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Infections

ACTEMRA/RoACTEMRA treatment should not be initiated in patients with active infections. Administration of ACTEMRA/RoACTEMRA 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/RoACTEMRA 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 biologic treatments for moderate to severe RA as signs and symptoms of acute inflammation may be lessened, associated with suppression of the acute-phase reaction. The effects of ACTEMRA/RoACTEMRA 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 biologic treatments in RA, patients should be screened for latent tuberculosis (TB) infection prior to starting ACTEMRA/RoACTEMRA therapy. Patients with latent TB should be treated with standard anti-mycobacterial therapy before initiating ACTEMRA/RoACTEMRA.

Viral reactivation

Viral reactivation (e.g. hepatitis B virus) has been reported with biologic therapies for rheumatoid arthritis. In clinical studies with ACTEMRA/RoACTEMRA, patients who screened positive for hepatitis were excluded.

Complications of diverticulitis

Events of diverticular perforations as complications of diverticulitis have been reported uncommonly with ACTEMRA/RoACTEMRA. ACTEMRA/RoACTEMRA 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/RoACTEMRA 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/RoACTEMRA.

Active hepatic disease and hepatic impairment

Treatment with ACTEMRA/RoACTEMRA, 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.

Hepatic transaminase elevations

In clinical trials, transient or intermittent mild and moderate elevations of hepatic transaminases have been reported commonly with ACTEMRA/RoACTEMRA 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/RoACTEMRA.

Caution should be exercised when considering initiation of ACTEMRA/RoACTEMRA 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 4 to 8 weeks for the first 6 months of treatment followed by every 12 weeks thereafter. For ALT or AST elevations >1-3 x ULN the dose of concomitant MTX should be modified if appropriate. For persistent increases in this range, ACTEMRA/RoACTEMRA dose should be reduced to 4 mg/kg or interrupted until the patient’s ALT or AST have normalised; ACTEMRA/RoACTEMRA should then be restarted with 4 mg/kg or 8 mg/kg, as clinically appropriate. For elevations of >3-5 x ULN, confirmed by repeat testing, ACTEMRA/RoACTEMRA treatment should be interrupted until ALT or AST are <3 x ULN, and then the recommendations above for 1-3 x ULN should be followed. For persistent increases of >3 x ULN, ACTEMRA/ RoACTEMRA should be discontinued.

Haematological abnormalities

Decreases in neutrophil and platelet counts have occurred following treatment with ACTEMRA/RoACTEMRA 8 mg/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/RoACTEMRA treatment in patients with a low neutrophil or platelet count (i.e. ANC <2 x 10⁹/l or platelet count <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.

Severe neutropenia may be associated with an increased risk of serious infections, although there has been no clear association between decreases in neutrophils and the occurrence of serious infections in clinical trials with ACTEMRA/RoACTEMRA to date.

Neutrophils and platelets should be monitored 4 to 8 weeks after start of therapy and thereafter according to standard clinical practice. For recommended dose modifications based on ANC and platelet counts, see the Dosage and Administration section.

Lipid parameters

Elevations in lipid parameters including total cholesterol, LDL, HDL and triglycerides were observed in patients treated with ACTEMRA/RoACTEMRA. 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 4 to 8 weeks following initiation of ACTEMRA/RoACTEMRA 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/RoACTEMRA 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/RoACTEMRA 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/RoACTEMRA with TNF antagonists or other biological treatments for RA. ACTEMRA/RoACTEMRA is not recommended for use with other biological agents.

Sodium

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

Pregnancy and lactation

Pregnancy

There are no adequate data from the use of ACTEMRA/RoACTEMRA 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 3 months after treatment. ACTEMRA/RoACTEMRA should not be used during pregnancy unless clearly necessary.

Lactation

It is unknown whether ACTEMRA/RoACTEMRA is excreted in human breast milk. The excretion of ACTEMRA/RoACTEMRA in milk has not been studied in animals. A decision on whether to continue/discontinue breastfeeding or to continue/discontinue therapy with ACTEMRA/RoACTEMRA should be made taking into account the benefit of breastfeeding to the child and the benefit of ACTEMRA/RoACTEMRA 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:
RoACTEMRA® (tocilizumab) Summary of Product Characteristics. Roche Registration Limited. August 2011.