Kineret Side Effects

Generic Name: anakinra

Please note - some side effects for Kineret may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Side Effects of Kineret - for the Consumer

Kineret

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Kineret:

Diarrhea; flu-like symptoms; headache; nausea; reaction at the injection site (eg, redness, swelling, bruising, itching, pain, stinging); sinus inflammation; stomach pain; upper respiratory tract infection.

Seek medical attention right away if any of these SEVERE side effects occur when using Kineret:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); cough; infection (fever, chills, sore throat); unexplained bone or joint pain.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

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Kineret Side Effects - for the Professional

Kineret

Clinical Studies Experience

The most serious adverse reactions were:

• Serious Infections – [see Warnings and Precautions (5.1)]
• Neutropenia, particularly when used in combination with TNF blocking agents

The most common adverse reaction with Kineret is injection-site reactions. These reactions were the most common reason for withdrawing from studies.

Because clinical trials are conducted under widely varying and controlled conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not predict the rates observed in a broader patient population in clinical practice.

The data described herein reflect exposure to Kineret in 3025 patients, including 2124 exposed for at least 6 months and 884 exposed for at least one year. Studies 1 and 4 [see Clinical Studies (14)] used the recommended dose of 100 mg per day. The patients studied were representative of the general population of patients with rheumatoid arthritis.

Injection-site Reactions:

The most common and consistently reported treatment related adverse event associated with Kineret is injection-site reaction (ISR). In Studies 1 and 4, 71% of patients developed an ISR, which was typically reported within the first 4 weeks of therapy. The majority of ISRs were reported as mild (72.6% mild, 24.1% moderate and 3.2% severe). The ISRs typically lasted for 14 to 28 days and were characterized by 1 or more of the following: erythema, ecchymosis, inflammation, and pain.

Infections:

In Studies 1 and 4 combined, the incidence of infection was 39% in the Kineret-treated patients and 37% in placebo-treated patients during the first 6 months of blinded treatment. The incidence of serious infections in Studies 1 and 4 was 2% in Kineret-treated patients and 1% in patients receiving placebo over 6 months. The incidence of serious infection over 1 year was 3% in Kineret-treated patients and 2% in patients receiving placebo. These infections consisted primarily of bacterial events such as cellulitis, pneumonia, and bone and joint infections. Majority of patients (73%) continued on study drug after the infection resolved. No serious opportunistic infections were reported. Patients with asthma appeared to be at higher risk of developing serious infections when treated with Kineret (8 of 177 patients, 4.5%) compared to placebo (0 of 50 patients, 0%).

In open-label extension studies, the overall rate of serious infections was stable over time and comparable to that observed in controlled trials. In clinical studies and postmarketing experience, cases of opportunistic infections have been observed and included fungal, mycobacterial and bacterial pathogens. Infections have been noted in all organ systems and have been reported in patients receiving Kineret alone or in combination with immunosuppressive agents.

In patients who received both Kineret and etanercept for up to 24 weeks, the incidence of serious infections was 7%. The most common infections consisted of bacterial pneumonia (4 cases) and cellulitis (4 cases). One patient with pulmonary fibrosis and pneumonia died due to respiratory failure.

Malignancies:

Among 5300 RA patients treated with Kineret in clinical trials for a mean of 15 months (approximately 6400 patient years of treatment), 8 lymphomas were observed for a rate of 0.12 cases/100 patient years. This is 3.6 fold higher than the rate of lymphomas expected in the general population, based on the National Cancer Institute's Surveillance, Epidemiology and End Results database.9 An increased rate of lymphoma, up to several fold, has been reported in the RA population, and may be further increased in patients with more severe disease activity. Thirty-seven malignancies other than lymphoma were observed. Of these, the most common were breast, respiratory system, and digestive system. There were 3 melanomas observed in Study 4 and its long-term open-label extension, greater than the 1 expected case. The significance of this finding is not known. While patients with RA, particularly those with highly active disease, may be at a higher risk (up to several fold) for the development of lymphoma, the role of IL-1 blockers in the development of malignancy is not known.

Hematologic Events:

In placebo-controlled studies with Kineret, 8% of patients receiving Kineret had decreases in total white blood counts of at least one WHO toxicity grade, compared with 2% of placebo patients. Nine Kineret-treated patients (0.4%) developed neutropenia (ANC < 1 x 109/L). 9 % of patients receiving Kineret had increases in eosinophil differential percentage of at least one WHO toxicity grade, compared with 3 % of placebo patients. Of patients treated concurrently with Kineret and etanercept 2% developed neutropenia (ANC < 1 x 109/L). While neutropenic, one patient developed cellulitis which recovered with antibiotic therapy. 2% of patients receiving Kineret had decreases in platelets, all of WHO toxicity grade one, compared to 0% of placebo patients.

Hypersensitivity Reactions:

Hypersensitivity reactions including anaphylactic reactions, angioedema, urticaria, rash, and pruritus have been reported with Kineret.

Immunogenicity:

In Studies 1 and 4, from which data is available for up to 36 months, 49% of patients tested positively at one or more timepoints for anti-anakinra antibodies in a highly sensitive, anakinra-binding biosensor assay. Of the 1615 patients with available data at Week 12 or later, 30 (2%) were seropositive in a cell-based bioassay for antibodies capable of neutralizing the biologic effects of Kineret. Of the 13 patients with available follow-up data, 5 patients remained positive for neutralizing antibodies at the end of the studies. No correlation between antibody development and adverse events was observed.

Antibody assay results are highly dependent on the sensitivity and specificity of the assays. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including sample handling, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Kineret with the incidence of antibodies to other products may be misleading.

Other Adverse Events:

Table 1 reflects adverse events in Studies 1 and 4, that occurred with a frequency of ≥ 5% in Kineret-treated patients over a 6-month period.

Table 1: Percent of RA Patients Reporting Adverse Events (Studies 1 and 4)

	Placebo			Kineret 100 mg/day
Preferred term	(n = 733)			(n = 1565)
Injection Site Reaction	29%			71%
Worsening of RA	29%			19%
Upper Respiratory Tract Infections	17%			14%
Headache	9%			12%
Nausea	7%			8%
Diarrhea	5%			7%
Sinusitis	7%			7%
Arthralgia	6%			6%
Flu Like Symptoms	6%			6%
Abdominal Pain	5%			5%

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Side Effects by Body System - for Healthcare Professionals

General

In general, the most serious side effects have included infections and neutropenia, while the most common side effects have included injection site reactions.

Local

Five patients with rheumatoid arthritis developed inflammatory lesions at the injection site coincident with anakinra therapy. The onset of the reaction was within the first month of therapy and appeared well-defined erythema and edema. The treatment had been discontinued in two patients, and in one patient it was associated with systemic involvement.

Local side effects have been reported the most frequently. These have included injection site reactions (55.83% to 72.6%) including erythema, ecchymosis, inflammation, and pain. The majority were characterized as mild severity and lasted for 14 to 28 days. At least 5 cases of inflammatory lesions at the injection site have also been reported.

Hematologic

Hematologic side effects have included decreases in absolute neutrophil count (8%), total white blood cell count, and platelets, and small increases in the eosinophil differential percentage. Neutropenia has been reported in 0.3% of study patients receiving anakinra monotherapy and in 3% of patients receiving combination therapy with etanercept.

Immunologic

Immunologic side effects have included development of immunogenicity. Twenty-eight percent of study patients tested positively for anti-anakinra antibodies at 6 months and less than 1% of patients tested seropositive for anakinra neutralizing antibodies.

Gastrointestinal

Gastrointestinal side effects have included nausea (8%), diarrhea (7%), and abdominal pain (5%).

Respiratory

Respiratory side effects have included upper respiratory tract infections (13%) sinusitis (6%), and bronchitis (3.4%).

Nervous system

Nervous system side effects have included headache (12%).

Musculoskeletal

Musculoskeletal side effects have included arthralgia (6%).

Genitourinary

Genitourinary side effects including urinary tract infections have been reported in 4.6% of patients.

Dermatologic

A 75-year-old female with a history of rheumatoid arthritis experienced psoriasis coincident with anakinra therapy. She was administered anakinra therapy 100 mg daily subcutaneously. Nine months later, the patient presented with typical psoriatic, scaly, erythematous plaques on the elbows. Skin biopsy from the patient's left elbow revealed psoriasiform hyperplasia, parakeratosis and lymphocytic infiltrate in the upper dermis, consistent with psoriasis. Therapy with anakinra was discontinued, and the psoriatic lesions improved significantly with the addition of topical steroids and vitamin D. The implication of anakinra in the development of psoriasis seems likely given the temporal relationship between the initiation of anakinra therapy and the onset of the skin condition; and the absence of other known triggering factors for the onset of psoriasis.

Dermatologic side effects including at least one case of psoriasis have been reported.

Other

Patients who received both anakinra and etanercept had a higher incidence of serious infections (7%).

Asthmatic patients had a higher risk of serious infections (5% vs. less than 1% for placebo).

Other side effects including Influenza-like symptoms have been reported in 5.8% of patients. Serious infections that were primarily bacterial have been reported in 1.8% of patients vs. 0.6% for placebo. These have included cellulitis, pneumonia, and bone and joint infections.

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