Dosage & Administration
For RA, pJIA and sJIA, ACTEMRA may be used alone or in combination with methotrexate: and in RA, other non-biologic DMARDs may be used.
General Administration and Dosing Information
Rheumatoid Arthritis
Recommended Adult Intravenous Dosage:
When used in combination with non-biologic DMARDs or as monotherapy the recommended starting dose is 4 mg per kg every 4 weeks followed by an increase to 8 mg per kg every 4 weeks based on clinical response.
Recommended Adult Subcutaneous Dosage:
| Patients less than 100 kg weight | 162 mg administered subcutaneously every other week, followed by an increase to every week based on clinical response |
| Patients at or above 100 kg weight | 162 mg administered subcutaneously every week |
Giant Cell Arteritis
Recommended Adult Intravenous Dosage:
The recommended dose is 6 mg per kg every 4 weeks in combination with a tapering course of glucocorticoids. ACTEMRA can be used alone following discontinuation of glucocorticoids.
Recommended Adult Subcutaneous Dosage:
The recommended dose is 162 mg given once every week as a subcutaneous injection, in combination with a tapering course of glucocorticoids.
A dose of 162 mg given once every other week as a subcutaneous injection, in combination with a tapering course of glucocorticoids, may be prescribed based on clinical considerations.
ACTEMRA can be used alone following discontinuation of glucocorticoids.
Systemic Sclerosis-Associated Interstitial Lung Disease (SSc-ILD)
Recommended Adult Subcutaneous Dosage:
The recommended dose of ACTEMRA for adult patients with SSc-ILD is 162 mg given once every week as a subcutaneous injection.
Polyarticular Juvenile Idiopathic Arthritis
| Recommended Intravenous PJIA Dosage Every 4 Weeks | |
|---|---|
| Patients less than 30 kg weight | 10 mg per kg |
| Patients at or above 30 kg weight | 8 mg per kg |
| Recommended Subcutaneous PJIA Dosage | |
|---|---|
| Patients less than 30 kg weight | 162 mg once every three weeks |
| Patients at or above 30 kg weight | 162 mg once every two weeks |
Systemic Juvenile Idiopathic Arthritis
| Recommended Intravenous SJIA Dosage Every 2 Weeks | |
|---|---|
| Patients less than 30 kg weight | 12 mg per kg |
| Patients at or above 30 kg weight | 8 mg per kg |
| Recommended Subcutaneous SJIA Dosage | |
|---|---|
| Patients less than 30 kg weight | 162 mg every two weeks |
| Patients at or above 30 kg weight | 162 mg every week |
Cytokine Release Syndrome
| Recommended Intravenous CRS Dosage | |
|---|---|
| Patients less than 30 kg weight | 12 mg per kg |
| Patients at or above 30 kg weight | 8 mg per kg |
| Alone or in combination with corticosteroids. | |
Coronavirus Disease 2019
The recommended dosage of ACTEMRA for adult patients with COVID-19 is 8 mg per kg administered by a 60-minute intravenous infusion.
Administration of Intravenous formulation
Administration of Subcutaneous formulation
Dose Modifications
By using PrescriberAI, you agree to the AI Terms of Use.
Actemra Prescribing Information
Patients treated with ACTEMRA are at increased risk for developing serious infections that may lead to hospitalization or death [see Warnings and Precautions (5.1), Adverse Reactions (6.1)]. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.
If a serious infection develops, interrupt ACTEMRA until the infection is controlled.
Reported infections include:
- Active tuberculosis, which may present with pulmonary or extrapulmonary disease. Patients, except those with COVID-19, should be tested for latent tuberculosis before ACTEMRA use and during therapy. Treatment for latent infection should be initiated prior to ACTEMRA use.
- Invasive fungal infections, including candidiasis, aspergillosis, and pneumocystis. Patients with invasive fungal infections may present with disseminated, rather than localized, disease.
- Bacterial, viral and other infections due to opportunistic pathogens.
The risks and benefits of treatment with ACTEMRA should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection.
Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with ACTEMRA, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy [see Warnings and Precautions (5.1)].
Rheumatoid Arthritis (RA)
ACTEMRA® (tocilizumab) is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more Disease-Modifying Anti-Rheumatic Drugs (DMARDs).
Giant Cell Arteritis (GCA)
ACTEMRA® (tocilizumab) is indicated for the treatment of giant cell arteritis (GCA) in adult patients.
Systemic Sclerosis-Associated Interstitial Lung Disease (SSc-ILD)
ACTEMRA® (tocilizumab) is indicated for slowing the rate of decline in pulmonary function in adult patients with systemic sclerosis-associated interstitial lung disease.
Polyarticular Juvenile Idiopathic Arthritis (PJIA)
ACTEMRA® (tocilizumab) is indicated for the treatment of active polyarticular juvenile idiopathic arthritis in patients 2 years of age and older.
Systemic Juvenile Idiopathic Arthritis (SJIA)
ACTEMRA® (tocilizumab) is indicated for the treatment of active systemic juvenile idiopathic arthritis in patients 2 years of age and older.
Cytokine Release Syndrome (CRS)
ACTEMRA® (tocilizumab) is indicated for the treatment of chimeric antigen receptor (CAR) T cell-induced severe or life-threatening cytokine release syndrome in adults and pediatric patients 2 years of age and older.
Coronavirus Disease 2019 (COVID-19)
ACTEMRA® (tocilizumab) is indicated for the treatment of coronavirus disease 2019 (COVID-19) in hospitalized adult patients who are receiving systemic corticosteroids and require supplemental oxygen, non-invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO).
General Considerations for Administration
Not Recommended for Concomitant Use with Biological DMARDs
ACTEMRA has not been studied in combination with biological DMARDs such as TNF antagonists, IL-1R antagonists, anti-CD20 monoclonal antibodies and selective co-stimulation modulators because of the possibility of increased immunosuppression and increased risk of infection. Avoid using ACTEMRA with biological DMARDs.
Baseline Laboratory Evaluation Prior to Treatment
Obtain and assess baseline complete blood count (CBC) and liver function tests prior to treatment.
- RA, GCA, SSc-ILD, PJIA and SJIA – It is recommended that ACTEMRA not be initiated in patients with an absolute neutrophil count (ANC) below 2000 per mm3, platelet count below 100,000 per mm3, or ALT or AST above 1.5 times the upper limit of normal (ULN) [see Warnings and Precautions (5.3, 5.4)].
- CRS – Patients with severe or life-threatening CRS frequently have cytopenias or elevated ALT or AST due to the lymphodepleting chemotherapy or the CRS. The decision to administer ACTEMRA should take into account the potential benefit of treating the CRS versus the risks of short-term treatment with ACTEMRA.
- COVID-19 – It is recommended that ACTEMRA not be initiated in patients with an absolute neutrophil count (ANC) below 1000 per mm3, platelet count below 50,000 mm3, or ALT or AST above 10 times ULN [see Warnings and Precautions (5.3, 5.4)].
Recommended Dosage for Rheumatoid Arthritis
ACTEMRA may be used as monotherapy or concomitantly with methotrexate or other non-biologic DMARDs as an intravenous infusion or as a subcutaneous injection.
Recommended Intravenous Dosage Regimen:
The recommended dosage of ACTEMRA for adult patients given as a 60-minute single intravenous drip infusion is 4 mg per kg every 4 weeks followed by an increase to 8 mg per kg every 4 weeks based on clinical response.
- Reduction of dose from 8 mg per kg to 4 mg per kg is recommended for management of certain dose-related laboratory changes including elevated liver enzymes, neutropenia, and thrombocytopenia [see Dosage and Administration (2.11), Warnings and Precautions (5.3, 5.4), and Adverse Reactions (6.1)].
- Doses exceeding 800 mg per infusion are not recommended in RA patients [see Clinical Pharmacology (12.3)].
Recommended Subcutaneous Dosage Regimen:
| Patients less than 100 kg weight | 162 mg administered subcutaneously every other week, followed by an increase to every week based on clinical response |
| Patients at or above 100 kg weight | 162 mg administered subcutaneously every week |
When transitioning from ACTEMRA intravenous therapy to subcutaneous administration administer the first subcutaneous dose instead of the next scheduled intravenous dose.
Interruption of dose or reduction in frequency of administration of subcutaneous dose from every week to every other week dosing is recommended for management of certain dose-related laboratory changes including elevated liver enzymes, neutropenia, and thrombocytopenia [see Dosage and Administration (2.11), Warnings and Precautions (5.3, 5.4), and Adverse Reactions (6.2)].
Recommended Dosage for Giant Cell Arteritis
Recommended Intravenous Dosage Regimen:
The recommended dosage of ACTEMRA for adult patients given as a 60-minute single intravenous drip infusion is 6 mg per kg every 4 weeks in combination with tapering course of glucocorticoids.
ACTEMRA can be used alone following discontinuation of glucocorticoids.
- Interruption of dosing may be needed for management of dose-related laboratory abnormalities including elevated liver enzymes, neutropenia, and thrombocytopenia [see Dosage and Administration (2.11)].
- Doses exceeding 600 mg per infusion are not recommended in GCA patients [see Clinical Pharmacology (12.3)].
Recommended Subcutaneous Dosage Regimen:
The recommended dose of ACTEMRA for adult patients with GCA is 162 mg given once every week as a subcutaneous injection in combination with a tapering course of glucocorticoids.
A dose of 162 mg given once every other week as a subcutaneous injection in combination with a tapering course of glucocorticoids may be prescribed based on clinical considerations.
ACTEMRA can be used alone following discontinuation of glucocorticoids.
When transitioning from ACTEMRA intravenous therapy to subcutaneous administration, administer the first subcutaneous dose instead of the next scheduled intravenous dose.
Interruption of dose or reduction in frequency of administration of subcutaneous dose from every week to every other week dosing may be needed for management of dose-related laboratory abnormalities including elevated liver enzymes, neutropenia, and thrombocytopenia [see Dosage and Administration (2.11)].
Recommended Dosage for Systemic Sclerosis-Associated Interstitial Lung Disease
The recommended dose of ACTEMRA for adult patients with SSc-ILD is 162 mg given once every week as a subcutaneous injection.
- Interruption of dosing may be needed for management of dose-related laboratory abnormalities including elevated liver enzymes, neutropenia, and thrombocytopenia [see Dosage and Administration (2.11)].
- Subcutaneous administration with the prefilled ACTPen® autoinjector has not been studied in SSc-ILD.
- Intravenous administration is not approved for SSc-ILD.
Recommended Dosage for Polyarticular Juvenile Idiopathic Arthritis
ACTEMRA may be used as an intravenous infusion or as a subcutaneous injection alone or in combination with methotrexate. Do not change dose based solely on a single visit body weight measurement, as weight may fluctuate.
Recommended Intravenous Dosage Regimen:
The recommended dosage of ACTEMRA for PJIA patients given once every 4 weeks as a 60-minute single intravenous drip infusion is:
| Recommended Intravenous PJIA Dosage Every 4 Weeks | |
|---|---|
| Patients less than 30 kg weight | 10 mg per kg |
| Patients at or above 30 kg weight | 8 mg per kg |
Recommended Subcutaneous Dosage Regimen:
| Recommended Subcutaneous PJIA Dosage | |
|---|---|
| Patients less than 30 kg weight | 162 mg once every 3 weeks |
| Patients at or above 30 kg weight | 162 mg once every 2 weeks |
When transitioning from ACTEMRA intravenous therapy to subcutaneous administration, administer the first subcutaneous dose instead of the next scheduled intravenous dose.
Interruption of dosing may be needed for management of dose-related laboratory abnormalities including elevated liver enzymes, neutropenia, and thrombocytopenia [see Dosage and Administration (2.11].
Recommended Dosage for Systemic Juvenile Idiopathic Arthritis
ACTEMRA may be used as an intravenous infusion or as a subcutaneous injection alone or in combination with methotrexate. Do not change a dose based solely on a single visit body weight measurement, as weight may fluctuate.
Recommended Intravenous Dosage Regimen:
The recommended dose of ACTEMRA for SJIA patients given once every 2 weeks as a 60-minute single intravenous drip infusion is:
| Recommended Intravenous SJIA Dosage Every 2 Weeks | |
|---|---|
| Patients less than 30 kg weight | 12 mg per kg |
| Patients at or above 30 kg weight | 8 mg per kg |
Recommended Subcutaneous Dosage Regimen:
| Recommended Subcutaneous SJIA Dosage | |
|---|---|
| Patients less than 30 kg weight | 162 mg once every two weeks |
| Patients at or above 30 kg weight | 162 mg once every week |
When transitioning from ACTEMRA intravenous therapy to subcutaneous administration, administer the first subcutaneous dose when the next scheduled intravenous dose is due.
Interruption of dosing may be needed for management of dose-related laboratory abnormalities including elevated liver enzymes, neutropenia, and thrombocytopenia [see Dosage and Administration (2.11)].
Recommended Dosage for Cytokine Release Syndrome (CRS)
Use only the intravenous route for treatment of CRS. The recommended dose of ACTEMRA for treatment of CRS given as a 60-minute intravenous infusion is:
| Recommended Intravenous CRS Dosage | |
|---|---|
| Patients less than 30 kg weight | 12 mg per kg |
| Patients at or above 30 kg weight | 8 mg per kg |
| Alone or in combination with corticosteroids | |
- If no clinical improvement in the signs and symptoms of CRS occurs after the first dose, up to 3 additional doses of ACTEMRA may be administered. The interval between consecutive doses should be at least 8 hours.
- Doses exceeding 800 mg per infusion are not recommended in CRS patients.
- Subcutaneous administration is not approved for CRS.
Coronavirus Disease 2019 (COVID-19)
Administer ACTEMRA by intravenous infusion only.
The recommended dosage of ACTEMRA for treatment of adult patients with COVID-19 is 8 mg per kg administered as a single 60-minute intravenous infusion. If clinical signs or symptoms worsen or do not improve after the first dose, one additional infusion of ACTEMRA may be administered at least 8 hours after the initial infusion.
- Doses exceeding 800 mg per infusion are not recommended in patients with COVID-19.
- Subcutaneous administration is not approved for COVID-19.
Preparation and Administration Instructions for Intravenous Infusion
ACTEMRA for intravenous infusion should be diluted by a healthcare professional using aseptic technique as follows:
- Use a sterile needle and syringe to prepare ACTEMRA.
- Patients less than 30 kg: use a 50 mL infusion bag or bottle of 0.9% or 0.45% Sodium Chloride Injection, USP, and then follow steps 1 and 2 below.
- Patients at or above 30 kg weight: use a 100 mL infusion bag or bottle, and then follow steps 1 and 2 below.
- Step 1. Withdraw a volume of 0.9% or 0.45% Sodium Chloride Injection, USP, equal to the volume of the ACTEMRA injection required for the patient's dose from the infusion bag or bottle [see Dosage and Administration (2.2, 2.5, 2.6, 2.7)].
| For Intravenous Use: Volume of ACTEMRA Injection per kg of Body Weight | ||
|---|---|---|
| Dosage | Indication | Volume of ACTEMRA injection per kg of body weight |
| 4 mg/kg | Adult RA | 0.2 mL/kg |
| 6 mg/kg | Adult GCA | 0.3 mL/kg |
| 8 mg/kg | Adult RA Adult COVID-19 SJIA, PJIA and CRS (greater than or equal to 30 kg of body weight) | 0.4 mL/kg |
| 10 mg/kg | PJIA (less than 30 kg of body weight) | 0.5 mL/kg |
| 12 mg/kg | SJIA and CRS (less than 30 kg of body weight) | 0.6 mL/kg |
- Step 2. Withdraw the amount of ACTEMRA for intravenous infusion from the vial(s) and add slowly into the 0.9% or 0.45% Sodium Chloride Injection, USP infusion bag or bottle. To mix the solution, gently invert the bag to avoid foaming.
- The fully diluted ACTEMRA solutions for infusion using 0.9% Sodium Chloride Injection, USP may be stored at 36°F to 46°F (2°C to 8°C) or room temperature for up to 24 hours and should be protected from light.
- The fully diluted ACTEMRA solutions for infusion using 0.45% Sodium Chloride Injection, USP may be stored at 36°F to 46°F (2°C to 8°C) for up to 24 hours or room temperature for up to 4 hours and should be protected from light.
- ACTEMRA solutions do not contain preservatives; therefore, unused product remaining in the vials should not be used.
- Allow the fully diluted ACTEMRA solution to reach room temperature prior to infusion.
- The infusion should be administered over 60 minutes, and must be administered with an infusion set. Do not administer as an intravenous push or bolus.
- ACTEMRA should not be infused concomitantly in the same intravenous line with other drugs. No physical or biochemical compatibility studies have been conducted to evaluate the co-administration of ACTEMRA with other drugs.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If particulates and discolorations are noted, the product should not be used.
- Fully diluted ACTEMRA solutions are compatible with polypropylene, polyethylene and polyvinyl chloride infusion bags and polypropylene, polyethylene and glass infusion bottles.
Preparation and Administration Instructions for Subcutaneous Injection
- ACTEMRA for subcutaneous injection is not intended for intravenous drip infusion.
- Assess suitability of patient for subcutaneous home use and instruct patients to inform a healthcare professional before administering the next dose if they experience any symptoms of allergic reaction. Patients should seek immediate medical attention if they develop symptoms of serious allergic reactions. ACTEMRA subcutaneous injection is intended for use under the guidance of a healthcare practitioner. After proper training in subcutaneous injection technique, a patient may self-inject ACTEMRA or the patient's caregiver may administer ACTEMRA if a healthcare practitioner determines that it is appropriate. PJIA and SJIA patients may self-inject with the ACTEMRA prefilled syringe or ACTPen® autoinjector, or the patient's caregiver may administer ACTEMRA if both the healthcare practitioner and the parent/legal guardian determines it is appropriate [see Use in Specific Populations (8.4)]. Patients, or patient caregivers, should be instructed to follow the directions provided in the Instructions for Use (IFU) for additional details on medication administration.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use ACTEMRA prefilled syringes (PFS) or prefilled ACTPen® autoinjectors exhibiting particulate matter, cloudiness, or discoloration. ACTEMRA for subcutaneous administration should be clear and colorless to pale yellow. Do not use if any part of the PFS or ACTPen® autoinjector appears to be damaged.
- Patients using ACTEMRA for subcutaneous administration should be instructed to inject the full amount in the syringe (0.9 mL) or full amount in the ACTPen® autoinjector (0.9 mL), which provides 162 mg of ACTEMRA, according to the directions provided in the IFU.
- Injection sites should be rotated with each injection and should never be given into moles, scars, or areas where the skin is tender, bruised, red, hard, or not intact.
Dosage Modifications due to Serious Infections or Laboratory Abnormalities
Serious Infections
Hold ACTEMRA treatment if a patient develops a serious infection until the infection is controlled.
Laboratory Abnormalities
Rheumatoid Arthritis, Giant Cell Arteritis and Systemic Sclerosis-Associated Interstitial Lung Disease
| Liver Enzyme Abnormalities [see Warnings and Precautions (5.3, 5.4)] | ||
|---|---|---|
| Lab Value | Recommendation for RA and SSc-ILD | Recommendation for GCA |
| Greater than 1 to 3× ULN | Dose modify concomitant DMARDs if appropriate For persistent increases in this range:
| Dose modify immunomodulatory agents if appropriate For persistent increases in this range:
|
| Greater than 3 to 5× ULN (confirmed by repeat testing) | Hold ACTEMRA dosing until less than 3× ULN and follow recommendations above for greater than 1 to 3× ULN For persistent increases greater than 3× ULN, discontinue ACTEMRA | Hold ACTEMRA dosing until less than 3x ULN and follow recommendations above for greater than 1 to 3x ULN For persistent increases greater than 3x ULN, discontinue ACTEMRA |
| Greater than 5× ULN | Discontinue ACTEMRA | Discontinue ACTEMRA |
| Low Absolute Neutrophil Count (ANC) [see Warnings and Precautions (5.4)] | ||
|---|---|---|
| Lab Value (cells per mm3) | Recommendation for RA and SSc-ILD | Recommendation for GCA |
| ANC greater than 1000 | Maintain dose | Maintain dose |
| ANC 500 to 1000 | Hold ACTEMRA dosing When ANC greater than 1000 cells per mm3:
| Hold ACTEMRA dosing When ANC greater than 1000 cells per mm3:
|
| ANC less than 500 | Discontinue ACTEMRA | Discontinue ACTEMRA |
| Low Platelet Count [see Warnings and Precautions (5.4)] | ||
|---|---|---|
| Lab Value (cells per mm3) | Recommendation for RA and SSc-ILD | Recommendation for GCA |
| 50,000 to 100,000 | Hold ACTEMRA dosing When platelet count is greater than 100,000 cells per mm3:
| Hold ACTEMRA dosing When platelet count is greater than 100,000 cells per mm3:
|
| Less than 50,000 | Discontinue ACTEMRA | Discontinue ACTEMRA |
Polyarticular and Systemic Juvenile Idiopathic Arthritis
Dose reduction of ACTEMRA has not been studied in the PJIA and SJIA populations. Dose interruptions of ACTEMRA are recommended for liver enzyme abnormalities, low neutrophil counts, and low platelet counts in patients with PJIA and SJIA at levels similar to what is outlined above for patients with RA and GCA. If appropriate, dose modify or stop concomitant methotrexate and/or other medications and hold ACTEMRA dosing until the clinical situation has been evaluated. In PJIA and SJIA the decision to discontinue ACTEMRA for a laboratory abnormality should be based upon the medical assessment of the individual patient.
Intravenous Infusion
Injection: 80 mg/4 mL, 200 mg/10 mL, 400 mg/20 mL as a clear, colorless to pale yellow solution in 20 mg/mL single-dose vials for further dilution prior to intravenous infusion.
Subcutaneous Injection
Injection: 162 mg/0.9 mL clear, colorless to slightly yellowish solution in a single-dose prefilled syringe or single-dose prefilled ACTPen® autoinjector.
Pregnancy
Risk Summary
The available data with ACTEMRA from a pregnancy exposure registry, retrospective cohort study, pharmacovigilance, and published literature are insufficient to draw conclusions about a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. These studies had methodological limitations, including small sample size of tocilizumab exposed groups, missing exposure and outcomes information, and lack of adjustment for confounders. Monoclonal antibodies, such as tocilizumab, are actively transported across the placenta during the third trimester of pregnancy and may affect immune response in the in utero exposed infant [see Clinical Considerations]. In animal reproduction studies, intravenous administration of tocilizumab to Cynomolgus monkeys during organogenesis caused abortion/embryo-fetal death at doses 1.25 times and higher than the maximum recommended human dose by the intravenous route of 8 mg per kg every 2 to 4 weeks. The literature in animals suggests that inhibition of IL-6 signaling may interfere with cervical ripening and dilatation and myometrial contractile activity leading to potential delays of parturition [see Data]. Based on the animal data, there may be a potential risk to the fetus.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Clinical Considerations
Fetal/Neonatal adverse reactions
Monoclonal antibodies are increasingly transported across the placenta as pregnancy progresses, with the largest amount transferred during the third trimester. Risks and benefits should be considered prior to administering live or live-attenuated vaccines to infants exposed to ACTEMRA in utero [see Warnings and Precautions 5.9)].
Disease-associated Maternal Risk
Published data suggest that the risk of adverse pregnancy outcomes in women with rheumatoid arthritis is associated with increased disease activity. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) infants, and small for gestational age at birth.
Data
Animal Data
An embryo-fetal developmental toxicity study was performed in which pregnant Cynomolgus monkeys were treated intravenously with tocilizumab at daily doses of 2, 10, or 50 mg/ kg during organogenesis from gestation day (GD) 20-50. Although there was no evidence for a teratogenic/dysmorphogenic effect at any dose, tocilizumab produced an increase in the incidence of abortion/embryo-fetal death at doses 1.25 times and higher the MRHD by the intravenous route at maternal intravenous doses of 10 and 50 mg/ kg. Testing of a murine analogue of tocilizumab in mice did not yield any evidence of harm to offspring during the pre- and postnatal development phase when dosed at 50 mg/kg intravenously with treatment every three days from implantation (GD 6) until post-partum day 21 (weaning). There was no evidence for any functional impairment of the development and behavior, learning ability, immune competence and fertility of the offspring.
Parturition is associated with significant increases of IL-6 in the cervix and myometrium. The literature suggests that inhibition of IL-6 signaling may interfere with cervical ripening and dilatation and myometrial contractile activity leading to potential delays of parturition. For mice deficient in IL-6 (ll6-/- null mice), parturition was delayed relative to wild-type (ll6+/+) mice. Administration of recombinant IL-6 to ll6-/- null mice restored the normal timing of delivery.
Lactation
Risk Summary
No information is available on the presence of tocilizumab in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. Maternal immunoglobulin G (IgG) is present in human milk. If tocilizumab is transferred into human milk, the effects of local exposure in the gastrointestinal tract and potential limited systemic exposure in the infant to tocilizumab are unknown. The lack of clinical data during lactation precludes clear determination of the risk of ACTEMRA to an infant during lactation; therefore the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ACTEMRA and the potential adverse effects on the breastfed child from tocilizumab or from the underlying maternal condition.
Pediatric Use
ACTEMRA by intravenous use is indicated for the treatment of pediatric patients with:
- Active systemic juvenile idiopathic arthritis in patients 2 years of age and older
- Active polyarticular juvenile idiopathic arthritis in patients 2 years of age and older
- Severe or life-threatening CAR T cell-induced cytokine release syndrome (CRS) in patients 2 years of age and older.
ACTEMRA by subcutaneous use is indicated for the treatment of pediatric patients with:
- Active polyarticular juvenile idiopathic arthritis in patients 2 years of age and older
- Active systemic juvenile idiopathic arthritis in patients 2 years of age and older
The safety and effectiveness of ACTEMRA in pediatric patients with conditions other than PJIA, SJIA or CRS have not been established. The safety and effectiveness in pediatric patients below the age of 2 have not been established in PJIA, SJIA, or CRS.
Systemic Juvenile Idiopathic Arthritis – Intravenous Use
A multicenter, open-label, single arm study to evaluate the PK, safety and exploratory PD and efficacy of ACTEMRA over 12-weeks in SJIA patients (N=11) under 2 years of age was conducted. Patients received intravenous ACTEMRA 12 mg/kg every two weeks. Concurrent use of stable background treatment with corticosteroids, MTX, and/or non-steroidal anti-inflammatory drugs was permitted. Patients who completed the 12-week period could continue to the optional extension period (a total of 52-weeks or until the age of 2 years, whichever was longer).
The primary PK endpoints (Cmax, Ctrough and AUC2weeks) of ACTEMRA at steady-state in this study were within the ranges of these parameters observed in patients with SJIA aged 2 to 17 years.
The safety and immunogenicity of ACTEMRA for patients with SJIA under 2 years of age was assessed descriptively. SAEs, AEs leading to discontinuation, and infectious AEs were reported by 27.3%, 36.4%, and 81.8% of patients. Six patients (54.5%) experienced hypersensitivity reactions, defined as all adverse events occurring during or within 24 hours after an infusion considered related to ACTEMRA. Three of these patients experienced serious hypersensitivity reactions and were withdrawn from the study. Three patients with hypersensitivity reactions (two with serious hypersensitivity reactions) developed treatment induced anti-tocilizumab antibodies after the event. There were no cases of MAS based on the protocol-specified criteria, but 2 cases of suspected MAS based on Ravelli criteria 1.
- 1
- Ravelli A, Minoia F, Davì S on behalf of the Paediatric Rheumatology International Trials Organisation, the Childhood Arthritis and Rheumatology Research Alliance, the Pediatric Rheumatology Collaborative Study Group, and the Histiocyte Society, et al. 2016 Classification Criteria for Macrophage Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis. Annals of the Rheumatic Diseases 2016;75:481-489.
Cytokine Release Syndrome – Intravenous Use
In the retrospective analysis of pooled outcome data for patients treated with ACTEMRA for CAR T cell-induced CRS, 25 patients were children (2 years up to 12 years of age), and 17 patients were adolescents (12 years up to 18 years of age). There were no differences between the pediatric patients and the adults for safety or efficacy.
Geriatric Use
Of the 2644 patients who received ACTEMRA in Studies I to V [see Clinical Studies (14)], a total of 435 rheumatoid arthritis patients were 65 years of age and older, including 50 patients 75 years and older. Of the 1069 patients who received ACTEMRA-SC in studies SC-I and SC-II there were 295 patients 65 years of age and older, including 41 patients 75 years and older. The frequency of serious infection among ACTEMRA treated subjects 65 years of age and older was higher than those under the age of 65. As there is a higher incidence of infections in the elderly population in general, caution should be used when treating the elderly.
Clinical studies that included ACTEMRA for CRS did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.
In the EMPACTA, COVACTA, and REMDACTA studies, of the 974 COVID-19 patients in the ACTEMRA arm, 375 (39%) were 65 years of age or older. No overall differences in safety or effectiveness of ACTEMRA were observed between patients 65 years of age and older and those under the age of 65 years of age in these studies [see Adverse Reactions (6.1) and Clinical Studies (14.11)].
In the RECOVERY study, of the 2022 COVID-19 patients in the ACTEMRA arm, 930 (46%) were 65 years of age or older. No overall differences in effectiveness of ACTEMRA were observed between patients 65 years of age and older and those under the age 65 years of age in this study [see Clinical Studies (14.11)].
Hepatic Impairment
The safety and efficacy of ACTEMRA have not been studied in patients with hepatic impairment, including patients with positive HBV and HCV serology [see Warnings and Precautions (5.8)].
Renal Impairment
No dose adjustment is required in patients with mild or moderate renal impairment. ACTEMRA has not been studied in patients with severe renal impairment [see Clinical Pharmacology (12.3)].
ACTEMRA is contraindicated in patients with known hypersensitivity to ACTEMRA [see Warnings and Precautions (5.6)].