ACTEMRA (Page 9 of 15)


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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.

8.5 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.

8.6 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)].

8.7 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)].

9 DRUG ABUSE AND DEPENDENCE

No studies on the potential for ACTEMRA to cause dependence have been performed. However, there is no evidence from the available data that ACTEMRA treatment results in dependence.

10 OVERDOSAGE

There are limited data available on overdoses with ACTEMRA. One case of accidental overdose was reported with intravenous ACTEMRA in which a patient with multiple myeloma received a dose of 40 mg per kg. No adverse drug reactions were observed. No serious adverse drug reactions were observed in healthy volunteers who received single doses of up to 28 mg per kg, although all 5 patients at the highest dose of 28 mg per kg developed dose-limiting neutropenia.

In case of an overdose, it is recommended that the patient be monitored for signs and symptoms of adverse reactions. Patients who develop adverse reactions should receive appropriate symptomatic treatment.

11 DESCRIPTION

Tocilizumab is a recombinant humanized anti-human interleukin 6 (IL-6) receptor monoclonal antibody of the immunoglobulin IgG1κ (gamma 1, kappa) subclass with a typical H2 L2 polypeptide structure. Each light chain and heavy chain consists of 214 and 448 amino acids, respectively. The four polypeptide chains are linked intra- and inter-molecularly by disulfide bonds. ACTEMRA has a molecular weight of approximately 148 kDa. The antibody is produced in mammalian (Chinese hamster ovary) cells.

Intravenous Infusion

ACTEMRA (tocilizumab) injection is a sterile, clear, colorless to pale yellow, preservative-free solution for further dilution prior to intravenous infusion with a pH of approximately 6.5. Each single-dose vial, formulated with a disodium phosphate dodecahydrate/sodium dihydrogen phosphate dihydrate buffered solution, is available at a concentration of 20 mg/mL containing 80 mg/4 mL, 200 mg/10 mL, or 400 mg/20 mL of ACTEMRA. Each mL of solution contains polysorbate 80 (0.5 mg), sucrose (50 mg), and Water for Injection, USP.

Subcutaneous Injection

ACTEMRA (tocilizumab) injection is a sterile, clear, colorless to slightly yellowish, preservative-free, histidine buffered solution for subcutaneous use with a pH of approximately 6.0.

It is supplied in a ready-to-use, single-dose 0.9 mL prefilled syringe (PFS) with a needle safety device or a ready-to-use, single-dose 0.9 mL autoinjector that delivers 162 mg tocilizumab, L-arginine hydrochloride (19 mg), L-histidine (1.52 mg), L-histidine hydrochloride monohydrate (1.74 mg), L-methionine (4.03 mg), polysorbate 80 (0.18 mg), and Water for Injection, USP.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Tocilizumab binds to both soluble and membrane-bound IL-6 receptors (sIL-6R and mIL-6R), and has been shown to inhibit IL-6-mediated signaling through these receptors. IL-6 is a pleiotropic pro-inflammatory cytokine produced by a variety of cell types including T- and B-cells, lymphocytes, monocytes and fibroblasts. IL-6 has been shown to be involved in diverse physiological processes such as T-cell activation, induction of immunoglobulin secretion, initiation of hepatic acute phase protein synthesis, and stimulation of hematopoietic precursor cell proliferation and differentiation. 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.

12.2 Pharmacodynamics

In clinical studies in RA patients with the 4 mg per kg and 8 mg per kg intravenous doses or the 162 mg weekly and every other weekly subcutaneous doses of ACTEMRA, decreases in levels of C-reactive protein (CRP) to within normal ranges were seen as early as week 2. Changes in pharmacodynamic parameters were observed (i.e., decreases in rheumatoid factor, erythrocyte sedimentation rate (ESR), serum amyloid A, fibrinogen and increases in hemoglobin) with doses, however the greatest improvements were observed with 8 mg per kg ACTEMRA. Pharmacodynamic changes were also observed to occur after ACTEMRA administration in GCA, SSc-ILD, PJIA, and SJIA patients (decreases in CRP, ESR, and increases in hemoglobin). The relationship between these pharmacodynamic findings and clinical efficacy is not known.

In healthy subjects administered ACTEMRA in doses from 2 to 28 mg per kg intravenously and 81 to 162 mg subcutaneously, absolute neutrophil counts decreased to the nadir 3 to 5 days following ACTEMRA administration. Thereafter, neutrophils recovered towards baseline in a dose dependent manner. Rheumatoid arthritis and GCA patients demonstrated a similar pattern of absolute neutrophil counts following ACTEMRA administration [see Warnings and Precautions (5.4)].

12.3 Pharmacokinetics

PK of tocilizumab is 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. Population pharmacokinetic analyses in any patient population tested so far indicate no relationship between apparent clearance and the presence of anti-drug antibodies.

Rheumatoid Arthritis — Intravenous and Subcutaneous Administration

The pharmacokinetics in healthy subjects and RA patients suggest that PK is similar between the two populations.

The population PK model was developed from an analysis dataset composed of an IV dataset of 1793 patients from Study I, Study III, Study IV, and Study V, and from an IV and SC dataset of 1759 patients from Studies SC-I and SC-II. Cmean is included in place of AUCtau , since for dosing regimens with different inter-dose intervals, the mean concentration over the dosing period characterizes the comparative exposure better than AUCtau.

At high serum concentrations, when total clearance of tocilizumab is dominated by linear clearance, a terminal half-life of approximately 21.5 days was derived from the population parameter estimates.

For doses of 4 mg/kg tocilizumab given every 4 weeks intravenously, the estimated median (range) Cmax , Ctrough , and Cmean of tocilizumab at steady state were 86.1 (44.8–202) mcg/mL, 0.1 (0.0–14.6) mcg/mL, and 18.0 (8.9–50.7) mcg/mL, respectively. For doses of 8 mg/kg tocilizumab given every 4 weeks intravenously, the estimated median (range) Cmax , Ctrough, and Cmean of tocilizumab were 176 (75.4–557) mcg/mL, 13.4 (0.1–154) mcg/mL, and 54.0 (17–260) mcg/mL, respectively. Cmax increased dose-proportionally between doses of 4 and 8 mg/kg IV every 4 weeks, while a greater than dose-proportional increase was observed in Cmean and Ctrough . At steady-state, Cmean and Ctrough were 3.0 and 134 fold higher at 8 mg/kg as compared to 4 mg/kg, respectively.

The accumulation ratios for AUC and Cmax after multiple doses of 4 and 8 mg/kg IV Q4W are low, while the accumulation ratios for Ctrough are higher (2.62 and 2.47, respectively). For Cmax , greater than 90% of the steady-state value was reached after the 1st IV infusion. For AUCtau and Cmean , 90% of the steady-state value was reached after the 1st and 3rd infusion for 4 mg/kg and 8 mg/kg IV, while for Ctrough , approximately 90% of the steady-state value was reached after the 4th IV infusion after both doses.

For doses of 162 mg given every other week subcutaneously, the estimated median (range) steady-state Cmax , Ctrough , and Cmean of tocilizumab were 12.1 (0.4–49.3) mcg/mL, 4.1 (0.0–34.2) mcg/mL, and 9.2 (0.2–43.6) mcg/mL, respectively.

For doses of 162 mg given every week subcutaneously, the estimated median (range) steady-state Cmax , Ctrough , and Cmean of tocilizumab were 49.8 (3–150) mcg/mL, 42.9 (1.3–144) mcg/mL, and 47.3 (2.4–147) mcg/mL, respectively. Exposures after the 162 mg SC QW regimen were greater by 5.1 (Cmean ) to 10.5 fold (Ctrough ) compared to the 162 mg SC Q2W regimen.

Accumulation ratios after multiple doses of either SC regimen were higher than after IV regimen with the highest ratios for Ctrough (6.02 and 6.30, for 162 mg SC Q2W and 162 mg SC QW, respectively). The higher accumulation for Ctrough was expected based on the nonlinear clearance contribution at lower concentrations. For Cmax , greater than 90% of the steady-state value was reached after the 5th SC and the 12th SC injection with the Q2W and QW regimens, respectively. For AUCtau and Cmean , 90% of the steady-state value was reached after the 6th and 12th injections for the 162 mg SC Q2W and QW regimens, respectively. For Ctrough , approximately 90% of the steady-state value was reached after the 6th and 12th injections for the 162 mg SC Q2W and QW regimens, respectively.

Population PK analysis identified body weight as a significant covariate impacting the pharmacokinetics of tocilizumab. When given IV on a mg/kg basis, individuals with body weight ≥ 100 kg are predicted to have mean steady-state exposures higher than mean values for the patient population. Therefore, tocilizumab doses exceeding 800 mg per infusion are not recommended in patients with RA [see Dosage and Administration (2.1)]. Due to the flat dosing employed for SC administration of tocilizumab, no modifications are necessary by this dosing route.

Giant Cell Arteritis – Subcutaneous and Intravenous Administration

The pharmacokinetics of tocilizumab SC in GCA patients was determined using a population pharmacokinetic analysis on a dataset composed of 149 GCA patients treated with 162 mg subcutaneously every week or with 162 mg subcutaneously every other week.

For the 162 mg every week dose, the estimated median (range) steady-state Cmax , Ctrough and Cmean of tocilizumab SC were 72.1 (12.2–151) mcg/mL, 67.2 (10.7–145) mcg/mL, and 70.6 (11.7–149) mcg/mL, respectively. The accumulation ratios for Cmean or AUCtau , Ctrough , and Cmax were 10.9, 9.6, and 8.9, respectively. Steady state was reached after 17 weeks. For the 162 mg every other week dose, the estimated median (range) steady-state Cmax , Ctrough , and Cmean of tocilizumab were 17.2 (1.1–56.2) mcg/mL, 7.7 (0.1–37.3) mcg/mL, and 13.7 (0.5–49) mcg/mL, respectively. The accumulation ratios for Cmean or AUCtau , Ctrough , and Cmax were 2.8, 5.6, and 2.3 respectively. Steady-state was reached after 14 weeks.

The pharmacokinetics of tocilizumab IV in GCA patients was characterized by a non-compartmental pharmacokinetic analysis which included 22 patients treated with 6 mg/kg intravenously every 4 weeks for 20 weeks. The median (range) Cmax , Ctrough and Cmean of tocilizumab at steady state were 178 (115-320) mcg/mL, 22.7 (3.38-54.5) mcg/mL and 57.5 (32.9-110) mcg/mL, respectively. Steady state trough concentrations were within the range observed in GCA patients treated with 162 mg TCZ SC administered every week or every other week.

Based on pharmacokinetic exposure and extrapolation between RA and GCA patients, when given IV on a mg/kg basis, tocilizumab doses exceeding 600 mg per infusion are not recommended in patients with GCA [see Dosage and Administration (2.2)].

Systemic Sclerosis-Associated Interstitial Lung Disease – Subcutaneous Administration

The pharmacokinetics of tocilizumab in SSc-ILD patients was determined using a population pharmacokinetic analysis on a dataset composed of 66 SSc-ILD patients treated with 162 mg tocilizumab SC every week.

The estimated median (range) steady-state Cmax , Ctrough and Cmean of tocilizumab were 52.5 (14.8-121) mcg/mL, 47.2 (10.8-114) mcg/mL, and 50.4 (13.4-119) mcg/mL, respectively. The accumulation ratios for Cmean or AUCtau , Ctrough , and Cmax were 7.11, 6.56, and 5.89, respectively. Steady-state was reached after 13 weeks.

Polyarticular Juvenile Idiopathic Arthritis – Intravenous and Subcutaneous Administration

The pharmacokinetics of tocilizumab (TCZ) in PJIA patients was characterized by a population pharmacokinetic analysis which included 188 patients who were treated with TCZ IV or 52 patients treated with TCZ SC.

For doses of 8 mg/kg tocilizumab (patients with a body weight at or above 30 kg) given every 4 weeks intravenously, the estimated median (range) Cmax , Ctrough , and Cmean of tocilizumab at steady state were 181 (114–331) mcg/mL, 3.28 (0.02–35.4) mcg/mL, and 38.6 (22.2–83.8) mcg/mL, respectively. For doses of 10 mg/kg tocilizumab (patients with a body weight less than 30 kg) given every 4 weeks intravenously, the estimated median (range) Cmax , Ctrough , and Cmean of tocilizumab were 167 (125–220) mcg/mL, 0.35 (0–11.8) mcg/mL, and 30.8 (16.0–48.0) mcg/mL, respectively.

The accumulation ratios were 1.05 and 1.16 for AUC4weeks , and 1.43 and 2.22 for Ctrough for 10 mg/kg (BW less than 30 kg) and 8 mg/kg (BW at or above 30 kg) intravenous doses, respectively. No accumulation for Cmax was observed. Following 10 mg/kg and 8 mg/kg TCZ IV every 4 weeks doses in PJIA patients (aged 2 to 17 years), steady state concentrations (trough and average) were within the range of exposures in adult RA patients following 4 mg/kg and 8 mg/kg every 4 weeks, and steady state peak concentrations in PJIA patients were comparable to those following 8 mg/kg every 4 weeks in adult RA patients.

For doses of 162 mg tocilizumab (patients with a body weight at or above 30 kg) given every 2 weeks subcutaneously, the estimated median (range) Cmax , Ctrough , and Cmean of tocilizumab were 29.7 (7.56–50.3) mcg/mL, 12.7 (0.19–23.8) mcg/mL, and 23.0 (3.86–36.9) mcg/mL, respectively. For doses of 162 mg tocilizumab (patients with a body weight less than 30 kg) given every 3 weeks subcutaneously, the estimated median (range) Cmax , Ctrough , and Cmean of tocilizumab were 62.4 (39.4–121) mcg/mL, 13.4 (0.21–52.3) mcg/mL, and 35.7 (17.4–91.8) mcg/mL, respectively.

The accumulation ratios were 1.46 and 2.04 for AUC4weeks , 2.08 and 3.58 for Ctrough , and 1.32 and 1.72 for Cmax , for 162 mg given every 3 weeks (BW less than 30 kg) and 162 mg given every 2 weeks (BW at or above 30 kg) subcutaneous doses, respectively. Following subcutaneous dosing, steady state Ctrough was comparable for patients in the two body weight groups, while steady-state Cmax and Cmean were higher for patients in the less than 30 kg group compared to the group at or above 30 kg. All patients treated with TCZ SC had steady-state Ctrough at or higher than that achieved with TCZ IV across the spectrum of body weights. The average and trough concentrations in patients after subcutaneous dosing were within the range of those achieved in adult patients with RA following the subcutaneous administration of the recommended regimens.

Systemic Juvenile Idiopathic Arthritis—Intravenous and Subcutaneous Administration

The pharmacokinetics of tocilizumab (TCZ) in SJIA patients was characterized by a population pharmacokinetic analysis which included 89 patients who were treated with TCZ IV or 51 patients treated with TCZ SC.

For doses of 8 mg/kg tocilizumab (patients with a body weight at or above 30 kg) given every 2 weeks intravenously, the estimated median (range) Cmax , Ctrough , and Cmean of tocilizumab were 253 (120–404) mcg/mL, 70.7 (5.26–127) mcg/mL, and 117 (37.6–199) mcg/mL, respectively. For doses of 12 mg/kg tocilizumab (patients with a body weight less than 30 kg) given every 2 weeks intravenously, the estimated median (range) Cmax , Ctrough , and Cmean of tocilizumab were 274 (149–444) mcg/mL, 65.9 (19.0–135) mcg/mL, and 124 (60–194) mcg/mL, respectively.

The accumulation ratios were 1.95 and 2.01 for AUC4weeks , and 3.41 and 3.20 for Ctrough for 12 mg/kg (BW less than 30 kg) and 8 mg/kg (BW at or above 30 kg) intravenous doses, respectively. Accumulation data for Cmax were 1.37 and 1.42 for 12 mg/kg (BW less than 30 kg) and 8 mg/kg (BW at or above 30 kg) intravenous doses, respectively. Following every other week dosing with tocilizumab IV, steady state was reached by 8 weeks for both body weight groups. Mean estimated tocilizumab exposure parameters were similar between the two dose groups defined by body weight.

For doses of 162 mg tocilizumab (patients with a body weight at or above 30 kg) given every week subcutaneously, the estimated median (range) Cmax , Ctrough , and Cmean of tocilizumab were 89.8 (26.4–190) mcg/mL, 72.4 (19.5–158) mcg/mL, and 82.4 (23.9–169) mcg/mL, respectively. For doses of 162 mg tocilizumab (patients with a body weight less than 30 kg) given every 2 weeks subcutaneously, the estimated median (range) Cmax , Ctrough , and Cmean of tocilizumab were 127 (51.7–266) mcg/mL, 64.2 (16.6–136) mcg/mL, and 92.7 (38.5–199) mcg/mL, respectively.

The accumulation ratios were 2.27 and 4.28 for AUC4weeks , 3.21 and 4.39 for Ctrough , and 1.88 and 3.66 for Cmax , for 162 mg given every 2 weeks (BW less than 30 kg) and 162 mg given every week (BW at or above 30 kg) subcutaneous doses, respectively. Following subcutaneous dosing, steady state was reached by 12 weeks for both body weight groups. All patients treated with tocilizumab SC had steady-state Cmax lower than that achieved with tocilizumab IV across the spectrum of body weights. Trough and mean concentrations in patients after SC dosing were similar to those achieved with tocilizumab IV across body weights.

Absorption

Following subcutaneous dosing, the absorption half-life was around 4 days in RA and GCA patients and 3 days in SSc-ILD patients. The bioavailability for the subcutaneous formulation was 80%.

Following subcutaneous dosing in PJIA patients, the absorption half-life was around 2 days, and the bioavailability for the subcutaneous formulation in PJIA patients was 96%.

Following subcutaneous dosing in SJIA patients, the absorption half-life was around 2 days, and the bioavailability for the SC formulation in SJIA patients was 95%.

In RA patients the median values of Tmax were 2.8 days after the tocilizumab every week dose and 4.7 days after the tocilizumab every other week dose.

In GCA patients, the median values of Tmax were 3 days after the tocilizumab every week dose and 4.5 days after the tocilizumab every other week dose.

In SSc-ILD patients, the median value of Tmax was 2.8 days after the tocilizumab every week dose.

Distribution

Following intravenous dosing, tocilizumab undergoes biphasic elimination from the circulation. In rheumatoid arthritis patients the central volume of distribution was 3.5 L and the peripheral volume of distribution was 2.9 L, resulting in a volume of distribution at steady state of 6.4 L.

In GCA patients, the central volume of distribution was 4.09 L, the peripheral volume of distribution was 3.37 L resulting in a volume of distribution at steady state of 7.46 L.

In SSc-ILD patients, the central volume of distribution was 4.16 L, the peripheral volume of distribution was 2.58 L resulting in a volume of distribution at steady state of 6.74 L.

In pediatric patients with PJIA, the central volume of distribution was 1.98 L, the peripheral volume of distribution was 2.1 L, resulting in a volume of distribution at steady state of 4.08 L.

In pediatric patients with SJIA, the central volume of distribution was 1.87 L, the peripheral volume of distribution was 2.14 L resulting in a volume of distribution at steady state of 4.01 L.

Elimination

ACTEMRA is eliminated by a combination of linear clearance and nonlinear elimination. The concentration-dependent nonlinear elimination plays a major role at low tocilizumab concentrations. Once the nonlinear pathway is saturated, at higher tocilizumab concentrations, clearance is mainly determined by the linear clearance. The saturation of the nonlinear elimination leads to an increase in exposure that is more than dose-proportional. The pharmacokinetic parameters of ACTEMRA do not change with time.

Population pharmacokinetic analyses in any patient population tested so far indicate no relationship between apparent clearance and the presence of anti-drug antibodies.

The linear clearance in the population pharmacokinetic analysis was estimated to be 12.5 mL per h in RA patients, 6.7 mL per h in GCA patients, 8.8 mL per h in SSc-ILD patients, 5.8 mL per h in pediatric patients with PJIA, and 5.7 mL per h in pediatric patients with SJIA.

Due to the dependence of total clearance on ACTEMRA serum concentrations, the half-life of ACTEMRA is also concentration-dependent and varies depending on the serum concentration level.

For intravenous administration in RA patients, the concentration-dependent apparent t1/2 is up to 11 days for 4 mg per kg and up to 13 days for 8 mg per kg every 4 weeks in patients with RA at steady-state. For subcutaneous administration in RA patients, the concentration-dependent apparent t1/2 is up to 13 days for 162 mg every week and 5 days for 162 mg every other week in patients with RA at steady-state.

In GCA patients at steady state, the effective t1/2 of tocilizumab varied between 18.3 and 18.9 days for 162 mg subcutaneously every week dosing regimen and between 4.2 and 7.9 days for 162 mg subcutaneously every other week dosing regimen. For intravenous administration in GCA patients, the TCZ concentration-dependent apparent t1/2 was 13.2 days following 6 mg/kg every 4 weeks.

In SSc-ILD patients at steady state, the effective t1/2 of tocilizumab varied between 12.1 and 13.0 days for the 162 mg subcutaneous every week dosing regimen.

The t1/2 of tocilizumab in children with PJIA is up to 17 days for the two body weight categories (8 mg/kg for body weight at or above 30 kg or 10 mg/kg for body weight below 30 kg) during a dosing interval at steady state. For subcutaneous administration, the t1/2 of tocilizumab in PJIA patients is up to 10 days for the two body weight categories (every other week regimen for body weight at or above 30 kg or every 3 week regimen for body weight less than 30 kg) during a dosing interval at steady state.

The t1/2 of tocilizumab intravenous in pediatric patients with SJIA is up to 16 days for the two body weight categories (8 mg/kg for body weight at or above 30 kg and 12 mg/kg for body weight below 30 kg every other week) during a dosing interval at steady-state. Following subcutaneous administration, the effective t1/2 of tocilizumab subcutaneous in SJIA patients is up to 14 days for both the body weight categories (162 mg every week for body weight at or above 30 kg and 162 mg every two weeks for body weight below 30 kg) during a dosing interval at steady state.

Pharmacokinetics in Special Populations

Population pharmacokinetic analyses in adult rheumatoid arthritis patients and GCA patients showed that age, gender and race did not affect the pharmacokinetics of tocilizumab. Linear clearance was found to increase with body size. In RA patients, the body weight-based dose (8 mg per kg) resulted in approximately 86% higher exposure in patients who are greater than 100 kg in comparison to patients who are less than 60 kg. There was an inverse relationship between tocilizumab exposure and body weight for flat dose subcutaneous regimens.

In GCA patients treated with ACTEMRA-SC, higher exposure was observed in patients with lower body weight. For the 162 mg every week subcutaneous dosing regimen, the steady-state Cmean was 51% higher in patients with body weight less than 60 kg compared to patients weighing between 60 to 100 kg. For the 162 mg every other week subcutaneous regimen, the steady-state Cmean was 129% higher in patients with body weight less than 60 kg compared to patients weighing between 60 to 100 kg. There is limited data for patients above 100 kg (n=7).

Hepatic Impairment

No formal study of the effect of hepatic impairment on the pharmacokinetics of tocilizumab was conducted.

Renal Impairment

No formal study of the effect of renal impairment on the pharmacokinetics of tocilizumab was conducted.

Most of the RA, GCA, and SSc-ILD patients in the population pharmacokinetic analysis had normal renal function or mild renal impairment. Mild renal impairment (estimated creatinine clearance less than 80 mL per min and at or above 50 mL per min based on Cockcroft-Gault formula) did not impact the pharmacokinetics of tocilizumab.

Approximately one-third of the patients in the ACTEMRA-SC GCA clinical trial had moderate renal impairment at baseline (estimated creatinine clearance of 30-59 mL/min). No impact on tocilizumab exposure was noted in these patients.

No dose adjustment is required in patients with mild or moderate renal impairment.

Drug Interactions

In vitro data suggested that IL-6 reduced mRNA expression for several CYP450 isoenzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4, and this reduced expression was reversed by co-incubation with tocilizumab at clinically relevant concentrations. Accordingly, inhibition of IL-6 signaling in RA patients treated with tocilizumab may restore CYP450 activities to higher levels than those in the absence of tocilizumab leading to increased metabolism of drugs that are CYP450 substrates. Its effect on CYP2C8 or transporters (e.g., P-gp) is unknown. This is clinically relevant for CYP450 substrates with a narrow therapeutic index, where the dose is individually adjusted. Upon initiation of ACTEMRA, in patients being treated with these types of medicinal products, therapeutic monitoring of the effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) should be performed and the individual dose of the medicinal product adjusted as needed. Caution should be exercised when ACTEMRA is coadministered with drugs where decrease in effectiveness is undesirable, e.g., oral contraceptives (CYP3A4 substrates) [see Drug Interactions (7.2)].

Simvastatin

Simvastatin is a CYP3A4 and OATP1B1 substrate. In 12 RA patients not treated with ACTEMRA, receiving 40 mg simvastatin, exposures of simvastatin and its metabolite, simvastatin acid, was 4- to 10-fold and 2-fold higher, respectively, than the exposures observed in healthy subjects. One week following administration of a single infusion of ACTEMRA (10 mg per kg), exposure of simvastatin and simvastatin acid decreased by 57% and 39%, respectively, to exposures that were similar or slightly higher than those observed in healthy subjects. Exposures of simvastatin and simvastatin acid increased upon withdrawal of ACTEMRA in RA patients. Selection of a particular dose of simvastatin in RA patients should take into account the potentially lower exposures that may result after initiation of ACTEMRA (due to normalization of CYP3A4) or higher exposures after discontinuation of ACTEMRA.

Omeprazole

Omeprazole is a CYP2C19 and CYP3A4 substrate. In RA patients receiving 10 mg omeprazole, exposure to omeprazole was approximately 2 fold higher than that observed in healthy subjects. In RA patients receiving 10 mg omeprazole, before and one week after ACTEMRA infusion (8 mg per kg), the omeprazole AUCinf decreased by 12% for poor (N=5) and intermediate metabolizers (N=5) and by 28% for extensive metabolizers (N=8) and were slightly higher than those observed in healthy subjects.

Dextromethorphan

Dextromethorphan is a CYP2D6 and CYP3A4 substrate. In 13 RA patients receiving 30 mg dextromethorphan, exposure to dextromethorphan was comparable to that in healthy subjects. However, exposure to its metabolite, dextrorphan (a CYP3A4 substrate), was a fraction of that observed in healthy subjects. One week following administration of a single infusion of ACTEMRA (8 mg per kg), dextromethorphan exposure was decreased by approximately 5%. However, a larger decrease (29%) in dextrorphan levels was noted after ACTEMRA infusion.

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