Anakinra

Anakinra
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]

Disclaimer

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Overview

Anakinra is an interleukin-1 receptor antagonist that is FDA approved for the {{{indicationType}}} of rheumatoid arthritis (RA)and cryopyrin-associated periodic syndromes (CAPS). Common adverse reactions include upper respiratory tract infection, headache, nausea, diarrhea, sinusitis, arthralgia, flu like-symptoms, and abdominal pain.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Rheumatoid Arthritis

• The recommended dose of Kineret for the treatment of patients with rheumatoid arthritis is 100 mg/day administered daily by subcutaneous injection. Higher doses did not result in a higher response. The dose should be administered at approximately the same time every day.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

Condition1

• Developed by:

• Class of Recommendation:

• Strength of Evidence:

• Dosing Information

• Dosage

Condition2

There is limited information regarding Off-Label Guideline-Supported Use of Anakinra in adult patients.

Non–Guideline-Supported Use

Condition1

• Dosing Information

• Dosage

Condition2

There is limited information regarding Off-Label Non–Guideline-Supported Use of Anakinra in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

Cryopyrin-Associated Periodic Syndromes (CAPS)

• The recommended starting dose of Kineret is 1-2 mg/kg for NOMID patients. The dose can be individually adjusted to a maximum of 8 mg/kg daily to control active inflammation.

• Adjust doses in 0.5 to 1.0 mg/kg increments. Once daily administration is generally recommended, but the dose may be split into twice daily administrations. Each syringe is intended for a single use. A new syringe must be used for each dose. Any unused portion after each dose should be discarded.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

Condition1

• Developed by:

• Class of Recommendation:

• Strength of Evidence:

• Dosing Information

• Dosage

Condition2

There is limited information regarding Off-Label Guideline-Supported Use of Anakinra in pediatric patients.

Non–Guideline-Supported Use

Condition1

• Dosing Information

• Dosage

Condition2

There is limited information regarding Off-Label Non–Guideline-Supported Use of Anakinra in pediatric patients.

Contraindications

• Kineret is contraindicated in patients with known hypersensitivity to E coli-derived proteins, Kineret, or any components of the product.

Warnings

Precautions

• Serious Infections

• Kineret has been associated with an increased incidence of serious infections (2%) vs. Placebo (< 1%) in clinical trials in RA. Administration of Kineret in RA should be discontinued if a patient develops a serious infection. In Kineret treated NOMID patients the risk of a NOMID flare when discontinuing Kineret treatment should be weighed against the potential risk of continued treatment. Treatment with Kineret should not be initiated in patients with active infections. The safety and efficacy of Kineret in immunosuppressed patients or in patients with chronic infections have not been evaluated.
• Drugs that affect the immune system by blocking tumor necrosis factor (TNF) have been associated with an increased risk of reactivation of latent tuberculosis (TB). It is possible that taking drugs such as Kineret that blocks IL-1 increases the risk of TB or other atypical or opportunistic infections. Health care providers should follow current CDC guidelines both to evaluate for and to treat possible latent tuberculosis infections before initiating therapy with Kineret.

• Use With TNF Blocking Agents

• In a 24-week study of concurrent Kineret and etanercept therapy in RA patients, the rate of serious infections in the combination arm (7%) was higher than with etanercept alone (0%). The combination of Kineret and etanercept did not result in higher ACR response rates compared to etanercept alone [see clinical studies (14)]. Use of Kineret in combination with TNF blocking agents is not recommended.

• Hypersensitivity Reactions

• Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been reported with Kineret. If a severe hypersensitivity reaction occurs, administration of Kineret should be discontinued and appropriate therapy initiated.
• The needle cover of the prefilled syringe contains dry natural rubber (a derivative of latex), which may cause allergic reactions in individuals sensitive to latex.

• Immunosuppression

• The impact of treatment with Kineret on active and/or chronic infections and the development of malignancies is not known [see Adverse Reactions (6)].

• Immunizations

• 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 the tetanus/diphtheria toxoids 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 the secondary transmission of infection by live vaccines in patients receiving Kineret. Therefore, live vaccines should not be given concurrently with Kineret.

• Neutrophil Count

• Patients receiving Kineret may experience a decrease in neutrophil counts. Neutrophil counts should therefore be assessed prior to initiating Kineret treatment, and while receiving Kineret, monthly for 3 months, and thereafter quarterly for a period up to 1 year.
• In the placebo-controlled studies, 8% of RA patients receiving Kineret had decreases in neutrophil counts of at least one World Health Organization (WHO) toxicity grade compared with 2% in the placebo control group. Nine Kineret-treated patients (0.4%) experienced neutropenia (ANC < 1 x 109/L). This is discussed in more detail in the Adverse Reactions (6): Hematologic Events (6.1) section.
• In 43 NOMID patients followed for up to 60 months 2 patients experienced neutropenia that resolved over time during continued Kineret treatment. [see Adverse Reactions (6.2)]

Adverse Reactions

Clinical Trials Experience

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

Clinical Studies Experience in RA

• The most serious adverse reactions were:

• Serious Infections
• 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.

• 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 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 (SEER) database.3 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

• As with all therapeutic proteins, there is potential for immunogenicity. In Studies 1 and 4, from which data is available for up to 36 months, 49% of patients tested positive for anti-anakinra binding antibodies at one or more time points using a biosensor assay. Of the 1615 patients with available data at Week 12 or later, 30 (2%) tested positive for neutralizing antibodies in a cell-based bioassay. 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.
• The detection of antibody formation is highly dependent on the sensitivity and specificity of the assays. Additionally, the observed incidence of antibody (including neutralizing 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.

T1

Clinical Study Experience in NOMID

• The data described herein reflect an open-label study in 43 NOMID patients exposed to Kineret for up to 60 months adding up to a total exposure of 159.8 patient years.

• Patients were treated with a starting dose of 1 to 2 mg/kg/day and an average maintenance dose of 3-4 mg/kg/day adjusted depending on the severity of disease. Among pediatric NOMID patients, doses up to 7.6 mg/kg/day have been maintained for up to 15 months.

• There were 24 serious adverse events (SAEs) reported in 14 of the 43 treated patients. The most common type of SAEs reported were infections [see Warnings and Precautions (5.1)]. Five SAEs were related to lumbar puncture, which was part of the study procedure.

• There were no permanent discontinuations of study drug treatment due to AEs. Doses were adjusted in 5 patients because of AEs; all were dose increases in connection with disease flares.

• The reporting frequency of AEs was highest during the first 6 months of treatment. The incidence of AEs did not increase over time, and no new types of AEs emerged.

• The most commonly reported AEs during the first 6 months of treatment (incidence >10%) were injection site reaction (ISR), headache, vomiting, arthralgia, pyrexia, and nasopharyngitis (Table 2).

• The most commonly reported AEs during the 60-month study period, calculated as the number of events/patient years of exposure, were arthralgia, headache, pyrexia, upper respiratory tract infection, nasopharyngitis, and rash.

• The AE profiles for different age groups <2 years, 2-11 years, and 12-17 years corresponded to the AE profile for patients ≥18 years, with the exception of infections and related symptoms being more frequent in patients <2 years.

• Infections

• The reporting rate for infections was higher during the first 6 months of treatment (2.3 infections/patient-year) compared to after the first 6 months (1.7 infections/patient year). The most common infections were upper respiratory tract infection, sinusitis, ear infections, and nasopharyngitis.
• There were no deaths or permanent treatment discontinuations due to infections. In one patient Kineret administration was temporarily stopped during an infection and in 5 patients the dose of Kineret was increased due to disease flares in connection with infections. Thirteen infections in 7 patients were classified as serious, the most common being pneumonia and gastroenteritis occurring in 3 and 2 patients, respectively. No serious opportunistic infections were reported.
• The reporting frequency for infections was highest in patients <12 years of age.

• Hematologic Events

• After start of Kineret treatment neutropenia was reported in 2 patients. One of these patients experienced an upper respiratory tract infection and an otitis media infection. Both episodes of neutropenia resolved over time with continued Kineret treatment.

• Injection Site Reactions

• In total, 17 injection site reactions (ISRs) were reported in 10 patients during the 60-month study period. Out of the 17 ISRs, 11 (65%) occurred during the first month and 13 (76%) were reported during the first 6 months. No ISR was reported after Year 2 of treatment. The majority of ISRs were reported as mild (76% mild, 24% moderate). No patient permanently or temporarily discontinued Kineret treatment due to injection site reactions.

• Immunogenicity

• The immunogenicity of Kineret in NOMID patients was not evaluated.

T2

• The most common adverse reactions occurring after the first 6-month period of treatment with Kineret (up to 60 months of treatment) included: arthralgia, headache, pyrexia, upper respiratory tract infection, nasopharyngitis, and rash.

Postmarketing Experience

• The following adverse reactions have been identified during postapproval use of Kineret. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Hepato-biliary disorders

Elevations of transaminases, non-infectious hepatitis

Drug Interactions

• TNF Blocking Agents

• A higher rate of serious infections has been observed in patients treated with concurrent Kineret and etanercept therapy than in patients treated with etanercept alone. Two percent of patients treated concurrently with Kineret and etanercept developed neutropenia (ANC < 1 x 109/L). Use of Kineret in combination with TNF blocking agents is not recommended.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA):

• Pregnancy Category

Pregnancy Category (AUS):

• Australian Drug Evaluation Committee (ADEC) Pregnancy Category

There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Anakinra in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Anakinra during labor and delivery.

Nursing Mothers

There is no FDA guidance on the use of Anakinra with respect to nursing mothers.

Pediatric Use

There is no FDA guidance on the use of Anakinra with respect to pediatric patients.

Geriatic Use

There is no FDA guidance on the use of Anakinra with respect to geriatric patients.

Gender

There is no FDA guidance on the use of Anakinra with respect to specific gender populations.

Race

There is no FDA guidance on the use of Anakinra with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Anakinra in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Anakinra in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Anakinra in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Anakinra in patients who are immunocompromised.

Administration and Monitoring

Administration

• Oral

• Intravenous

Monitoring

There is limited information regarding Monitoring of Anakinra in the drug label.

• Description

IV Compatibility

There is limited information regarding IV Compatibility of Anakinra in the drug label.

Overdosage

Acute Overdose

Signs and Symptoms

• Description

Management

• Description

Chronic Overdose

There is limited information regarding Chronic Overdose of Anakinra in the drug label.

Pharmacology

There is limited information regarding Anakinra Pharmacology in the drug label.

Mechanism of Action

Structure

This image is provided by the National Library of Medicine.

Pharmacodynamics

There is limited information regarding Pharmacodynamics of Anakinra in the drug label.

Pharmacokinetics

There is limited information regarding Pharmacokinetics of Anakinra in the drug label.

Nonclinical Toxicology

There is limited information regarding Nonclinical Toxicology of Anakinra in the drug label.

Clinical Studies

There is limited information regarding Clinical Studies of Anakinra in the drug label.

How Supplied

Storage

There is limited information regarding Anakinra Storage in the drug label.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

There is limited information regarding Patient Counseling Information of Anakinra in the drug label.

Precautions with Alcohol

• Alcohol-Anakinra interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

• ®

Look-Alike Drug Names

• A® — B®

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

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