Anakinra

Medicines can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of anakinra there are no specific foods that you must exclude from your diet when receiving anakinra.

• Store anakinra in its original carton in the refrigerator between 36°F to 46°F (2°C to 8°C).
• Do not freeze or shake anakinra.
• Keep anakinra away from light.
• When traveling, make sure you store anakinra at the correct temperature.
• Keep anakinra and all medicines out of the reach of children.

Contraindications

Hypersensitivity to anakinra, E. coli-derived proteins

Cautions

Renal impairment, chronic infections, immunosuppression, neutropenia

In rheumatoid arthritis, discontinue if severe infection develops and do not initiate with active infection

Use in combination with TNF blocker not recommended

Use caution in geriatric patients because of higher incidence of infection

Not for concomitant administration with live vaccines

Neutrophil counts should be assessed prior to initiating therapy, and while receiving treatment, monthly for 3 months, and thereafter quarterly for a period of up to 1 year

Hypersensitivity reactions, including angioedema and anaphylactic reactions reported

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Recombinant human interleukin-1 (IL-1) receptor antagonist; biologic response modifier and disease-modifying antirheumatic drug (DMARD).1 11

General

• Monitor neutrophil counts prior to and during anakinra therapy.1 12 (See Neutropenia under Cautions.)

Administration

Sub-Q Administration

Administer sub-Q at approximately the same time each day.1

Administer sub-Q injections into the thighs, abdomen, upper arms, or buttocks.17 Rotate injection sites.17 Do not make injections into areas where the skin is tender, bruised, red, or hard; into scars or stretch marks; or close to a vein.17

Allow anakinra prefilled syringe to reach room temperature (about 60–90 minutes) prior to administration.17 Do not remove the needle cover until the prefilled syringe has reached room temperature.17

Intended for use under the guidance and supervision of a clinician, but may be self-administered if the clinician determines that the patient and/or their caregiver is competent to prepare and safely administer the drug.1

Dosage

Adults

100 mg (entire contents [0.67 mL] of one prefilled syringe) daily.1

Prescribing Limits

Adults

Dosages >100 mg daily do not appear to provide additional benefit.1

Special Populations

Renal Impairment

Consider decreasing dosage to 100 mg every other day in patients with severe renal insufficiency or end-stage renal disease (Clcr <30 mL/minute, as estimated from Scr).1 15 (See the Special Populations sections under Pharmacokinetics and under Cautions.)

Storage

Parenteral

2–8°C; do not freeze or shake.1 Protect from light.1

• A biosynthetic (recombinant DNA origin) form of human interleukin-1 (IL-1) receptor antagonist (IL-1Ra).

• A biologic response modifier that blocks the biologic activity of endogenous IL-1.1 3 4 5 9 10 12 11

• Competitively inhibits binding of IL-1 to the interleukin-1 type I receptor (IL-1RI) expressed in many tissues and organs.1 10 Decreases inflammation and cartilage degradation associated with rheumatoid arthritis.1 2 5 10 12

• Importance of providing patient a copy of manufacturer’s patient information.1

• Importance of patient informing clinician about existing or recurrent infections prior to initiating therapy.1 17

• Importance of instructing patient and/or caregiver regarding proper dosage and administration of anakinra, including the use of aseptic technique and safe disposal of needles and syringes, in patients whose clinician has determined that the drug can safely and effectively be self-administered in the patient’s home by the patient, family member, or other responsible individual.1

• Importance of advising patient and/or caregiver about recognition and reporting of adverse effects of anakinra (e.g., sensitivity reactions, infection).1

• Importance of informing clinician if allergy to latex exists.11

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.1

• Importance of informing patients of other important precautionary information.1 (See Cautions.)

Use this medicine as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• It is given as a shot into the fatty part of the skin.
• To gain the most benefit, do not miss doses.
• Keep taking anakinra as you have been told by your doctor or other health care provider, even if you feel well.
• If you will be giving yourself the shot, your doctor or nurse will teach you how to give the shot.
• Follow how to use as you have been told by the doctor or read the package insert.
• Take this medicine at the same time of day.
• Before using anakinra, take it out of the refrigerator and leave it at room temperature for 30 minutes.
• Wash your hands before and after use.
• Move the site where you give the shot with each shot.
• Do not give into red or irritated skin.
• Do not use this medicine if it has been dropped or if it is broken.
• Do not shake.
• Throw away any part left over after the dose is given.
• Throw syringe away after use. Do not use the same syringe more than one time.
• This product may contain small white particles. Do not use if the solution is cloudy, leaking, or has large lumps, flakes, or other particles.
• Do not use if solution changes color.
• Throw away needles in a needle/sharp disposal box. Do not reuse needles or other items. When the box is full, follow all local rules for getting rid of it. Talk with a doctor or pharmacist if you have any questions.

What do I do if I miss a dose?

• Call your doctor to find out what to do.

• Store in a refrigerator. Do not freeze.
• Protect from light.
• Store in original container.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Prefilled Syringe, Subcutaneous [preservative free]:

Kineret: 100 mg/0.67 mL (0.67 mL) [contains disodium edta, polysorbate 80]

Neonatal-onset multisystem inflammatory disease: Treatment of neonatal-onset multisystem inflammatory disease (NOMID).

Rheumatoid arthritis: Reduction in signs and symptoms and slowing the progression of structural damage of moderately to severely active rheumatoid arthritis (RA) in patients 18 years and older who have failed 1 or more disease-modifying antirheumatic drugs (DMARDs).

Hypersensitivity to E. coli-derived proteins, anakinra, or any component of the formulation

There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache, nausea, vomiting, diarrhea, joint pain, pharyngitis, rhinorrhea, rhinitis, or abdominal pain. Have patient report immediately to prescriber signs of infection, bruising, bleeding, severe injection site irritation, severe dizziness, passing out, tachycardia, abnormal heartbeat, or sweating a lot (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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 - [see WARNINGS AND PRECAUTIONS]
• 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.

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.

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.

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.

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

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.

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)

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]. 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.

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.

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.

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.

The immunogenicity of Kineret in NOMID patients was not evaluated.

Table 2: Most common ( > 10% of patients) treatment-emergent adverse events during the first 6 months of Kineret treatment

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

Read the entire FDA prescribing information for Kineret (Anakinra)

Commonly reported side effects of anakinra include: infection, antibody development, and inflammation at injection site. Other side effects include: neutropenia. See below for a comprehensive list of adverse effects.

Initial dose: 1 to 2 mg/kg subcutaneously daily
Maximum dose: 8 mg/kg subcutaneously daily

Comments:
-Doses should be adjusted 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.
-The therapeutic response is primarily reflected by reduction in symptoms such as fever, rash, joint pain, and headache, but also in inflammatory serum markers (CRP/SAA levels), or occurrence of flares.

Use: Cryopyrin-Associated Periodic Syndromes (CAPS): Treatment of Neonatal-Onset Multisystem Inflammatory Disease (NOMID)

Initial dose: 1 to 2 mg/kg subcutaneously daily
Maximum dose: 8 mg/kg subcutaneously daily

Comments:
-Doses should be adjusted 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.
-The therapeutic response is primarily reflected by reduction in symptoms such as fever, rash, joint pain, and headache, but also in inflammatory serum markers (CRP/SAA levels), or occurrence of flares.

Use: Cryopyrin-Associated Periodic Syndromes (CAPS): Treatment of Neonatal-Onset Multisystem Inflammatory Disease (NOMID)

Substance Name

Anakinra

CAS Registry Number

143090-92-0

Drug Class

Antirheumatic Agents\

Cytokines