KINERET 150mg / ml injection solution in pre-filled syringe medication leaflet

Kineret 100 mg/0.67 ml solution for injection in pre-filled syringe.

Each graduated pre-filled syringe contains 100 mg of anakinra* per 0.67 ml (150 mg/ml).

* Human interleukin-1 receptor antagonist (r-metHuIL-1ra) produced in Escherichia coli cells byrecombinant DNA technology.

For the full list of excipients, see section 6.1.

Solution for injection (injection).

Clear, colourless-to-white solution for injection that may contain some product-related translucent-to-white amorphous particles.

Rheumatoid Arthritis (RA)

Kineret is indicated in adults for the treatment of the signs and symptoms of RA in combination withmethotrexate, with an inadequate response to methotrexate alone.

COVID-19

Kineret is indicated for the treatment of coronavirus disease 2019 (COVID-19) in adult patients withpneumonia requiring supplemental oxygen (low- or high-flow oxygen) who are at risk of progressingto severe respiratory failure determined by plasma concentration of soluble urokinase plasminogenactivator receptor (suPAR) ≥ 6 ng/ml (see sections 4.2, pct. 4.4 and 5.1).

Periodic fever syndromes

Kineret is indicated for the treatment of the following autoinflammatory periodic fever syndromes inadults, adolescents, children and infants aged 8 months and older with a body weight of 10 kg orabove:

Cryopyrin-Associated Periodic Syndromes (CAPS)

Kineret is indicated for the treatment of CAPS, including:

- Neonatal-Onset Multisystem Inflammatory Disease (NOMID)/Chronic Infantile Neurological,

Cutaneous, Articular Syndrome (CINCA)

- Muckle-Wells Syndrome (MWS)

- Familial Cold Autoinflammatory Syndrome (FCAS)

Familial Mediterranean Fever (FMF)

Kineret is indicated for the treatment of Familial Mediterranean Fever (FMF). Kineret should be givenin combination with colchicine, if appropriate.

Still’s Disease

Kineret is indicated in adults, adolescents, children and infants aged 8 months and older with a bodyweight of 10 kg or above for the treatment of Still’s disease, including Systemic Juvenile Idiopathic

Arthritis (SJIA) and Adult-Onset Still’s Disease (AOSD), with active systemic features of moderate tohigh disease activity, or in patients with continued disease activity after treatment with non-steroidalanti-inflammatory drugs (NSAIDs) or glucocorticoids.

Kineret can be given as monotherapy or in combination with other anti-inflammatory drugs anddisease-modifying antirheumatic drugs (DMARDs).

Kineret treatment should be initiated and supervised by specialist physicians experienced in thediagnosis and treatment of RA, COVID-19, CAPS, FMF and Still’s disease, respectively.

suPAR testing

If specified in the indication, patient selection for treatment with Kineret based on suPAR level≥ 6 ng/ml should be measured by a validated test (see sections 4.1, pct. 4.4, and 5.1).

RA: Adults

The recommended dose of Kineret is 100 mg administered once a day by subcutaneous injection. Thedose should be administered at approximately the same time each day.

COVID-19: Adults

The recommended dose of Kineret is 100 mg administered once a day by subcutaneous injection for10 days.

CAPS: Adults, adolescents, children and infants aged 8 months and older with a body weight of 10 kgor above

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 offlares.

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 usualmaintenance dose in severe CAPS is 3-4 mg/kg/day, which can be adjusted to a maximum of8 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, andaudiology) and eyes (ophthalmological assessments) are recommended after an initial 3 months oftreatment, and thereafter every 6 months, until effective treatment doses have been identified. Whenpatients are clinically well-controlled, CNS and ophthalmological monitoring may be conductedyearly.

FMF

The recommended dose for patients weighing 50 kg or more is 100 mg/day by subcutaneous injection.

Patients weighing less than 50 kg should be dosed by body weight with a recommended dose of 1-2 mg/kg/day.

Still’s disease

The recommended dose for patients weighing 50 kg or more is 100 mg/day by subcutaneous injection.

Patients weighing less than 50 kg should be dosed by body weight with a starting dose of1-2 mg/kg/day.

Response to treatment should be evaluated after 1 month: In case of persistent systemic manifestationsdose may be adjusted in children or continued treatment with Kineret should be reconsidered by thetreating physician.

Elderly population (≥ 65 years)

RA and COVID-19: No dose adjustment is required. Posology and administration are the same as foradults 18 to 64 years of age.

CAPS: Data in elderly patients are limited. No dose adjustments are expected to be required.

Still’s disease: Data in elderly patients are limited. No dose adjustment are expected to be required.

Paediatric population (< 18 years)

No data are available in children under the age of 8 months.

RA: The efficacy of Kineret in children with RA (JIA) aged 0 to 18 years has not been established.

COVID-19: The efficacy of Kineret in children with COVID-19 aged 0 to 18 years has not beenestablished.

CAPS: Posology and administration in children and infants aged 8 months and older with a bodyweight of 10 kg or above are the same as for adult CAPS patients, based on body weight.

FMF: Children weighing less than 50 kg are dosed by body weight with a recommended dose of1-2 mg/kg/day, patients weighing 50 kg or more are dosed with 100 mg/day. In children withinadequate response the dose can be escalated up to 4 mg/kg/day.

The efficacy data of Kineret in children under 2 years of age with FMF are limited.

Still’s disease: Children weighing less than 50 kg are dosed by body weight with a starting dose of1-2 mg/kg/day, patients weighing 50 kg or more are dosed with 100 mg/day. In children withinadequate response the dose can be escalated up to 4 mg/kg/day.

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.

No dose adjustment is needed for patients with mild renal impairment (CLcr 60 to 89 ml/min). Kineretshould be used with caution in patients with moderate renal impairment (CLcr 30 to 59 ml/min). Inpatients with severe renal impairment (CLcr < 30 ml/min) or end stage renal disease, includingdialysis, administration of the prescribed dose of Kineret every other day should be considered.

Kineret is administered by subcutaneous injection.

Kineret is supplied ready for use in a graduated pre-filled syringe. The graduated pre-filled syringeallows for doses between 20 and 100 mg. As the minimum dose is 20 mg the syringe is not suitable forpaediatric patients with a body weight below 10 kg. The pre-filled syringe should not be shaken. Theinstructions for use and handling are given in section 6.6.

Alternating the injection site is recommended to avoid discomfort at the site of injection. Cooling ofthe injection site, warming the injection liquid to room temperature, use of cold packs (before and afterthe injection), and use of topical glucocorticoids and antihistamines after the injection can alleviate thesigns and symptoms of injection site reactions.

Hypersensitivity to the active substance or to to any of the excipients listed in section 6.1 or to E. coliderived proteins.

Kineret treatment must not be initiated in patients with neutropenia (ANC <1.5 x 109/l) (seesection 4.4).

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

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 appropriatetreatment initiated.

Hepatic Events

In clinical studies transient elevations of liver enzymes have been seen. These elevations have notbeen associated with signs or symptoms of hepatocellular damage, except for one patient with SJIAthat developed a serious hepatitis in connection with a cytomegalovirus infection.

During post-marketing use hepatic events, not affecting liver function, have been reported. Themajority of patients have been treated for Still’s disease or have had predisposing factors, e.g. a historyof transaminase elevations. In addition cases of non-infectious hepatitis, including occasional events ofacute 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 Kinerettreatment. Routine testing of hepatic enzymes during the first month should be considered, especiallyif 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 notbeen evaluated.

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 infectionwas higher in Kineret-treated patients (4.5%) vs. placebo-treated patients (0%), these infections weremainly related to the respiratory tract.

The safety and efficacy of Kineret treatment in patients with chronic and serious infections have notbeen evaluated.

Kineret treatment should not be initiated in patients with active infections. Kineret treatment should bediscontinued in RA patients if a serious infection develops. In Kineret treated CAPS or FMF patients,there is a risk for disease flares when discontinuing Kineret treatment. With careful monitoring,

Kineret treatment can be continued also during a serious infection. Treatment with Kineret for

COVID-19 can be continued despite (secondary) infections.

Physicians should exercise caution when administering Kineret to patients with a history of recurringinfections 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 oftuberculosis in patients receiving several biological anti-inflammatory treatment regimens. Patientsshould be screened for latent tuberculosis prior to initiating Kineret. The available medical guidelinesshould also be taken into account.

Other anti-rheumatic therapies have been associated with hepatitis B reactivation. Therefore, screeningfor viral hepatitis should be performed in accordance with published guidelines also before startingtherapy with Kineret.

Kineret is eliminated by glomerular filtration and subsequent tubular metabolism. Consequentlyplasma clearance of Kineret decreases with decreasing renal function.

No dose adjustment is needed for patients with mild renal impairment (CLcr 60 to 89 ml/min). Kineretshould be used with caution in patients with moderate renal impairment (CLcr 30 to 59 ml/min). Inpatients with severe renal impairment (CLcr <30 ml/min) or end stage renal disease, includingdialysis, administration of the prescribed dose of Kineret every other day should be considered.

Kineret was commonly associated with neutropenia (ANC < 1.5 x 109/l) in placebo-controlled studiesin RA and cases of neutropenia have been observed in patients with COVID-19, CAPS and Still’sdisease. For more information on neutropenia see section 4.3 and 4.8.

Kineret treatment should not be initiated in patients with neutropenia (ANC < 1.5 x 109/l). It isrecommended that neutrophil counts be assessed prior to initiating Kineret treatment, and whilereceiving Kineret, monthly during the first 6 months of treatment and quarterly hereafter. In patientswho become neutropenic (ANC < 1.5 x 109/l) the ANC should be monitored closely and Kinerettreatment should be discontinued. The safety and efficacy of Kineret in patients with neutropenia havenot been evaluated.

Pulmonary Events

During post-marketing use events of interstitial lung disease, pulmonary alveolar proteinosis andpulmonary hypertension have been reported mainly in paediatric patients with Still’s disease treatedwith IL-6 and IL-1 inhibitors, including Kineret. Patients with trisomy 21 seem to be overrepresented.

In company-sponsored clinical studies in Still’s disease no such events were reported. In a non-interventional long-term safety study in 306 paediatric patients with Still’s disease one patientexperienced a serious pulmonary event, an unspecified interstitial lung disease. There was no patientwith pulmonary alveolar proteinosis or pulmonary hypertension in the study. A causal relationshipbetween Kineret and pulmonary events 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 patientstreated with Kineret, predominantly in patients with systemic juvenile idiopathic arthritis (SJIA).

Patients with DRESS may require hospitalization, as this condition may be fatal. If signs andsymptoms of DRESS are present and an alternative aetiology cannot be established, Kineret should bediscontinued and a different treatment considered.

Amyloidosis (systemic)

In patients with NOMID/CINCA who received high doses of Kineret over extended periods of timeand presented with injection site amyloid deposits (see section 4.8) isolated cases of systemic

AIL1RAP (IL-1 receptor antagonist protein) amyloidosis have been reported during post-marketinguse.

In patients with confirmed injection site amyloid deposits, observation for symptoms of systemicamyloidosis, including close monitoring for proteinuria, is recommended.

The impact of treatment with Kineret on pre-existing malignancy has not been studied. Therefore theuse of Kineret in patients with pre-existing malignancy is not recommended.

RA patients may be at a higher risk (on average 2-3 fold) for the development of lymphoma. Inclinical studies, whilst patients treated with Kineret had a higher incidence of lymphoma than theexpected rate in the general population, this rate is consistent with rates reported in general for RApatients.

In clinical studies, the crude incidence rate of malignancy was the same in the Kineret-treated patientsand 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.

In a placebo-controlled clinical study (n = 126), no difference was detected in anti-tetanus antibodyresponse between the Kineret and placebo treatment groups when a tetanus/diphtheria toxoid vaccinewas administered concurrently with Kineret. No data are available on the effects of vaccination withother inactivated antigens, or COVID-19 vaccines, in patients receiving Kineret.

No data are available on either the effects of live vaccination or on the secondary transmission ofinfection by live vaccines in patients receiving Kineret. Therefore, live vaccines should not be givenconcurrently with Kineret.

Elderly population (≥ 65 years)

A total of 752 RA patients ≥ 65 years of age, including 163 patients ≥ 75 years of age, and 173

COVID-19 patients ≥ 65 years of age were studied in clinical studies. No overall differences in safetyor effectiveness were observed between these patients and younger patients. There is limitedexperience in treating elderly CAPS, FMF and Still’s disease patients. Because there is a higherincidence of infections in the elderly population in general, caution should be used in treating elderlypatients.

Concurrent Kineret and TNF-α antagonist treatment

Concurrent administration of Kineret and etanercept has been associated with an increased risk ofserious infections and neutropenia compared to etanercept alone in RA patients. This treatmentcombination has not demonstrated increased clinical benefit.

The concurrent administration of Kineret and etanercept or other TNF-α antagonists is notrecommended (see section 4.5).

COVID-19 Patients

The effect of treatment with Kineret has not been established in COVID-19 patients with suPAR< 6 ng/ml.

Kineret treatment should not be initiated in patients requiring non-invasive or invasive mechanicalventilation, or extracorporeal membrane oxygenation (ECMO) as efficacy has not been established inthese patient populations.

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

Interactions between Kineret and other medicinal products have not been investigated in formalstudies. In clinical studies, interactions between Kineret and other medicinal products (includingnonsteroidal anti-inflammatory medicinal products, glucocorticoids, and DMARDs) have not beenobserved.

Concurrent Kineret and TNF-α antagonist treatment

In a clinical study with RA patients receiving background methotrexate, patients treated with Kineretand etanercept were observed to have a higher rate of serious infections (7%) and neutropenia thanpatients treated with etanercept alone and higher than observed in previous studies where Kineret wasused alone. Concurrent Kineret and etanercept treatment has not demonstrated increased clinicalbenefit.

The concurrent use of Kineret with etanercept or any other TNF-α antagonist is not recommended (seesection 4.4).

Cytochrome P450 Substrates

The formation of CYP450 enzymes is suppressed by increased levels of cytokines (e.g., IL-1) duringchronic 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 clinicallyrelevant for CYP450 substrates with a narrow therapeutic index (e.g. warfarin and phenytoin). Uponstart or end of Kineret treatment in patients on these types of medicinal products, it may be relevant toconsider therapeutic monitoring of the effect or concentration of these products and the individual doseof the medicinal product may need to be adjusted.

For information on vaccinations see section 4.4.

There are limited amount of data from the use of anakinra in pregnant women. Animal studies do notindicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As aprecautionary measure, it is preferable to avoid the use of anakinra during pregnancy and in woman ofchildbearing 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.

Not relevant.

In placebo-controlled studies in RA patients, the most frequently reported adverse reactions with

Kineret were injection site reactions (ISRs), which were mild to moderate in the majority of patients.

The most common reason for withdrawal from study in Kineret-treated RA patients was injection sitereaction. The subject incidence of serious adverse reactions in RA studies at the recommended dose of

Kineret (100 mg/day) was comparable with placebo (7.1% compared with 6.5% in the placebo group).

The incidence of serious infection was higher in Kineret-treated patients compared to patientsreceiving placebo (1.8% vs. 0.7%). Neutrophil decreases occurred more frequently in patientsreceiving Kineret compared with placebo.

Adverse reactions data in COVID-19 are based on a randomized placebo-controlled study of 405

Kineret-treated patients with COVID-19 pneumonia (SAVE-MORE study). The incidence of seriousadverse reactions in the anakinra-treatment group was comparable with the placebo group.

Neutropenia, elevation of liver function test, rash and injection site reactions were reported morefrequently in patients receiving Kineret compared with placebo. The overall safety profile in patientswith COVID-19 treated with Kineret is similar to that in Kineret-treated patients with RA.

Adverse reactions data in CAPS patients are based on an open-label study of 43 patients with

NOMID/CINCA treated with Kineret for up to 5 years, with a total Kineret exposure of 159.8 patientyears. During the 5-year study 14 patients (32.6%) reported 24 serious events. Eleven serious events in4 (9.3%) patients were considered related to Kineret. No patient withdrew from Kineret treatment dueto adverse reactions.

Adverse events data in patients with Still’s disease is based on a partially open-label and partiallyblinded, placebo-controlled study of 15 SJIA patients, treated for up to 1.5 years and a randomiseddouble blind placebo-controlled study of 11 adult and paediatric patients with Still’s disease (6 Kineretand 5 placebo) treated for 12 weeks and followed for an additional 4 weeks. In addition, a non-interventional long-term safety study in 306 paediatric patients with Still’s disease, post-marketingadverse event reports and published studies constitute supporting data.

Adverse events data in patients with FMF are based on post-marketing adverse event reports andpublished studies.

There are no indications either from these studies or from post-marketing adverse reaction reports thatthe overall safety profile in patients with CAPS, FMF or Still’s disease is different from that inpatients with RA, with the exception of the postmarketing observation of a higher frequency ofreported hepatic events in patients with Still’s disease. The adverse reactions table below thereforeapplies to Kineret treatment of RA, CAPS, FMF and Still’s disease. During long term treatment of

RA, CAPS, and Still’s disease the safety profile remains unchanged over time.

Adverse reactions are listed according to MedDRA system organ class and frequency category.

Frequency categories are defined using the following convention: very common (≥ 1/10); common(≥ 1/100 to < 1/10); uncommon (≥ 1/1 000 to < 1/100); rare (≥ 1/10 000 to < 1/1 000); very rare(< 1/10 000); not known (cannot be estimated from the available data). Within each frequencygrouping, adverse reactions are presented in order of decreasing seriousness.

MedDRA Organ System Frequency Undesirable Effect

Infections and infestations Common (≥ 1/100 to < 1/10) Serious infections

Blood and lymphatic system Common (≥ 1/100 to < 1/10) Neutropeniadisorders Thrombocytopenia

Immune system disorders Uncommon (≥ 1/1 000 to < 1/100) Allergic reactions includinganaphylactic reactions,angioedema, urticaria andpruritus

Nervous system disorders Very common (≥ 1/10) Headache

Hepatobiliary disorders Uncommon (≥ 1/1 000 to < 1/100) Hepatic enzyme increased

Not known (cannot be estimated Non-infectious hepatitisfrom the available data)

General disorders and Very common (≥ 1/10) Injection site reactionadministration siteconditions

Skin and subcutaneous tissue Uncommon (≥ 1/1 000 to < 1/100) Rashdisorders Not known (cannot be estimated Injection site amyloid depositsfrom the available data)

Investigations Very common (≥ 1/10) Blood cholesterol increased

The incidence of serious infections in RA studies conducted at the recommended dose (100 mg/day)was 1.8% in Kineret treated patients and 0.7% in placebo-treated patients. In observations up to3 years, the serious infection rate remained stable over time. The infections observed consistedprimarily of bacterial events such as cellulitis, pneumonia, and bone and joint infections. Most patientscontinued on study medicinal product after the infection resolved.

In the clinical study in COVID-19, secondary serious infections were common, however lessfrequently observed in patients treated with Kineret compared to placebo-treated patients.

In a study with 43 CAPS patients followed for up to 5 years the frequency of serious infections was0.1/year, the most common being pneumonia and gastroenteritis. Kineret was temporarily stopped inone patient, all other patients continued Kineret treatment during the infections.

In a study with 15 SJIA patients followed for up to 1.5 years, one patient developed a serious hepatitisin connection with a cytomegalovirus infection. In a study with 11 patients with Still’s disease (SJIAand AOSD) randomized to Kineret (6 patients) or Placebo (5 patients) and followed for 16 weeks, noserious infections were reported. In a non-interventional long-term safety study of Kineret in306 paediatric patients with Still’s disease followed for up to more than 9 years (mean duration of atreatment course with Kineret was 17.0 (standard deviation 21.1) months and the median duration was8.9 months), serious infections were reported in 13 patients. There are no indications from post-marketing adverse event reports and published studies that types and severity of infections in patientswith FMF differ from those in patients with RA, CAPS or Still’s disease.

In clinical studies and during post-marketing use, rare cases of opportunistic infections have beenobserved and have included fungal, mycobacterial, bacterial, and viral pathogens. Infections have beennoted in all organ systems and have been reported in patients receiving Kineret alone or incombination with immunosuppressive agents.

In placebo-controlled RA studies with Kineret, treatment was associated with small reductions in themean values for total white blood count and absolute neutrophil count (ANC). Neutropenia(ANC < 1.5 x 109/l) was reported in 2.4% patients receiving Kineret compared with 0.4% of placebopatients. None of these patients had serious infections associated with the neutropenia.

In the clinical study in COVID-19, events of neutropenia were reported in 3.0% of Kineret-treatedpatients and 0.5% of patients receiving placebo. All adverse events of neutropenia were mild ormoderate in severity.

In a study with 43 CAPS patients followed for up to 5 years neutropenia was reported in 2 patients.

Both episodes of neutropenia resolved over time with continued Kineret treatment.

In a study with 15 SJIA patients followed for up to 1.5 years, one event of transient neutropenia wasreported. In a study with 11 patients with Still’s disease (SJIA and AOSD) randomized to Kineret(6 patients) or Placebo (5 patients) and followed for 16 weeks, no neutropenia was reported. In a non-interventional long-term safety study in 306 paediatric patients with Still’s disease followed for up tomore than 9 years, (mean duration of treatment course with Kineret was 17.0 (standard deviation 21.1)months and the median duration was 8.9 months), 5 events of neutropenia including 1 event of febrileneutropenia, were reported.

In clinical studies in RA patients, thrombocytopenia has been reported in 1.9% of treated patientscompared to 0.3% in the placebo group. The thrombocytopenias have been mild, i.e. platelet countshave been > 75 x109/l. Mild thrombocytopenia has also been observed in CAPS patients.

During post-marketing use of Kineret, thrombocytopenia has been reported, including occasional casereports indicating severe thrombocytopenia (i.e. platelet counts <10 x109/l).

Allergic reactions including anaphylactic reactions, angioedema, urticaria, rash, and pruritus havebeen reported uncommonly with Kineret. The majority of these reactions were maculopapular orurticarial rashes.

In a study with 43 CAPS patients followed for up to 5 years, no allergic event was serious and noevent required discontinuation of Kineret treatment.

In a study with 15 SJIA patients followed for up to 1.5 years, no allergic event was serious and noevent required discontinuation of Kineret. In a study with 11 patients with Still’s disease (SJIA and

AOSD) randomised to Kineret (6 patients) or Placebo (5 patients) and followed for 16 weeks, noallergic reactions were reported.

In a study with 12 FMF patients treated 4 months with Kineret in a published randomized controlledstudy no allergic event was reported as serious and no event required discontinuation of Kineret.

In the clinical study in COVID-19, no allergic reaction was considered related to Kineret.

In clinical studies in RA, up to 3% of adult patients tested seropositive at least once during the studyfor neutralizing anti-anakinra antibodies. The occurrence of antibodies was typically transient and notassociated with clinical adverse reactions or diminished efficacy. In addition, in a clinical study 6% of86 paediatric patients with JIA, whereof none of the 15 SJIA subtype patients, tested seropositive atleast once during the study for neutralizing anti-anakinra antibodies. In a clinical study with 6 patientsrandomized to anakinra for 12 weeks for Still’s disease (SJIA and AOSD), all patients developed

ADAs but none of the patients were tested seropositive for neutralizing anti anakinra antibodies.

The majority of CAPS patients in Study 03-AR-0298 developed anakinra anti-drug antibodies. Thiswas not associated with any clinically significant effects on pharmacokinetics, efficacy, or safety.

Hepatic Events

In clinical studies transient elevations of liver enzymes have been seen. These elevations have notbeen associated with signs or symptoms of hepatocellular damage, except for one patient with SJIAthat developed serious hepatitis in connection with a cytomegalovirus infection.

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 that have been treatedfor Still’s disease and in patients with predisposing factors, e.g. a history of transaminase elevationsbefore start of Kineret treatment.

ISRs typically appear within 2 weeks of therapy and disappear within 4-6 weeks. The development of

ISRs in patients who had not previously experienced ISRs was uncommon after the first month oftherapy.

In RA patients the most common and consistently reported treatment-related adverse reactionsassociated with Kineret were ISRs. The majority (95%) of ISRs were reported as mild to moderate.

These were typically characterised by 1 or more of the following: erythaema, ecchymosis,inflammation, and pain. At a dose of 100 mg/day, 71% of RA patients developed an ISR compared to28% of the placebo treated patients.

In a study with 43 CAPS patients followed for up to 5 years no patient permanently or temporarilydiscontinued Kineret treatment due to injection site reactions.

In a study with 15 SJIA patients followed for up to 1.5 years, the most common and consistentlyreported treatment-related adverse reactions associated with Kineret treatment were ISRs. One out ofthe 15 patients discontinued due to ISRs. In a placebo-controlled study with 11 patients with Still’sdisease (SJIA and AOSD) randomized to Kineret (6 patients) or Placebo (5 patients) for 12 weeks,

ISRs occurred in both treatment groups, of which all were mild in severity. No patient discontinuedtreatment due to ISRs. In a non-interventional long-term safety study in 306 paediatric patients with

Still’s disease followed for up to more than 9 years (mean duration of a treatment course with Kineretwas 17.0 (standard deviation 21.1) months and the median duration was 8.9 months), ISRs ofmoderate or severe intensity had an incidence rate of 1.6 per 100 patient years.

In patients with FMF the types and frequencies of ISRs are similar to those seen in RA and SJIA.

Discontinuations due to ISRs have occurred also in patients with FMF.

In patients with COVID-19 treated with Kineret, injection site reactions were reported with lowfrequency.

Injection site amyloid deposits

During post-marketing use, isolated cases of injection site amyloid deposits have been reported inpatients with NOMID/CINCA who received high doses of Kineret injected subcutaneously into thesame area of skin over long periods of time. Rotation of injection sites is therefore recommended.

Blood cholesterol increase

In clinical studies of RA, 775 patients treated with daily Kineret doses of 30 mg, 75 mg, 150 mg,1 mg/kg or 2 mg/kg, there was an increase of 2.4% to 5.3% in total cholesterol levels 2 weeks afterstart of Kineret treatment, without a dose-response relationship. A similar pattern was seen after24 weeks Kineret treatment. Placebo treatment (n=213) resulted in a decrease of approximately 2.2%in total cholesterol levels at week 2 and 2.3% at week 24. No data are available on LDL or HDLcholesterol.

Kineret has been studied in 36 patients with CAPS, 21 patients with SJIA and 71 patients with otherforms of JIA, aged 8 months to <18 years, for up to 5 years. With the exception of infections andrelated symptoms that were more frequently reported in patients <2 years of age, the safety profile wassimilar in all paediatric age groups. In addition, 306 paediatric patients with Still’s disease have beenfollowed for up to more than 9 years in a non-interventional long-term safety study. The safety profilein paediatric patients was similar to that seen in adult populations and no clinically relevant newadverse reactions were seen.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

No dose-limiting toxicities were observed during clinical studies.

In studies of sepsis, 1 015 patients received Kineret at doses up to 2 mg/kg/hour i.v. (~35 times therecommended dose in RA) over a 72 hour treatment period. The adverse event profile from thesestudies show no overall difference from that seen in the rheumatoid arthritis studies.

Pharmacotherapeutic group: Immunosuppressants, Interleukin inhibitors, ATC code: L04AC03

Anakinra neutralises the biologic activity of interleukin-1α (IL-1α) and interleukin-1β (IL-1β) bycompetitively inhibiting their binding to interleukin-1 type I receptor (IL-1RI). Interleukin-1 (IL-1) isa pivotal pro-inflammatory cytokine mediating many cellular responses including those important insynovial inflammation.

IL-1 is found in the plasma and synovial fluid of patients with rheumatoid arthritis, and a correlationhas been reported between IL-1 concentrations in the plasma and the activity of the disease.

Anakinra inhibits responses elicited by IL-1 in vitro, including the induction of nitric oxide andprostaglandin E2 and/or collagenase production by synovial cells, fibroblasts, and chondrocytes.

In COVID-19 patients, progression from lower respiratory tract infection (LRTI) to severe respiratoryfailure (SRF) is dependent on the early release of IL-1α from virally infected lung epithelial cells,which in turn stimulates further cytokine production including IL-1β from alveolar macrophages.

Spontaneous mutations in the CIAS1/NLRP3 gene have been identified in a majority of patients with

CAPS. CIAS1/NLRP3 encodes for cryopyrin, a component of the inflammasome. The activatedinflammasome results in proteolytic maturation and secretion of IL-1β, which has a broad range ofeffects including systemic inflammation. Untreated CAPS patients are characterized by increased

CRP, SAA and IL-6 relative to normal serum levels. Administration of Kineret results in a decrease inthe acute phase reactants and a decrease in IL-6 expression level has been observed. Decreased acutephase protein levels are noted within the first weeks of treatment.

In patients with FMF, mutation of the MEFV gene encoding for pyrin is leading to malfunctioning andoverproduction of interleukin-1β (IL-1β) in the FMF inflammasome. Untreated FMF is characterizedby increased CRP and SAA. Administration of Kineret results in a decrease in acute phase reactants(e.g. CRP and SAA).

Still’s disease, in addition to various degrees of arthritis, is characterised by systemic inflammatoryfeatures such as spiking fever, skin rash, hepatosplenomegaly, serositis, and increased acute phasereactants driven by IL-1 activity. Systemically, IL-1 is known to cause the hypothalamic feverresponse and promote hyperalgesia. The role of IL-1 in the pathogenesis of Still’s disease has beendemonstrated by ex vivo and gene expression studies.

Clinical efficacy and safety in RA

The safety and efficacy of anakinra in combination with methotrexate have been demonstrated in1 790 RA patients ≥ 18 years of age with varying degrees of disease severity.

A clinical response to anakinra generally appeared within 2 weeks of initiation of treatment and wassustained with continued administration of anakinra. Maximal clinical response was generally seenwithin 12 weeks after starting treatment.

Combined anakinra and methotrexate treatment demonstrates a statistically and clinically significantreduction in the severity of the signs and symptoms of RA in patients who have had an inadequateresponse to methotrexate alone (38% vs. 22% responders as measured by ACR20 criteria). Significantimprovements are seen in the pain, tender joint count, physical function (HAQ score), acute phasereactants and in the patient’s and physician’s global assessment.

X-ray examinations have been undertaken in one clinical study with anakinra. These have shown nodeleterious effect on joint cartilage.

Clinical efficacy and safety in COVID-19

The safety and efficacy of Kineret was evaluated in patients with COVID-19 pneumonia ≥ 18 years ofage with a risk of developing severe respiratory failure in a randomized double-blind placebo-controlled study. The patient population enrolled into the SAVE-MORE study was hospitalized withconfirmed COVID-19 pneumonia (LRTI radiologically confirmed by chest X-ray or CT) and wasconsidered to be at risk of developing SRF, determined by an elevation in suPAR (≥ 6 ng/ml). Patientshad suPAR level ≥ 6 ng/ml measured by the suPARnostic Quick Triage kit. These patients had not yetprogressed to SRF (i.e., exclusion criteria were: pO2/FiO2 ratio less than 150 mmHg or therequirement of mechanical ventilation, NIV, or ECMO). The majority of patients received low- orhigh-flow supplementary oxygen at screening (81.6%). The study enrolled 606 patients and efficacyanalysis was performed in the intention-to-treat (ITT) population comprising of 594 patients of whom189 patients were randomized to the placebo+SoC arm and 405 patients to the anakinra+SoC arm. Themajority of the patients (91.4%) had severe COVID-19 pneumonia and 8.6 % of patients had moderate

COVID-19 pneumonia at start of treatment. 85.9% of patients received dexamethasone. The mean(SD) duration of Kineret treatment was 8.4 (2.1) days. The primary endpoint of the study was thecomparative 11-point WHO Clinical Progression ordinal Scale (CPS) between the two arms oftreatment by Day 28. The 11-point WHO CPS provides a measure of illness severity across a rangefrom 0 (not infected); 1-3 (mild disease), 4-5 (hospitalized - moderate disease), 6-9 (hospitalized -severe disease with increasing degrees of NIV, MV and ECMO) to 10 (dead). Of the patientsrandomised in the SAVE-MORE study 8.6% had a baseline WHO-CPS of 4; 84.7% had a baseline

WHO-CPS of 5 and 6.7% had a baseline WHO-CPS of 6.

In patients treated with Kineret for up to 10 days a significant improvement of the clinical statusaccording to the WHO-CPS was demonstrated by Day 28 compared to placebo (OR: 0.36 [95% CI0.26 to 0.50] P<0.001). Improvement of the patients’ clinical status was seen by Day 14. Thetreatment benefit of Kineret was supported by increase in the number of patients fully recovered andreduction in the number of patients who progressed to severe respiratory failure or death compared toplacebo. No new safety signals or safety concerns were observed from the use of Kineret for treatmentof COVID-19.

Clinical efficacy and safety in CAPS

The safety and efficacy of Kineret have been demonstrated in CAPS patients with varying degrees ofdisease severity. In a clinical study including 43 adult and paediatric patients (36 patients aged8 months to < 18 years) with severe CAPS (NOMID/CINCA and MWS), a clinical response toanakinra was seen within 10 days after initiation of treatment in all patients and was sustained for upto 5 years with the continued administration of Kineret.

Kineret treatment significantly decreases the manifestations of CAPS, including a reduction infrequently occurring symptoms as fever, rash, joint pain, headache, fatigue, and eye redness. A rapidand sustained decrease in the levels of the inflammatory biomarkers; serum amyloid A (SAA),

C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), and a normalization ofinflammatory hematological changes are seen. In the severe form of CAPS, long-term treatmentimproves the systemic inflammatory organ manifestations of the eye, inner ear, and CNS. Hearing andvisual acuity did not deteriorate further during anakinra treatment.

Analysis of treatment-emergent AEs classified by presence of CIAS1 mutation showed that there wereno major differences between the CIAS1 and non-CIAS1 groups in overall AE reporting rates, 7.4 and9.2, respectively. Similar rates were obtained for the groups on the SOC level, except for eye disorderswith 55 AEs (rate 0.5), whereof 35 ocular hyperemia (which could also be a symptom of CAPS) in the

CIAS1 group, and 4 AEs in the non-CIAS1 group (rate 0.1).

Clinical efficacy and safety in FMF

The safety and efficacy of Kineret in the treatment of patients with colchicine resistant FMF has beendemonstrated in a randomized, double-blind, and placebo-controlled published study with a treatmentperiod of 4 months. Primary efficacy outcomes were number of attacks per month, and number ofpatients with a mean of <1 attack per month. 25 patients with colchicine resistant FMF were enrolled;12 randomized to receive Kineret and 13 to receive placebo. The mean number of attacks per patientper month was significantly lower in those receiving Kineret (1.7) compared to placebo (3.5). Thenumber of patients with <1 attack per month was significantly higher in the Kineret group; 6 patients,compared to none in the placebo group.

Additional published data in patients with FMF, intolerant to colchicine or with colchicine resistant

FMF, demonstrate that the clinical effect of Kineret is evident in both clinical symptoms of attacks aswell as in reduced levels of inflammatory markers, such as CRP and SAA. In the published studies thesafety profile of anakinra in patients with FMF was generally similar to that in other indications.

Clinical efficacy and safety in Still’s disease

The efficacy and safety of Kineret for the treatment of Still’s disease (SJIA and AOSD) wereevaluated in a randomized double-blind placebo-controlled multi-center study of 11 patients (aged 1 to51 years) treated for 12 weeks, whereof 6 patients received Kineret. Kineret was efficacious in thetreatment of Still’s disease as demonstrated by superiority to placebo in the primary endpoint ACR30response with absence of fever at Week 2 (p-value = 0.0022). The demonstrated efficacy of Kineret in

ACR30, ACR50, ACR70 and ACR90 responses at Week 2 were sustained throughout the 12 weekstreatment period. No relevant unexpected safety findings were observed in the study, and the resultswere in line with the known safety profile of Kineret.

The safety and efficacy have been demonstrated in a published randomized controlled study in24 SJIA patients treated with Kineret for up to 1 year. After a 1-month blinded phase, 8 of 12 patientsin the Kineret treated group were identified as modified ACRpedi30 responders compared to 1 of 12 inthe placebo group. At the same time point, 7 of 12 in the Kineret treated group were classified as

ACRpedi50 and 5 of 12 as ACRpedi70 responders compared to none in the placebo group. 16 patientscompleted the subsequent open label phase and among 7 responders at month 12, 6 had stoppedglucocorticoid treatment and 5 of them had inactive disease.

In a published prospective, uncontrolled, observational cohort study of 20 patients with new-onset

SJIA Kineret was used as initial therapy after failure to respond to NSAIDs, but before the use of

DMARDs, systemic glucocorticoids, or other biologic agents. Treatment with Kineret resulted innormalization of body temperature in 18 of 20 patients. At 1 year follow-up, 18 of 20 patients showedat least an adapted ACRpedi 70 response, and 17 of 20 patients reached an adapted ACRpedi 90response as well as inactive disease.

A non-interventional safety study in 306 paediatric patients with Still’s disease confirmed the long-term safety profile of Kineret without any new safety findings. Approximately half (46.1%) of thepatients were continuously treated with Kineret for at least 1 year, and 28.1% for at least 2 years. Thepattern and frequency of AEs, including SAEs, were in line with the known safety profile of Kineret.

In general, the rate of AEs was highest during the first 6 months of treatment and considerably lowerduring later time periods. There were no deaths during Kineret treatment. Few patients discontinueddue to AEs. The main reason for Kineret discontinuation was inefficacy however, the second mostcommon reason for discontinuation was disease remission. Long-term treatment with Kineret in SJIApatients was well tolerated, with no overall increase in incidence rate of AEs, including Macrophageactivation syndrome (MAS), over time.

The safety and efficacy of Kineret versus DMARD have been reported in a published 24-weekmulticenter, randomized, open-label study of 22 patients with glucocorticoid-dependent refractory

AOSD. At Week 24, 6 of 12 patients on Kineret were in remission versus 2 of 10 patients on

DMARDs. During an open-label extension phase, switching or add-on treatment with the comparatordrug was possible if improvement did not occur within 24 weeks. 17 patients completed the open-labelextension phase (Week 52), of which 7 of 14 Kineret-treated patients, and 2 of 3 patients on

DMARDs, were in remission at that time point.

Additional published data in Still’s disease indicate that Kineret induces a rapid resolution of systemicfeatures such as fever, rash, and elevation of acute phase reactants. Glucocorticoid doses can in manycases be reduced after initiation of Kineret therapy.

Overall, the efficacy and safety profile of Kineret is comparable in adult and paediatric patients with

CAPS or Still’s disease.

The European Medicines Agency has waived the obligation to submit the results of studies with

Kineret in one or more subsets of the paediatric population in CAPS and RA (JIA) (see section 4.2 forinformation on paediatric use).

Safety in paediatric RA (JIA) patients

Kineret was studied in a single randomized, blinded multi-center study in 86 patients withpolyarticular course JIA (ages 2-17 years) receiving a dose of 1 mg/kg subcutaneously daily, up to amaximum dose of 100 mg. The 50 patients who achieved a clinical response after a 12-week open-label run-in were randomized to Kineret (25 patients) or placebo (25 patients), administered daily foran additional 16 weeks. A subset of these patients continued open-label treatment with Kineret for upto 1 year in a companion extension study. An adverse event profile similar to that seen in adult RApatients was observed in these studies. These study data are insufficient to demonstrate efficacy and,therefore, Kineret is not recommended for paediatric use in JIA.

See section 4.8.

The absolute bioavailability of anakinra after a 70 mg subcutaneous bolus injection in healthy subjects(n = 11) is 95%. The absorption process is the rate-limiting factor for the disappearance of anakinrafrom the plasma after subcutaneous injection. In subjects with RA, maximum plasma concentrationsof anakinra occurred at 3 to 7 hours after subcutaneous administration of anakinra at clinically relevantdoses (1 to 2 mg/kg; n = 18). The plasma concentration decreased with no discernible distributionphase and the terminal half-life ranged from 4 to 6 hours. In RA patients, no unexpected accumulationof anakinra was observed after daily subcutaneous doses for up to 24 weeks. Mean (SD) estimates ofclearance (CL/F) and volume of distribution (Vd/F) by population analysis of data from two PKstudies in 35 RA patients were 105(27) ml/min and 18.5(11) l, respectively. Human and animal datademonstrated that the kidney is the major organ responsible for elimination of anakinra. The clearanceof anakinra in RA patients increased with increasing creatinine clearance.

The influence of demographic covariates on the pharmacokinetics of anakinra was studied usingpopulation pharmacokinetic analysis encompassing 341 patients receiving daily subcutaneousinjection of anakinra at doses of 30, 75, and 150 mg for up to 24 weeks. The estimated anakinraclearance increased with increasing creatinine clearance and body weight. Population pharmacokineticanalysis demonstrated that the mean plasma clearance value after subcutaneous bolus administrationwas approximately 14% higher in men than in women and approximately 10% higher in subjects< 65 years than in subjects ≥ 65 years. However, after adjusting for creatinine clearance and bodyweight, gender and age were not significant factors for mean plasma clearance. No dose adjustment isrequired based on age or gender.

In general the pharmacokinetics in CAPS patients is similar to that in RA patients. In CAPS patientsapproximate dose linearity with a slight tendency to higher than proportional increase has been noted.

Pharmacokinetic data in children < 4 years are lacking, but clinical experience is available from8 months of age, and when started at the recommended daily dose of 1-2 mg/kg, no safety concernshave been identified. Pharmacokinetic data are lacking in older CAPS patients. Distribution into thecerebrospinal fluid has been demonstrated.

The median steady-state dose-normalized anakinra concentration in SJIA patients (aged 3 to 17 years)over 28 weeks was comparable to that observed in RA patients.

A study including 12 patients with hepatic dysfunction (Child-Pugh Class B) given a single 1mg/kgintravenous dose has been performed. Pharmacokinetic parameters were not substantially differentfrom healthy volunteers, other than a decrease in clearance of approximately 30% in comparison withdata from a study with healthy volunteers. A corresponding decrease in creatinine clearance was seenin the hepatic failure population. Accordingly, the decrease in clearance is most likely explained by adecrease in renal function in this population. These data support that no dose adjustment is requiredfor patients with hepatic dysfunction of Child-Pugh Class B. See section 4.2.

The mean plasma clearance of Kineret in subjects with mild (creatinine clearance 50-80 ml/min) andmoderate (creatinine clearance 30-49 ml/min) renal insufficiency was reduced by 16% and 50%,respectively. In severe renal insufficiency and end stage renal disease (creatinine clearance< 30 ml/min), mean plasma clearance declined by 70% and 75%, respectively. Less than 2.5% of theadministered dose of Kineret was removed by hemodialysis or continuous ambulatory peritonealdialysis. These data support that no dose adjustment is needed for patients with mild renal impairment(CLcr 50 to 80 ml/minute). See section 4.2.

Anakinra had no observed effect on the fertility, early development, embryo-foetal development, orperi- and postnatal development in the rat at doses up to 100 times the human dose (2 mg/kg/day). Noeffects on embryo-foetal development in the rabbit were observed at doses 100 times the human dose.

In a standard battery of tests designed to identify hazards with respect to DNA, anakinra did notinduce bacterial or mammalian cell gene mutations. Neither did anakinra increase the incidence ofchromosomal abnormalities or micronuclei in bone marrow cells in mice. Long-term studies have notbeen performed to evaluate the carcinogenic potential of anakinra. Data from mice over expressing

IL-1ra and IL-1ra mutant knock-out mice, did not indicate an increased risk of tumour development.

A formal toxicologic and toxicokinetic interaction study in rats revealed no evidence that Kineretalters the toxicologic or pharmacokinetic profile of methotrexate.

Juvenile rats treated at doses up to 100 times the human dose from day 7 postparturition up toadolescence did not show any signs of adverse effects of the treatment.

Citric acid, anhydrous

Sodium chloride

Disodium edetate dihydrate

Polysorbate 80

Sodium hydroxide

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

3 years.

Store in a refrigerator (2 °C - 8 °C).

Do not freeze.

Store in the original container in order to protect from light.

For the purpose of ambulatory use, Kineret may be kept at room temperature up to 25 °C for amaximum of 72 hours. After removal from the refrigerator, Kineret must be used within 72 hours ordiscarded. Once stored at room temperature, Kineret should not be placed back in the refrigerator.

0.67 ml of solution for injection in a graduated pre-filled syringe (Type I glass) with a plunger stopper(bromobutyl rubber) and 29 gauge needle. The pre-filled syringe has an outer rigid plastic needleshield attached to an inner needle cover.

Pack sizes of 1, 7 or 28 (multipack containing 4 packs of 7 pre-filled syringes) pre-filled syringes.

Not all pack sizes may be marketed.

Kineret is a sterile solution. For single use only.

Do not shake. Allow the pre-filled syringe to reach room temperature before injecting.

Before administration, visually inspect the solution for particulate matter and discolouration. Onlyclear, colourless-to-white solutions that may contain some product-related translucent-to-whiteamorphous particles should be injected.

The presence of these particles does not affect the quality of the product.

The pre-filled syringe is for single use only. Discard any unused medicinal product.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Swedish Orphan Biovitrum AB (publ)

SE-112 76 Stockholm

Sweden

EU/1/02/203/005 - 1-pack

EU/1/02/203/006 - 7-pack

EU/1/02/203/007 - 28-pack

Date of first authorisation: 8 March 2002

Date of latest renewal: 20 March 2007

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.