Kineret

/ Megapharm

RA: Adults: The recommended dose of Kineret is 100 mg administered once a day by subcutaneous injection. The dose should be administered at approximately the same time each day.
CAPS: Adults, adolescents, children and infants aged 8 months and older with a body weight of 10 kg or above: Starting dose: 2 The recommended starting dose in all CAPS subtypes is 1-2 mg/kg/day by subcutaneous injection. The therapeutic response is primarily reflected by reduction in clinical symptoms such as fever, rash, joint pain, and headache, but also in inflammatory serum markers (CRP/SAA levels), or occurrence of flares.
Maintenance dose in mild CAPS (FCAS, mild MWS): Patients are usually well-controlled by maintaining the recommended starting dose (1-2 mg/kg/day).
Maintenance dose in severe CAPS (MWS and NOMID/CINCA): Dose increases may become necessary within 1-2 months based on therapeutic response. The usual maintenance dose in severe CAPS is 3-4 mg/kg/day, which can be adjusted to a maximum of 8 mg/kg/day. In addition to the evaluation of clinical symptoms and inflammatory markers in severe CAPS, assessments of inflammation of the CNS, including the inner ear (MRI or CT, lumbar puncture, and audiology) and eyes (ophthalmological assessments) are recommended after an initial 3 months of treatment, and thereafter every 6 months, until effective treatment doses have been identified. When patients are clinically well-controlled, CNS and ophthalmological monitoring may be conducted yearly.
Elderly population (≥ 65 years): No dose adjustment is required in RA patients. Posology and administration are the same as for adults 18 to 64 years of age. Data in elderly CAPS patients are limited. No dose adjustments are expected to be required.
Paediatric population (< 18 years) RA: The efficacy of Kineret in children with RA (JIA) aged 0 to 18 years has not been established. CAPS: Posology and administration in children and infants aged 8 months and older with a body weight of 10 kg or above are the same as for adult CAPS patients, based on body weight. No data are available in children under the age of 8 months.
Hepatic impairment: No dose adjustment is required for patients with moderate hepatic impairment (Child-Pugh Class B). Kineret should be used with caution in patients with severe hepatic impairment.
Renal impairment: No dosage adjustment is needed for patients with mild renal impairment (CLcr 50 to 80 ml/minute). In the absence of adequate data, Kineret should be used with caution in patients with moderate renal impairment (CLcr 30 to 50 ml/minute). Kineret must not be used in patients with severe renal impairment (CLcr < 30 ml/minute).

Kineret is indicated for the treatment of the signs and symptoms of Rheumatoid Arthritis (RA) in combination with methotrexate, in patients with an inadequate response to methotrexate alone. Kineret is indicated in adults, adolescents, children and infants aged 8 months and older with a body weight of 10 kg or above for the treatment of Cryopyrin-Associated Periodic Syndromes (CAPS), including: Neonatal-Onset Multisystem Inflammatory Disease (NOMID) / Chronic Infantile Neurological, Cutaneous, Articular Syndrome (CINCA). Muckle-Wells Syndrome (MWS). Familial Cold Autoinflammatory Syndrome (FCAS).

Hypersensitivity to the active substance or to to any of the excipients or to E. coli derived proteins. Kineret must not be used in patients with severe renal impairment (CLcr < 30 ml/minute) (see section 4.2). Kineret treatment must not be initiated in patients with neutropenia (ANC <1.5 x 109 /l).

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 should be discontinued and appropriate treatment initiated. The inner needle cover of the pre-filled syringe contains dry natural rubber (a derivative of latex), which may cause severe allergic reactions.
Hepatic Events: In clinical studies in RA and CAPS patients, transient elevations of liver enzymes have been seen uncommonly. These elevations have not been associated with signs or symptoms of hepatocellular damage. During post-marketing use isolated case reports indicating non-infectious hepatitis have been received. Hepatic events during post marketing use have mainly been reported in patients with predisposing factors, e.g history of transaminase elevations before start of Kineret treatment. 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 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 treatment in patients with chronic and serious infections have not been evaluated. Kineret treatment should not be initiated in patients with active infections. Kineret treatment should be discontinued in RA patients if a severe infection develops. In Kineret treated CAPS patients, there is a risk for disease flares when discontinuing Kineret treatment. This should be taken into account when deciding on discontinuing Kineret during a severe infection. Physicians should exercise caution when administering Kineret to patients with a history of recurring infections or with underlying conditions which may predispose them to infections. The safety of Kineret 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. The available medical guidelines should also be taken into account. 4 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.
Neutropenia: Kineret 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 CAPS patients. Kineret 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 treatment, and while receiving Kineret, 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 treatment should be discontinued. The safety and efficacy of Kineret in patients with neutropenia have not been evaluated.
Immunosuppression: The impact of treatment with Kineret on pre-existing malignancy has not been studied. Therefore the use of Kineret in patients with pre-existing malignancy is not recommended.
Vaccinations: In a placebo-controlled clinical trial (n = 126), no difference was detected in anti-tetanus antibody response between the Kineret and placebo treatment groups when a tetanus/diphtheria toxoid vaccine was administered concurrently with Kineret. No data are available on the effects of vaccination with other inactivated antigens in patients receiving Kineret. 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. Therefore, live vaccines should not be given concurrently with Kineret.
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 trials. No overall differences in safety or effectiveness were observed between these patients and younger patients. There is limited experience in treating elderly CAPS 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 and TNF antagonist treatment: Concurrent administration of Kineret 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 and etanercept or other TNF antagonists is not recommended. This medicinal product contains less than 1 mmol sodium (23 mg) per 100 mg dose, i.e. essentially ‘sodium-free’.

Very common: Injection site reaction (usually mild or moderate and more common at the beginning of treatment.), Headaches, Severe infections, Neutropenia, Thrombocytopenia and Blood cholesterol increase.
Side effects requiring special attention by physician: Severe infections, neutropenia, Thrombocytopenia, pneumonia, skin infections.
Severe allergic reactions are not common. However, should any of the following symptoms appear, treatment should be discontinued and medical attention should be sought immediately: Swelling of the face, tongue or throat; problems swallowing or breathing; sudden appearance of rapid pulse or sweating; skin itching or rash.
For full details see prescribing information.

Interactions between Kineret and other medicinal products have not been investigated in formal studies. In clinical trials, interactions between Kineret and other medicinal products (including nonsteroidal anti-inflammatory medicinal products, corticosteroids, and DMARDs) have not been observed.
Concurrent Kineret and TNF antagonist treatment: In a clinical trial with RA patients receiving background methotrexate, patients treated with Kineret and etanercept were observed to have a higher rate of serious infections (7%) and neutropenia than patients treated with etanercept alone and higher than observed in previous trials where Kineret was used alone. Concurrent Kineret and etanercept treatment has not demonstrated increased clinical benefit. The concurrent use of Kineret with etanercept or any other TNF antagonist is not recommended.
Cytochrome P450 Substrates: The formation of CYP450 enzymes is suppressed by increased levels of cytokines (e.g., IL-1) during chronic inflammation. Thus, it may be expected that for an IL-1 receptor antagonist, such as anakinra, the formation of CYP450 enzymes could be normalized during treatment. This would be clinically relevant for CYP450 substrates with a narrow therapeutic index (e.g. warfarin and phenytoin). Upon start or end of Kineret treatment in patients on these types of medicinal products, it may be relevant to consider therapeutic monitoring of the effect or concentration of these products and the individual dose of the medicinal product may need to be adjusted.
For full details see prescribing information.

There are limited amount of data from the use of anakinra in pregnant women. However, reproductive studies have been conducted with Kineret on rats and rabbits at doses up to 100 times the human RA dose and have revealed no evidence of impaired fertility or harm to the foetus. Kineret is not recommended during pregnancy and in women of childbearing potential not using contraception. It is unknown whether anakinra/metabolites are excreted in human milk. A risk to the newborns/ infants cannot be excluded. Breast-feeding should be discontinued during treatment with Kineret.

No dose-limiting toxicities were observed during clinical trials in RA or CAPS patients. In studies of sepsis, 1015 patients received Kineret at doses up to 2 mg/kg/hour i.v. (~35 times the recommended dose in RA) over a 72 hour treatment period. The adverse event profile from these studies show no overall difference from that seen in the rheumatoid arthritis studies.