Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use

Traceability
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Allergic reactions
Allergic reactions, including anaphylactic reactions and angioedema have been reported uncommonly. The majority of these reactions were maculopapular or urticarial rashes.

If a severe allergic reaction occurs, administration of Kineret 100 mg solution for injection should be discontinued and appropriate treatment initiated.
Hepatic Events
In clinical studies transient elevations of liver enzymes have been seen. These elevations have not been associated with signs or symptoms of hepatocellular damage, except for one patient with SJIA that developed a serious hepatitis in connection with a cytomegalovirus infection.

During post-marketing use hepatic events, not affecting liver function, have been reported.
The majority of patients have been treated for Still’s disease or have had predisposing factors, e.g.
a history of transaminase elevations. In addition cases of non-infectious hepatitis, including occasional events of acute liver failure, have been reported in patients with Still’s disease during Kineret treatment. Hepatic events in patients with Still’s disease predominantly occur during the first month of Kineret treatment. Routine testing of hepatic enzymes during the first month should be considered, especially if the patient has pre-disposing factors or develops symptoms indicating liver dysfunction. The efficacy and safety of Kineret in patients with AST/ALT ≥ 1.5 x upper level of normal have not been evaluated.

Serious infections
Kineret 100 mg solution for injection has been associated with an increased incidence of serious infections (1.8%) vs. placebo (0.7%) in RA patients. For a small number of patients with asthma, the incidence of serious infection was higher in Kineret-treated patients (4.5%) vs. placebo- treated patients (0%); these infections were mainly related to the respiratory tract.

The safety and efficacy of Kineret 100 mg solution for injection treatment in patients with chronic and serious infections have not been evaluated.

Kineret 100 mg solution for injection treatment should not be initiated in patients with active infections. Kineret treatment should be discontinued in RA patients if a serious infection develops. In Kineret 100 mg solution for injection treated CAPS or FMF patients, there is a risk for disease flares when discontinuing Kineret 100 mg solution for injection treatment. With careful monitoring, Kineret 100 mg solution for injection treatment can be continued also during a serious infection.

Physicians should exercise caution when administering Kineret 100 mg solution for injection to patients with a history of recurring infections or with underlying conditions which may predispose them to infections.

The safety of Kineret 100 mg solution for injection in individuals with latent tuberculosis is unknown. There have been reports of tuberculosis in patients receiving several biological anti- inflammatory treatment regimens. Patients should be screened for latent tuberculosis prior to initiating Kineret 100 mg solution for injection. The available medical guidelines should also be taken into account.

Other anti-rheumatic therapies have been associated with hepatitis B reactivation. Therefore, screening for viral hepatitis should be performed in accordance with published guidelines also before starting therapy with Kineret 100 mg solution for injection.

Renal impairment
Kineret 100 mg solution for injection is eliminated by glomerular filtration and subsequent tubular metabolism. Consequently, plasma clearance of Kineret 100 mg solution for injection decreases with decreasing renal function.
No dose adjustment is needed for patients with mild renal impairment (CLcr 60 to 89 ml/min).
Kineret 100 mg solution for injection should be used with caution in patients with moderate renal impairment (CLcr 30 to 59 ml/min). Kineret must not be used in patients with severe renal impairment (CLcr < 30 ml/minute).

Neutropenia
Kineret 100 mg solution for injection was commonly associated with neutropenia (ANC < 1.5 x 109/l) in placebo-controlled studies in RA and cases of neutropenia have been observed in patients with CAPS. For more information on neutropenia see section 4.8.

Kineret 100 mg solution for injection treatment should not be initiated in patients with neutropenia (ANC < 1.5 x 109/l). It is recommended that neutrophil counts be assessed prior to initiating Kineret 100 mg solution for injection treatment, and while receiving Kineret 100 mg solution for injection, monthly during the first 6 months of treatment and quarterly hereafter. In patients who become neutropenic (ANC < 1.5 x 109/l) the ANC should be monitored closely and Kineret 100 mg solution for injection treatment should be discontinued. The safety and efficacy of Kineret 100 mg solution for injection in patients with neutropenia have not been evaluated.

Pulmonary Events
During post-marketing use events of interstitial lung disease, pulmonary alveolar proteinosis and pulmonary hypertension have been reported mainly in paediatric patients with Still’s disease treated with IL-6 and IL-1 inhibitors, including Kineret. Patients with trisomy 21 seem to be overrepresented. A causal relationship with Kineret has not been established.

Drug reaction with eosinophilia and systemic symptoms (DRESS)
Drug reaction with eosinophilia and systemic symptoms (DRESS) has rarely been reported in patients treated with Kineret 100 mg solution for injection, predominantly in patients with systemic juvenile idiopathic arthritis (SJIA). Patients with DRESS may require hospitalization, as this condition may be fatal. If signs and symptoms of DRESS are present and an alternative aetiology cannot be established, Kineret 100 mg solution for injection should be discontinued and a different treatment considered.

Immunosuppression
The impact of treatment with Kineret 100 mg solution for injection on pre-existing malignancy has not been studied. Therefore, the use of Kineret 100 mg solution for injection in patients with pre-existing malignancy is not recommended.

Malignancies
RA patients may be at a higher risk (on average 2-3 fold) for the development of lymphoma. In clinical trials, whilst patients treated with Kineret 100 mg solution for injection had a higher incidence of lymphoma than the expected rate in the general population, this rate is consistent with rates reported in general for RA patients.

In clinical studies, the crude incidence rate of malignancy was the same in the Kineret-treated patients and the placebo-treated patients and did not differ from that in the general population.
Furthermore, the overall incidence of malignancies was not increased during 3 years of patient exposure to Kineret 100 mg solution for injection.

Vaccinations
In a placebo-controlled clinical study (n = 126), no difference was detected in anti-tetanus antibody response between the Kineret 100 mg solution for injection and placebo treatment groups when a tetanus/diphtheria toxoid vaccine was administered concurrently with Kineret 100 mg solution for injection. No data are available on the effects of vaccination with other inactivated antigens in patients receiving Kineret 100 mg solution for injection.

No data are available on either the effects of live vaccination or on the secondary transmission of infection by live vaccines in patients receiving Kineret 100 mg solution for injection. Therefore, live vaccines should not be given concurrently with Kineret 100 mg solution for injection.

Elderly population (≥ 65 years)
A total of 752 RA patients ≥ 65 years of age, including 163 patients ≥ 75 years of age, were studied in clinical studies. No overall differences in safety or effectiveness were observed between these patients and younger patients. There is limited experience in treating elderly CAPS and FMF disease patients. Because there is a higher incidence of infections in the elderly population in general, caution should be used in treating elderly patients.

Concurrent Kineret 100 mg solution for injection and TNF-α antagonist treatment Concurrent administration of Kineret 100 mg solution for injection and etanercept has been associated with an increased risk of serious infections and neutropenia compared to etanercept alone in RA patients. This treatment combination has not demonstrated increased clinical benefit.

The concurrent administration of Kineret 100 mg solution for injection and etanercept or other TNF-α antagonists is not recommended (see section 4.5).

Sodium content
This medicinal product contains less than 1 mmol sodium (23 mg) per 100 mg dose, that is to say essentially ‘sodium-free’.

Effects on Driving

4.7   Effects on ability to drive and use machines

Not relevant.