumab therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.
Tacrolimus: (Moderate) Monitor tacrolimus levels and adjust the dose of tacrolimus as appropriate if coadministration with tocilizumab is necessary. Inhibition of IL-6 signaling by tocilizumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as tacrolimus, may have fluctuations in drug levels and therapeutic effect when tocilizumab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Tacrolimus is a CYP3A4 substrate and narrow therapeutic index drug.
Theophylline, Aminophylline: (Moderate) Monitor drug concentrations and watch for decreased efficacy of aminophylline or theophylline if coadministration with tocilizumab is necessary; a dosage increase of these methylxanthines may be necessary. Inhibition of IL-6 signaling by tocilizumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index may have fluctuations in drug levels and therapeutic effect when tocilizumab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Aminophylline and Theophylline are CYP1A2 substrates and narrow therapeutic index drugs.
Thioridazine: (Moderate) Monitor for an altered patient response to thioridazine if coadministration with tocilizumab is necessary. Inhibition of IL-6 signaling by tocilizumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as thioridazine, may have fluctuations in drug levels and therapeutic effect when tocilizumab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Thioridazine is a CYP2D6 substrate and narrow therapeutic index drug.
Tizanidine: (Moderate) Monitor for reduced efficacy of tizanidine if coadministered with tocilizumab. An adjustment of tizanidine dose may be required. Inhibition of IL-6 signaling by tocilizumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as tizanidine, may have fluctuations in drug levels and therapeutic effect when tocilizumab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Tizanidine is a CYP1A2 substrate and narrow therapeutic index drug.
Tofacitinib: (Major) Avoid the concomitant use of tocilizumab with other biological DMARDs such as tofacitinib; coadministration has not been studied and may result in additive immunosuppression and increased risk of infection.
Tumor Necrosis Factor modifiers: (Major) Avoid the concomitant use of tocilizumab with biological DMARDs, such as tumor necrosis factor (TNF) modifiers; coadministration has not been studied and may result in additive immunosuppression and increased risk of infection.
Typhoid Vaccine: (Major) Avoid concurrent use of live vaccines during treatment with tocilizumab due to potentially increased risk of infections; clinical safety of live vaccines during tocilizumab treatment has not been established. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving tocilizumab. The interval between live vaccinations and initiation of tocilizumab therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.
Upadacitinib: (Major) Avoid the concomitant use of tocilizumab with other biological DMARDs such as upadacitinib; coadministration has not been studied and may result in additive immunosuppression and increased risk of infection.
Ustekinumab: (Major) Avoid the concomitant use of tocilizumab with other biological DMARDs such as ustekinumab; coadministration has not been studied and may result in additive immunosuppression and increased risk of infection.
Varicella-Zoster Virus Vaccine, Live: (Major) Avoid concurrent use of live vaccines during treatment with tocilizumab due to potentially increased risk of infections; clinical safety of live vaccines during tocilizumab treatment has not been established. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving tocilizumab. The interval between live vaccinations and initiation of tocilizumab therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.
Warfarin: (Moderate) Monitor the INR if tocilizumab is coadministered with warfarin due to the potential for decreased warfarin efficacy; adjust the dose of warfarin as necessary. Inhibition of IL-6 signaling by tocilizumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as warfarin, may have fluctuations in drug levels and therapeutic effect when tocilizumab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab.
Yellow Fever Vaccine, Live: (Major) Avoid concurrent use of live vaccines during treatment with tocilizumab due to potentially increased risk of infections; clinical safety of live vaccines during tocilizumab treatment has not been established. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving tocilizumab. The interval between live vaccinations and initiation of tocilizumab therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.

Actemra Intravenous Inj Sol: 1mL, 20mg
Actemra Subcutaneous Sol: 0.9mL, 162mg

Rheumatoid arthritis, weighing more than 100 kg: 800 mg per dose IV or 162 mg per dose subcutaneously.
Rheumatoid arthritis, weighing 100 kg or less: 8 mg/kg per dose IV or 162 mg per dose subcutaneously.
Giant cell arteritis, weighing more than 100 kg: 600 mg per dose IV or 162 mg per dose subcutaneously.
Giant cell arteritis, weighing 100 kg or less: 6 mg/kg per dose IV or 162 mg per dose subcutaneously.
Systemic sclerosis-associated interstitial lung disease: 162 mg per dose subcutaneously.
Cytokine Release Syndrome (CRS), weighing 30 kg or more: 800 mg per dose IV.
CRS, weighing less than 30 kg: 12 mg/kg IV.
COVID-19, weighing more than 100 kg: 800 mg per dose IV.
COVID-19, weighing 100 kg or less: 8 mg/kg per dose IV.

Rheumatoid arthritis, weighing more than 100 kg: 800 mg per dose IV or 162 mg per dose subcutaneously.
Rheumatoid arthritis, weighing 100 kg or less: 8 mg/kg per dose IV or 162 mg per dose subcutaneously.
Giant cell arteritis, weighing more than 100 kg: 600 mg per dose IV or 162 mg per dose subcutaneously.
Giant cell arteritis, weighing 100 kg or less: 6 mg/kg per dose IV or 162 mg per dose subcutaneously.
Systemic sclerosis-associated interstitial lung disease: 162 mg per dose subcutaneously.
Cytokine Release Syndrome (CRS), weighing 30 kg or more: 800 mg per dose IV.
CRS, weighing less than 30 kg: 12 mg/kg IV.
COVID-19, weighing more than 100 kg: 800 mg per dose IV.
COVID-19, weighing 100 kg or less: 8 mg/kg per dose IV.

Weighing 30 kg or more: 8 mg/kg per dose IV and 162 mg per dose subcutaneously.
Weighing less than 30 kg: 12 mg/kg per dose IV for systemic juvenile idiopathic arthritis (SJIA) and cytokine release syndrome (CRS); 10 mg/kg per dose IV for polyarticular juvenile idiopathic arthritis (PJIA); 162 mg per dose subcutaneously for SJIA and PJIA.
COVID-19 per the Emergency Use Authorization, weighing more than 100 kg: 800 mg per dose IV.
COVID-19 per the Emergency Use Authorization, weighing 30 to 100 kg: 8 mg/kg per dose IV.
COVID-19 per the Emergency Use Authorization, weighing less than 30 kg: 12 mg/kg per dose IV.

2 to 12 years weighing 30 kg or more: 8 mg/kg per dose IV and 162 mg per dose subcutaneously.
2 to 12 years weighing less than 30 kg: 12 mg/kg per dose IV for systemic juvenile idiopathic arthritis (SJIA) and cytokine release syndrome (CRS); 10 mg/kg per dose IV for polyarticular juvenile idiopathic arthritis (PJIA); 162 mg per dose subcutaneously for SJIA and PJIA.
COVID-19 per the Emergency Use Authorization, 2 to 12 years weighing more than 100 kg: 800 mg per dose IV.
COVID-19 per the Emergency Use Authorization, 2 to 12 years weighing 30 to 100 kg: 8 mg/kg per dose IV.
COVID-19 per the Emergency Use Authorization, 2 to 12 years weighing less than 30 kg: 12 mg/kg per dose IV.
Less than 2 years: Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Tocilizumab inhibits IL-6-mediated signaling by competitively binding to both soluble and membrane-bound IL-6 receptors. IL-6 is a proinflammatory cytokine that is involved in diverse physiological processes such as T-cell activation, immunoglobulin secretion induction, hepatic acute-phase protein synthesis initiation, and hematopoietic precursor cell proliferation and differentiation stimulation. IL-6 is produced by various cell types, including T- and B-cells, lymphocytes, monocytes, and fibroblasts. IL-6 is also produced by synovial and endothelial cells leading to local production of IL-6 in joints affected by inflammatory processes such as rheumatoid arthritis.[38283]

Tocilizumab is administered subcutaneously or intravenously as an infusion. The pharmacokinetics of tocilizumab are characterized by nonlinear elimination which is a combination of linear clearance and Michaelis-Menten elimination. The nonlinear part of tocilizumab elimination leads to an increase in exposure that is more than dose-proportional. The pharmacokinetic parameters of tocilizumab do not change with time. Due to the dependence of total clearance on tocilizumab serum concentrations, the half-life of tocilizumab is also concentration-dependent and varies depending on the serum concentration level. At higher concentrations, clearance is mainly determined by the linear clearance, which was estimated to be 12.5 mL/hour. Linear clearance increases with body size. The concentration-dependent nonlinear clearance plays a major role at low concentrations. The half-life of tocilizumab is dependent on the concentration.[38283]
 
The pharmacokinetics of tocilizumab in adults with COVID-19 was estimated by a population pharmacokinetic analysis of 380 patients treated with intravenous doses of 8 mg/kg. The volume of distribution (Vd) was 8.75 L (4.52 central Vd and 4.23 peripheral Vd). The average linear clearance in the population pharmacokinetic analysis was estimated to be 17.6 mL/hour in patients with baseline ordinal scale (OS) category 3 (i.e., patients requiring supplemental oxygen), 22.5 mL/hour in patients with baseline OS category 4 (i.e., patients requiring high-flow oxygen or noninvasive ventilation), 29 mL/hour in patients with baseline OS category 5 (i.e., patients requiring mechanical ventilation), and 35.4 mL/hour in patients with baseline OS category 6 (i.e., patients requiring ECMO or mechanical ventilation plus additional organ support). Following a single 8 mg/kg infusion, the serum concentrations were below the limit of quantification after 35 days on average.
 
A population pharmacokinetic model, based on data in rheumatoid arthritis patients who received either intravenous or subcutaneous tocilizumab, found a terminal half-life of approximately 21.5 days at high serum concentrations and linear clearance of tocilizumab. Among adult patients with rheumatoid arthritis (RA), the tocilizumab Vd at steady-state was 6.4 L: the central Vd was 3.5 L, and the peripheral Vd was 2.9 L. For patients with rheumatoid arthritis, the concentration-dependent apparent half-life at steady-state is up to 11 days for 4 mg/kg/dose IV, up to 13 days for 8 mg/kg/dose IV every 4 weeks, up to 13 days for 162 mg subcutaneously every week, and 5 days for 162 mg subcutaneously every other week. For adults with giant cell arteritis (GCA) at steady-state, the effective half-life for 162 mg subcutaneously every week and every other week was 18.3 to 18.9 days and 4.2 to 7.9 days, respectively. Following 6 mg/kg IV every 4 weeks to GCA patients, the concentration-dependent apparent half-life was 13.2 days. In GCA patients, the Vd at steady-state was 7.46 L: central Vd was 4.09 L and peripheral Vd was 3.37 L. For adults with systemic sclerosis-associated interstitial lung disease (SSc-ILD) at steady-state, the effective half-life for 162 mg subcutaneously every week was between 12.1 to 13 days. In SSc-ILD patients, the Vd at steady-state was 6.74 L: central Vd was 4.16 L and peripheral Vd was 2.58L.[38283]
 
Decreases in C-reactive protein to within normal ranges were seen as early as week 2 after tocilizumab 4 mg/kg/dose or 8 mg/kg/dose initiation in adults with RA. Decreases in rheumatoid factor, erythrocyte sedimentation rate, serum amyloid A, fibrinogen, and increases in hemoglobin were noted with both tocilizumab doses, but the greatest improvements were noted with the 8 mg/kg dose. Population pharmacokinetic analyses in any patient population tested so far indicate no relationship between apparent clearance and the presence of anti-drug antibodies.[38283]
 
Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: Unknown, possibly influences CYP enzyme activity
In vitro data suggest that IL-6 reduces mRNA expression for several CYP450 isoenzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4, and this reduced expression was reversed by coincubation with tocilizumab at clinically relevant concentrations. Accordingly, inhibition of IL-6 signaling in patients treated with tocilizumab may restore CYP450 activities to higher levels than those in the absence of the drug, leading to increased metabolism of drugs that are CYP450 substrates. The drug's effect on CYP2C8 or drug transporters (e.g., P-glycoprotein) is unknown.[38283]
 
The restoration of CYP450 enzyme activities may be clinically relevant for CYP450 substrate drugs with a narrow therapeutic index (NTI), where the dose is individually adjusted. Upon initiation of tocilizumab, therapeutic monitoring of the effect or drug concentration of the NTI drug should be performed; adjust the dose of the NTI drug as needed. Caution should be exercised when tocilizumab is coadministered with drugs where a decrease in effectiveness is undesirable (e.g., oral contraceptives, which are CYP3A4 substrates). The effect of tocilizumab on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab.[38283]

The pharmacokinetics of tocilizumab in adults with COVID-19 was estimated by a population pharmacokinetic analysis of 380 patients treated with intravenous doses of 8 mg/kg. The estimated median maximum plasma concentration (Cmax) and Cmax on day 28 were 151 mcg/mL (range: 77.5 to 319 mcg/mL) and 0.229 mcg/mL (range: 0.00119 to 19.4 mcg/mL), respectively, after a single dose. After 2 doses, separated by 8 hours, the estimated median Cmax was 290 mcg/mL (range: 152 to 604 mcg/mL) and the Cmax on day 28 was 7.04 mcg/mL (0.00474 to 54.8 mcg/mL).
 
After receipt of either 4 mg/kg/dose IV or 8 mg/kg/dose IV every 4 weeks, a more than dose-proportional increase in systemic exposure and in the trough concentration was noted in rheumatoid arthritis (RA) patients. At steady-state, the mean concentration with 8 mg/kg dosing was 3-fold higher than the systemic exposure after 4 mg/kg dosing. The trough concentration at steady-state with 8 mg/kg dosing was 134-fold higher than the trough concentration after 4 mg/kg dosing. In contrast, the maximum tocilizumab concentration (Cmax) increased dose-proportionally. After 4 mg/kg/dose IV every 4 weeks, the estimated median (range) Cmean at steady-state was 18 mcg/mL (8.9 to 50.7 mcg/mL), the median (range) steady-state Cmin was 0.1 mcg/mL (0.0 to 14.6 mcg/mL), and the median (range) steady-state Cmax was 86.1 mcg/mL (44.8 to 202 mcg/mL). Ninety percent of steady-state was reached after the first dose for Cmax and AUC and after the fourth dose for Cmin. After 8 mg/kg/dose IV every 4 weeks, the median (range) Cmean at steady-state was 54 mcg/mL (17 to 260 mcg/mL), the median (range) Cmin at steady-state 13.4 mcg/mL (0.1 to 154 mcg/mL), and median (range) Cmax at steady-state was 176 mcg/mL (75.4 to 557 mcg/mL). Approximately 90% of steady-state was reached after the first dose for Cmax, after the third dose for AUC, and after the fourth dose for Cmin. In a non-compartmental pharmacokinetic analysis of 22 giant cell arteritis (GCA) patients treated with 6 mg/kg IV every 4 weeks, the median (range) Cmax, Ctrough, and Cmean at steady-state were 178 mcg/mL (115 to 320 mcg/mL), 22.7 mcg/mL (3.38 to 54.5 mcg/mL), and 57.5 mcg/mL (32.9 to 110 mcg/mL), respectively. Steady-state trough concentrations with IV tocilizumab were within range of those seen in GCA patients treated with 162 mg subcutaneously every week or every other week. Based on pharmacokinetic exposure and extrapolation between RA and GCA patients, when tocilizumab is given on a mg/kg basis, doses greater than 600 mg per infusion are not recommended in GCA patients.[38283]

After weekly or every other week of 162 mg subcutaneous tocilizumab receipt to patients with rheumatoid arthritis (RA), steady-state was achieved after 10 weeks and 12 weeks, respectively. At steady state, the estimated median (range) Cmean was 47.3 mcg/mL (2.4 to 147 mcg/mL), Cmin was 42.9 mcg/mL (1.3 to 144 mcg/mL), and Cmax was 49.8 mcg/mL (3 to 150 mcg/mL) with once-weekly subcutaneous dosing. After every other week subcutaneous dosing, the estimated median (range) Cmean was 9.2 mcg/mL (0.2 to 43.6 mcg/mL), Cmin was 4.1 mcg/mL (0.0 to 34.2 mcg/mL), and Cmax was 12.1 mcg/mL (0.4 to 49.3 mcg/mL) at steady-state. Systemic exposures with once-weekly dosing were 5.1-fold higher for Cmean and 10.5-fold higher for Cmin compared to every other week dosing. Accumulation for Cmin was greater following subcutaneous, both once weekly and every other week regimens, compared to intravenous administration and is expected based on the non-linear clearance at lower concentrations. Greater than 90% of the steady-state value for Cmax was achieved after the fifth dose with the once-weekly regimen and 12th dose with every other week regimen. Ninety percent of the steady-state values for the Cmean and Cmin were achieved after the 6th and 12th injections, for the every other week and once-weekly regimens, respectively.[38283]
 
In patients, at steady-state, with giant cell arteritis (GCA) who received 162 mg tocilizumab subcutaneously every week, the estimated median (range) Cmax was 72.1 mcg/mL (12.2 to 151 mcg/mL), Cmin was 67.2 mcg/mL (10.7 to 145 mcg/mL), and Cmean was 70.6 mcg/mL (11.7 to 149 mcg/mL). For patients at steady-state who received 162 mg every other week, the estimated median (range) Cmax, Cmin, and Cmean were 17.2 mcg/mL (1.1 to 56.2 mcg/mL), 7.7 mcg/mL (0.1 to 37.3 mcg/mL), and 13.7 mcg/mL (0.5 to 49 mcg/mL), respectively. Steady-state was reached at 17 weeks and 14 weeks following once weekly and every other week dosing regimens, respectively.[38283]
 
Following administration of 162 mg tocilizumab subcutaneously every week for systemic sclerosis-associated interstitial lung disease, the estimated median (range) Cmax was 52.5 mcg/mL (14.8 to 121 mcg/mL), Cmin was 47.2 mcg/mL (10.8 to 114 mcg/mL), and Cmean was 50.4 mcg/mL (13.4 to 119 mcg/mL) at steady-state. Steady-state was reached after 13 weeks of therapy. The accumulation ratios for Cmean, Cmin, and Cmax were 7.11, 6.56, and 5.89, respectively.

Limited available data are not sufficient to determine whether the use of tocilizumab during human pregnancy is associated with risk for major birth defects or miscarriage. Based on animal data, there may be a potential risk to the fetus. In animal reproduction studies, intravenous administration of tocilizumab to Cynomolgus monkeys during organogenesis resulted in abortion/embryo-fetal death at doses 1.25-times or more of the maximum recommended human dose (MRHD). Monoclonal antibodies, like tocilizumab, are increasingly transported across the placenta as pregnancy progresses, with the largest amount transferred during the third trimester. This may affect the immune response in the in utero exposed infant; consider risks and benefits before administering live or live-attenuated vaccines to neonates or infants exposed to tocilizumab in utero.[38283] Due to limited data during pregnancy, guidelines state that tocilizumab should be replaced before conception by another medication, if possible. The drug should be used during pregnancy only when no other pregnancy-compatible drug can effectively control the maternal disease.[62180] For COVID-19, the National Institutes of Health (NIH) states that the decision to administer tocilizumab to a pregnant patient must be shared between the patient and their healthcare providers, and that potential maternal benefit and fetal risks must be considered. Tocilizumab may affect labor and obstetric delivery. Inhibition of IL-6 signaling may interfere with cervical ripening and dilatation and myometrial contractile activity, leading to potential delays in parturition. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to tocilizumab; information about the registry can be obtained at mothertobaby.org/ongoing-study/actemra/ or by calling 1-877-311-8972.[38283]