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A total of 3,778 patients received at least one dose of ACTEMRA 4mg/kg or 8mg/kg.

The adverse drug reactions (ADRs) presented in Table 1 are based on the safety of ACTEMRA studied in four placebo-controlled studies (OPTION, TOWARD, RADIATE, and LITHE) and one methotrexate (MTX)-controlled study (AMBITION). In these studies, 774 patients received ACTEMRA 4mg/kg in combination with MTX, 1,582 patients received ACTEMRA 8mg/kg in combination with MTX or other disease modifying anti-rheumatic drugs (DMARDs) and 288 patients received ACTEMRA 8mg/kg monotherapy.

The long-term, open-label extension studies included 2,562 patients who received ACTEMRA 8mg/kg with or without DMARDs. The total exposure in the long-term safety analysis was 3,685 patient years.

The most commonly reported ADRs (occurring in ≥5% of patients treated with ACTEMRA monotherapy or in combination with DMARDs) were upper respiratory tract infections, nasopharyngitis, headache, hypertension and increased alanine aminotransferase (ALT).

The ADRs listed in Table 1 are presented by system, organ, class and frequency categories, defined using the following convention: very common (≥1/10); common (≥1/100 to <1/10) or uncommon (>=1/1,000 to <1/100). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 1. Summary of ADRs occurring in patients with RA receiving ACTEMRA as monotherapy or in combination with MTX or other DMARDs

System Organ Class	Very common	Common	Uncommon
Infections and infestations	Upper respiratory tract infections	Cellulitis, pneumonia, oral herpes simplex, herpes zoster	Diverticulitis
Gastrointestinal disorders		Mouth ulceration, gastritis	Stomatitis
Skin and subcutaneous tissue disorders		Rash, pruritus	Urticaria
Nervous system disorders		Headache, dizziness
Investigations		Hepatic transaminases increased	Total bilirubin increased
Vascular disorders		Hypertension
Blood and lymphatic system disorders		Leukopenia, neutropenia
Metabolism and nutrition disorders		Hypercholesterolaemia	Hypertriglyceridaemia
General disorders and administration site conditions			Hypersensitivity reactions
Eye disorders		Conjunctivitis

Infections

In the controlled studies the rate of all infections reported with ACTEMRA 8mg/kg plus DMARD treatment was 127 events per 100 patient years compared with 112 events per 100 patient years in the placebo plus DMARD group. In the long-term, open-label extension studies, the rate of infections with ACTEMRA plus DMARDs was 116 events per 100 patient years exposure.

In controlled clinical studies, the rate of serious infections with ACTEMRA 8mg/kg plus DMARDs was 5.3 events per 100 patient years exposure compared to 3.9 events per 100 patient years exposure in the placebo plus DMARD group. In the monotherapy study the rate of serious infections was 3.6 events per 100 patient years of exposure in the ACTEMRA group and 1.5 events per 100 patient years of exposure in the MTX group.

In the long-term safety population (core and extension studies), the rate of serious infections observed with ACTEMRA plus DMARD treatment was 3.9 events per 100 patient years exposure. Reported serious infections included pneumonia, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis and bacterial arthritis. Serious infections were rarely fatal. Cases of opportunistic infections have been reported.

Complications of Diverticulitis

During the six month controlled trials, complications of diverticulitis including generalised purulent peritonitis, lower gastrointestinal perforation, fistulae and abscess have been reported uncommonly with ACTEMRA therapy.

Infusion Reactions

Adverse events associated with infusion (selected events occurring during or within 24 hours of infusion) were reported by 6.9% of patients in the ACTEMRA 8mg/kg plus DMARD group and 5.1% of patients in the placebo plus DMARD group. Events reported during the infusion were primarily episodes of hypertension; events reported within 24 hours of finishing an infusion were headache and skin reactions (rash, urticaria). These events were not treatment limiting.

The rate of anaphylactic reactions (occurring in a total of 6 out of 3,778 patients, 0.2%) was several fold higher with the 4mg/kg dose, compared with the 8mg/kg dose. Clinically significant hypersensitivity reactions associated with ACTEMRA and requiring treatment discontinuation were reported in a total of 13 out of 3,778 patients (0.3%) treated with ACTEMRA during the controlled and open-label clinical studies. These reactions were generally observed during the second to fifth infusions of ACTEMRA.

Immunogenicity

A total of 2,876 patients have been tested for anti-tocilizumab antibodies in the controlled clinical trials. Of the 46 patients (1.6%) who developed anti-tocilizumab antibodies, six had an associated medically significant hypersensitivity reaction, of which five led to permanent discontinuation of treatment. In 30 patients (1.1%) who developed neutralising antibodies, no apparent correlation to clinical response was observed.

Haematological Abnormalities

Decreases in neutrophil counts below 1 x 10⁹/ℓ occurred in 3.4% of patients on ACTEMRA 8mg/kg plus DMARDs compared with <0.1% of patients on placebo plus DMARDs. Approximately half of the patients who developed an absolute neutrophil count (ANC) <1 x 10⁹/ℓ did so within 8 weeks after starting therapy. Decreases below 0.5 x 10⁹/ℓ were reported in 0.3% patients receiving ACTEMRA 8mg/kg plus DMARDs. There was no clear association between decreases in neutrophils and the occurrence of serious infections.

Decreases in platelet counts below 100 x 10³/μℓ occurred in 1.7% of patients on ACTEMRA 8mg/kg plus DMARDs compared to <1% on placebo plus DMARDs. These decreases occurred without associated bleeding events.

Hepatic Transaminase Elevations

Transient elevations in aspartate aminotransferase (AST) >3 x upper limit of normal (ULN) were observed in 2.1% of patients on ACTEMRA 8mg/kg compared with 4.9% of patients on MTX and in 6.5% of patients who received 8mg/kg ACTEMRA plus DMARDs compared with 1.5% of patients on placebo plus DMARDs.

The addition of potentially hepatotoxic drugs (e.g. MTX) to ACTEMRA monotherapy resulted in increased frequency of these elevations. Elevations of ALT/AST >5 x ULN were observed in 0.7% of ACTEMRA monotherapy patients and 1.4% of ACTEMRA plus DMARD patients, the majority of whom were discontinued permanently from ACTEMRA treatment. These elevations were not associated with clinically relevant increases in direct bilirubin, nor were they associated with clinical evidence of hepatitis or hepatic impairment.

Lipid Parameters

During the six month controlled trials, increases of lipid parameters such as total cholesterol, triglycerides, low-density lipoprotein (LDL) cholesterol, and/or high-density lipoprotein (HDL) cholesterol have been reported commonly. Approximately 24% of patients receiving ACTEMRA in clinical trials experienced sustained elevations in total cholesterol ≥6.2 mmol/l, with 15% experiencing a sustained increase in LDL to ≥4.1 mmol/l. Elevations in lipid parameters responded to treatment with lipid-lowering agents.

Malignancies

The clinical data are insufficient to assess the potential incidence of malignancy following exposure to ACTEMRA. Long-term safety evaluations are ongoing.

Overdose

There are limited data available on overdose with ACTEMRA. One case of accidental overdose was reported in which a patient with multiple myeloma received a single dose of 40mg/kg. No adverse reactions were observed.

No serious adverse reactions were observed in healthy volunteers who received a single dose up to 28mg/kg, although dose-limiting neutropenia was observed.

Contraindications

Hypersensitivity to the active substance or to any of the excipients.
Active, severe infections (see below).

Special Warnings and Precautions for Use

Infections

ACTEMRA treatment should not be initiated in patients with active infections. Administration of ACTEMRA should be interrupted if a patient develops a serious infection until the infection is controlled. Healthcare professionals should exercise caution when considering the use of ACTEMRA in patients with a history of recurring or chronic infections or with underlying conditions (e.g. diverticulitis, diabetes) which may predispose patients to infections.

Vigilance for the timely detection of serious infection is recommended for patients receiving biological treatments for moderate to severe rheumatoid arthritis (RA) as signs and symptoms of acute inflammation may be lessened, associated with suppression of the acute phase reaction. The effects of ACTEMRA on C-reactive protein (CRP), neutrophils and signs and symptoms of infection should be considered when evaluating a patient for a potential infection. Patients should be instructed to contact their healthcare professional immediately when any symptoms suggesting infection appear, in order to assure rapid evaluation and appropriate treatment.

Tuberculosis

As recommended for other biological treatments in RA, patients should be screened for latent tuberculosis (TB) infection prior to starting ACTEMRA therapy. Patients with latent TB should be treated with standard anti-mycobacterial therapy before initiating ACTEMRA.

Complications of diverticulitis

Events of diverticular perforations as complications of diverticulitis have been reported uncommonly with ACTEMRA. ACTEMRA should be used with caution in patients with previous history of intestinal ulceration or diverticulitis. Patients presenting with symptoms potentially indicative of complicated diverticulitis, such as abdominal pain, haemorrhage and/or unexplained change in bowel habits with fever should be evaluated promptly for early identification of diverticulitis which can be associated with gastrointestinal perforation.

Hypersensitivity reactions

Serious hypersensitivity reactions have been reported in association with infusion of ACTEMRA in approximately 0.3% of patients. Appropriate treatment should be available for immediate use in the event of an anaphylactic reaction during administration of ACTEMRA.

Active hepatic disease and hepatic impairment

Treatment with ACTEMRA, particularly when administered concomitantly with MTX, may be associated with elevations in hepatic transaminases. Therefore, caution should be exercised when considering treatment of patients with active hepatic disease or hepatic impairment, as the safety of ACTEMRA in these patients has not been adequately studied.

Hepatic transaminase elevations

In clinical trials, transient or intermittent mild and moderate elevations of hepatic transaminases have been reported commonly with ACTEMRA treatment, without progression to hepatic injury. An increased frequency of these elevations was observed when potentially hepatotoxic drugs (e.g. MTX) were used in combination with ACTEMRA.

Caution should be exercised when considering initiation of ACTEMRA treatment in patients with elevated ALT or AST >1.5 x ULN. In patients with baseline ALT or AST >5 x ULN, treatment is not recommended.

ALT and AST levels should be monitored every four to eight weeks for the first six months of treatment followed by every 12 weeks thereafter. For recommended modifications based on transaminases. For ALT or AST elevations >3-5 x ULN, confirmed by repeat testing, ACTEMRA treatment should be interrupted. Once the patients hepatic transaminases are below 3 x ULN, treatment with ACTEMRA may recommence at 4 or 8mg/kg.

Haematological abnormalities

Decreases in neutrophil and platelet counts have occurred following treatment with ACTEMRA 8mg/kg in combination with MTX. There may be an increased risk of neutropenia in patients who have previously been treated with a TNF antagonist.

Caution should be exercised when considering initiation of ACTEMRA treatment in patients with a low neutrophil or platelet count (i.e. ANC <2 x 10⁹/ℓ or platelet count below 100 x 10³/μℓ). In patients with an ANC <0.5 x 10⁹/ℓ or a platelet count <50 x 10³/μℓ treatment is not recommended.

Neutrophils and platelets should be monitored four to eight weeks after start of therapy and thereafter according to standard clinical practice. For recommended dose modifications based on ANC and platelet counts, see the dosing and administration section.

Lipid parameters

Elevations in lipid parameters including total cholesterol, LDL, HDL and triglycerides were observed in patients treated with ACTEMRA. In the majority of patients, there was no increase in atherogenic indices, and elevations in total cholesterol responded to treatment with lipid lowering agents.

Assessment of lipid parameters should be performed four to eight weeks following initiation of ACTEMRA therapy. Patients should be managed according to local clinical guidelines for management of hyperlipidaemia.

Neurological disorders

Physicians should be vigilant for symptoms potentially indicative of new-onset central demyelinating disorders. The potential for central demyelination with ACTEMRA is currently unknown.

Malignancy

The risk of malignancy is increased in patients with RA. Immunomodulatory medicinal products may increase the risk of malignancy.

Vaccinations

Live and live attenuated vaccines should not be given concurrently with ACTEMRA as clinical safety has not been established.

Cardiovascular risk

RA patients have an increased risk for cardiovascular disorders and should have risk factors (e.g. hypertension, hyperlipidaemia) managed as part of usual standard of care.

Combination with TNF antagonists

There is no experience with the use of ACTEMRA with TNF antagonists or other biological treatments for RA. ACTEMRA is not recommended for use with other biological agents.

Sodium

This medicinal product contains 1.17mmol (or 26.55mg) sodium per maximum dose of 1200mg. To be taken into consideration by patients on a controlled sodium diet. Doses below 1025mg of this medicinal product contain less than 1mmol sodium (23mg), i.e. essentially 'sodium free'.

Interaction with other Medicinal Products and other forms of Interaction

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

Population pharmacokinetic analyses did not detect any effect of MTX, non-steroidal anti-inflammatory drugs (NSAIDs) or corticosteroids on ACTEMRA clearance.

The expression of hepatic CYP450 enzymes is suppressed by cytokines, such as interleukin-6 (IL-6), that stimulate chronic inflammation. Thus, CYP450 expression may be reversed when potent cytokine inhibitory therapy, such as ACTEMRA, is introduced.

In vitro studies with cultured human hepatocytes demonstrated that IL-6 caused a reduction in CYP1A2, CYP2C9, CYP2C19, and CYP3A4 enzyme expression. ACTEMRA normalises expression of these enzymes.

When starting or stopping therapy with ACTEMRA, patients taking medicinal products which are individually adjusted and are metabolised via CYP450 3A4, 1A2, 2C9 or 2C19 (e.g. atorvastatin, calcium channel blockers, theophylline, warfarin, phenytoin, ciclosporin, or benzodiazepines) should be monitored as doses may need to be increased to maintain therapeutic effect. Given its long elimination half-life (t_½), the effect of ACTEMRA on CYP450 enzyme activity may persist for several weeks after stopping therapy.

Pregnancy and Lactation

Pregnancy

There are no adequate data from the use of ACTEMRA in pregnant women. A study in animals has shown an increased risk of spontaneous abortion/embryo-foetal death at a high dose. The potential risk for humans is unknown. Women of childbearing potential must use effective contraception during and up to six months after treatment.

ACTEMRA should not be used during pregnancy unless clearly necessary.

Lactation

It is unknown whether ACTEMRA is excreted in human breast milk. The excretion of ACTEMRA in milk has not been studied in animals. A decision on whether to continue/discontinue breastfeeding or to continue/discontinue therapy with ACTEMRA should be made taking into account the benefit of breastfeeding to the child and the benefit of ACTEMRA therapy to the woman.

Effects on Ability to Drive and use Machines

No studies on the effects on the ability to drive and use machines have been performed. However, given that dizziness has been commonly reported, patients who experience this adverse reaction should be advised not to drive or use machines until it has resolved.

Reference:
Actemra Product Information (HK). Current at August 2010