Acterma

Uses

Rheumatoid Arthritis (RA): Acterma is used 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): Acterma is used for the treatment of giant cell arteritis (GCA) in adult patients.

Polyarticular Juvenile Idiopathic Arthritis (PJIA): Acterma is used for the treatment of active polyarticular juvenile idiopathic arthritis in patients 2 years of age and older.

Systemic Juvenile Idiopathic Arthritis (SJIA): Acterma is used for the treatment of active systemic juvenile idiopathic arthritis in patients 2 years of age and older.

Cytokine Release Syndrome (CRS): Acterma is used 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.

Acterma is also used to associated treatment for these conditions: Cytokine Release Syndrome caused by CAR-T Cell Therapy, Giant Cell Arteritis (GCA), Moderate to Severe Rheumatoid Arthritis, Polyarticular Juvenile Idiopathic Arthritis, Systemic Juvenile Idiopathic Arthritis (SJIA)

How Acterma works

Interleukin 6 (IL-6) is a pro-inflammatory cytokine produced by cells including T-cells, B-cells, lymphocytes, monocytes, fibroblasts. IL-6 rapidly induces C-reactive protein, serum amyloid A, fibrinogen, haptoglobin, and α-1-antichymotrypsin while inhibiting production of fibronectin, albumin, and transferrin. IL-6 also induces antibody production, induces cytotoxic T-cell differentiation, and inhibits regulatory T-cell differentiation. Acterma binds soluble and membrane bound IL-6 receptors, preventing IL-6 mediated inflammation.

Dosage

Acterma dosage

General (IV or SC Injection): Substitution by any other biological medicinal product requires the consent of the prescribing physician.

For adult patients with RA, tocilizumab may be administered as an IV infusion or a SC injection. For patients with pJIA and sJIA, tocilizumab is administered as an IV infusion.

Acterma IV formulation should be diluted by a healthcare professional with sterile 0.9% w/v sodium chloride solution using aseptic technique (see Caution for Usage).

Acterma is recommended for IV infusion over 1 hr.

Acterma SC formulation is administered with a single-use PFS+NSD or pre-filled pen. The 1st injection should be performed under the supervision of a qualified healthcare professional. The recommended injection sites (abdomen, thigh and upper arm) should be rotated and injections should never be given into moles, scars or areas where the skin is tender, bruised, red, hard or not intact.

SC Injection: Adults: Rheumatoid Arthritis (RA): Recommended Dose: 162 mg given once every week as a SC injection. Acterma can be used alone or in combination with MTX and/or other DMARDs.

Patients transitioning from tocilizumab IV therapy to SC administration should administer the 1st SC dose at the time of the next scheduled IV dose under the supervision of a qualified healthcare professional.

Acterma SC formulation is not intended for IV administration. Assess suitability of patient for SC home use and instruct patients to inform a healthcare professional if they experience symptoms of allergic reaction before administering the next dose. Patients should seek immediate medical attention if developing symptoms of serious allergic reactions

Side Effects

Rheumatoid Arthritis: Patients Treated with Subcutaneous Acterma: The safety of SC tocilizumab in RA was study in SC-I. The study compared the efficacy and safety of tocilizumab 162 mg administered every week SC versus 8 mg/kg IV in 1,262 subjects with adult RA. All patients in the study received background non-biologic DMARD(s). The safety and immunogenicity observed for tocilizumab administered SC was consistent with the known safety profile of tocilizumab IV and no new or unexpected adverse drug reactions were observed (see Table 7). A higher frequency of injection site reactions was observed in the SC arms compared with placebo SC injections in the IV arms

Toxicity

Data regarding overdoses of tocilizumab are not readily available. Patients experiencing an overdose may develop neutropenia. In case of overdose, monitor patients for signs of adverse reactions and provide symptomatic and supportive treatment.

Precaution

Serious infections leading to hospitalization or death (ie, tuberculosis; bacterial, invasive fungal, viral, or other opportunistic infections) have occurred with use Stop therapy if serious infection occurs; can restart if infection is controlled Test for latent tuberculosis before initiating; if positive, initiate tuberculosis therapy before starting tocilizumab. Continue to monitor all patients for active tuberculosis during therapy

Interaction

Interactions with Other Medicinal Products and Other Forms of Interaction: Population pharmacokinetic analyses did not detect any effect of MTX, nonsteroidal anti-inflammatory drugs or corticosteroids on tocilizumab clearance.

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

Acterma has not been studied in combination with other biological DMARDs.

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

In vitro studies with cultured human hepatocytes demonstrated that IL-6 caused a reduction in CYP1A2, CYP2C9, CYP2C19 and CYP3A4 enzyme expression. Acterma normalizes expression of these enzymes. The effect of tocilizumab on CYP enzymes (except CYP2C19 and CYP2D6) is clinically relevant for CYP450 substrates with a narrow therapeutic index and/or where the dose is individually adjusted.

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

When starting or stopping therapy with tocilizumab, patients taking medicinal products, which are individually dose-adjusted and are metabolised via CYP450 3A4, 1A2, or 2C9 (eg, atorvastatin, calcium channel blockers, theophylline, warfarin, phenytoin, ciclosporin or benzodiazepines) should be monitored as doses of these products may need to be adjusted to maintain their therapeutic effect. Given its long elimination half-life (t½), the effect of tocilizumab on CYP450 enzyme activity may persist for several weeks after stopping therapy.

Food Interaction

Acterma Drug Interaction

Moderate: apixaban, atorvastatinUnknown: aspirin, erenumab, aspirin, amoxicillin / clavulanate, celecoxib, ubiquinone, duloxetine, ethanol, omega-3 polyunsaturated fatty acids, heparin, esomeprazole, acetaminophen, budesonide / formoterol, tramadol, sildenafil, ascorbic acid, cholecalciferol, menaquinone

Acterma Disease Interaction

Major: immunizationModerate: infections, tuberculosis, demyelinating disorders, gastrointestinal perforation, liver dysfunction, renal impairment

Volume of Distribution

In rheumatoid arthritis patients, the central volume of distribution is 3.5L, the peripheral volume of distribution is 2.9L, and the volume of distribution at steady state is 6.4L. In giant cell arteritis patients, the central volume of distribution is 4.09L, the peripheral volume of distribution if 3.37L, and the volume of distribution at steady state is 7.46L. In pediatric patients with polyarticular juvenile arthritis, the central volume of distribution is 1.98L, the peripheral volume of distribution is 2.1L, and the volume of distribution at steady state is 4.08L. In pediatric patients with systemic juvenile idiopathic arthritis, the central volume of distribution is 1.87L, the peripheral volume of distribution is 2.14L, and the volume of distribution at steady state is 4.01L.

Elimination Route

A 162mg subcutaneous dose given weekly has a C_max of 51.3±23.2µg/mL and an AUC of 8254±3833µg*h/mL. A 162mg subcutaneous dose given every 2 weeks has a C_max of 13±8.3µg/mL and an AUC of 3460±2530µg*h/mL. A 162mg subcutaneous dose given every 4 weeks has a C_max of 154±42µg/mL and an AUC of 39216±14304µg*h/mL.

Half Life

The half life of tocilizumab is concentration dependent. The terminal half life in rheumatoid arthritis patients is 21.5 days. The absorption half life in rheumatoid arthritis and giant cell arteritis patients was 4 days, and in polyarticular juvenile idiopathic arthritis patients and systemic juvenile idiopathic arthritis patients was 2 days.

Clearance

The linear clearance in rheumatoid arthritis patients is 12.5mL/h, in giant cell arteritis patients is 6.7mL/h, in polyarticular juvenile idiopathic arthritis patients is 5.8mL/h, and in systemic juvenile idiopathic arthritis is 5.7mL/h. Clearance is dose dependent and changes from non linear at low doses to linear at higher doses.

Elimination Route

Data regarding the exact route of elimination of monoclonal antibodies is not readily available.

Pregnancy & Breastfeeding use

Pregnancy Category- C. Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks

Lactation: Unknown whether distributed in breast milk, do not breast feed

Contraindication

Hypersensitivity to tocilizumab or to any of the excipients.

Special Warning

Children: The safety and efficacy of tocilizumab in children with conditions other than pJIA or sJIA have not been established.

Children Elderly: No dose adjustment is required in elderly patients ≥65 years.

Renal Impairment: No dose adjustment is required in patients with mild renal impairment (see Pharmacology: Pharmacokinetics under Actions). Acterma has not been studied in patients with moderate to severe renal impairment.

Hepatic Impairment: The safety and efficacy of tocilizumab has not been studied in patients with hepatic impairment (see Precautions).

Acute Overdose

There are limited data available on overdosage with tocilizumab. One (1) case of accidental overdose was reported in which a patient with multiple myeloma received a single dose of 40 mg/kg IV. No adverse drug reactions were observed. No serious adverse drug reactions were observed in healthy volunteers who received a single dose up to 28 mg/kg IV, although dose-limiting neutropenia was observed.

Storage Condition

Store at a temperature of 2-8°C. Do not freeze. Protect from light and keep dry.

Innovators Monograph

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