KINERET 100 MG SOLUTION FOR INJECTION

Israel - English - Ministry of Health

Buy It Now

Active ingredient:
ANAKINRA
Available from:
MEGAPHARM LTD
ATC code:
L04AC03
Pharmaceutical form:
SOLUTION FOR INJECTION
Composition:
ANAKINRA 150 MG/ML
Administration route:
S.C
Prescription type:
Required
Manufactured by:
SOBI SWEDISH ORPHAN BIOVITRUM AB
Therapeutic group:
ANAKINRA
Therapeutic area:
ANAKINRA
Therapeutic indications:
Kineret is indicated in adults for the treatment of the signs and symptoms of rheumatoid arthritis in combination with Methotrexate, in patients with an inadequate response to Methotrexate alone.Kineret is indicated in adults, adolescents, children and infants aged 8 months and older with a body weight of 10 kg or above for the treatment of Cryopyrin-Associated Periodic Syndromes (CAPS), including:- Neonatal-Onset Multisystem Inflammatory Disease (NOMID) / Chronic Infantile Neurological, Cutaneous, Articular Syndrome (CINCA)- Muckle-Wells Syndrome (MWS)- Familial Cold Autoinflammatory Syndrome (FCAS)
Authorization number:
145 79 33059 00
Authorization date:
2016-03-31

Documents in other languages

Patient Information leaflet Patient Information leaflet - Arabic

26-01-2021

Patient Information leaflet Patient Information leaflet - Hebrew

04-04-2017

KINPIL 082016 P.2

Summary of Product Characteristics

1. NAME OF THE MEDICINAL PRODUCT

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

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

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 by

recombinant DNA technology.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Solution for injection (injection).

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

to-white amorphous particles.

4. CLINICAL PARTICULARS

4.1

Therapeutic indications

Kineret is indicated in adults for the treatment of the signs and symptoms of Rheumatoid Arthritis

(RA) in combination with methotrexate, in patients with an inadequate response to methotrexate

alone.

Kineret is indicated in adults, adolescents, children and infants aged 8 months and older with a body

weight of 10 kg or above for the treatment of Cryopyrin-Associated Periodic Syndromes (CAPS),

including:

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

Cutaneous, Articular Syndrome (CINCA)

Muckle-Wells Syndrome (MWS)

Familial Cold Autoinflammatory Syndrome (FCAS)

4.2 Posology and method of administration

Kineret treatment should be initiated and supervised by specialist physicians experienced in the

diagnosis and treatment of rheumatoid arthritis and CAPS, respectively.

Posology

RA: Adults

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

The dose should be administered at approximately the same time each day.

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

or above

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Starting dose:

The recommended starting dose in all CAPS subtypes is 1-2 mg/kg/day by subcutaneous injection.

The therapeutic response is primarily reflected by reduction in clinical symptoms such as fever, rash,

joint pain, and headache, but also in inflammatory serum markers (CRP/SAA levels), or occurrence of

flares.

Maintenance dose in mild CAPS (FCAS, mild MWS):

Patients are usually well-controlled by maintaining the recommended starting dose (1-2 mg/kg/day).

Maintenance dose in severe CAPS (MWS and NOMID/CINCA):

Dose increases may become necessary within 1-2 months based on therapeutic response. The usual

maintenance dose in severe CAPS is 3-4 mg/kg/day, which can be adjusted to a maximum of 8

mg/kg/day.

In addition to the evaluation of clinical symptoms and inflammatory markers in severe CAPS,

assessments of inflammation of the CNS, including the inner ear (MRI or CT, lumbar puncture, and

audiology) and eyes (ophthalmological assessments) are recommended after an initial 3 months of

treatment, and thereafter every 6 months, until effective treatment doses have been identified.

When patients are clinically well-controlled, CNS and ophthalmological monitoring may be conducted

yearly.

Elderly population (≥ 65 years)

No dose adjustment is required in RA patients. Posology and administration are the same as for

adults 18 to 64 years of age.

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

Paediatric population (< 18 years)

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

CAPS: Posology and administration in children and infants aged 8 months and older with a body

weight of 10 kg or above are the same as for adult CAPS patients, based on body weight. No data are

available in children under the age of 8 months.

Hepatic impairment

No dose adjustment is required for patients with moderate hepatic impairment (Child-Pugh Class B).

Kineret should be used with caution in patients with severe hepatic impairment.

Renal impairment

No dosage adjustment is needed for patients with mild renal impairment (CL

50 to 80 ml/minute).

In the absence of adequate data, Kineret should be used with caution in patients with moderate

renal impairment (CL

30 to 50 ml/minute). Kineret must not be used in patients with severe renal

impairment (CL

< 30 ml/minute) (see section 4.3).

Method of administration

Kineret is administered by subcutaneous injection.

Kineret is supplied ready for use in graduated a pre-filled syringe. The graduated pre-filled syringe

allows for doses between 20 and 100 mg. As the minimum dose is 20 mg the syringe is not suitable

for paediatric patients with a body weight below 10 kg. The pre-filled syringe should not be shaken.

The instructions 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 of

the injection site, warming the injection liquid, use of cold packs (before and after the injection), and

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use of topical corticosteroids and antihistamines after the injection can alleviate the signs and

symptoms of injection site reactions.

4.3

Contraindications

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

derived proteins.

Kineret must not be used in patients with severe renal impairment (CL

< 30 ml/minute) (see

section 4.2).

Kineret treatment must not be initiated in patients with neutropenia (ANC <1.5 x 10

/l) (see section

4.4).

4.4

Special warnings and precautions for use

Allergic reactions

Allergic reactions, including anaphylactic reactions and angioedema have been reported

uncommonly. The majority of these reactions were maculopapular or urticarial rashes.

If a severe allergic reaction occurs, administration of Kineret should be discontinued and appropriate

treatment initiated.

Hepatic Events

In clinical studies in RA and CAPS patients, transient elevations of liver enzymes have been seen

uncommonly. These elevations have not been associated with signs or symptoms of hepatocellular

damage. During post-marketing use isolated case reports indicating non-infectious hepatitis have

been received. Hepatic events during post marketing use have mainly been reported in patients with

predisposing factors, e.g history of transaminase elevations before start of Kineret treatment.

The efficacy and safety of Kineret in patients with AST/ALT ≥1.5 x upper level of normal have not

been evaluated

Serious infections

Kineret has been associated with an increased incidence of serious infections (1.8%) vs. placebo

(0.7%) in RA patients. For a small number of patients with asthma, the incidence of serious infection

was higher in Kineret-treated patients (4.5%) vs. placebo-treated patients (0%), these infections were

mainly related to the respiratory tract.

The safety and efficacy of Kineret treatment in patients with chronic and serious infections have not

been evaluated.

Kineret treatment should not be initiated in patients with active infections. Kineret treatment should

be discontinued in RA patients if a severe infection develops. In Kineret treated CAPS patients, there

is a risk for disease flares when discontinuing Kineret treatment. This should be taken into account

when deciding on discontinuing Kineret during a severe infection.

Physicians should exercise caution when administering Kineret to patients with a history of recurring

infections or with underlying conditions which may predispose them to infections.

The safety of Kineret in individuals with latent tuberculosis is unknown. There have been reports of

tuberculosis in patients receiving several biological anti-inflammatory treatment regimens. Patients

should be screened for latent tuberculosis prior to initiating Kineret. The available medical guidelines

should also be taken into account.

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Other anti-rheumatic therapies have been associated with hepatitis B reactivation. Therefore,

screening for viral hepatitis should be performed in accordance with published guidelines also before

starting therapy with Kineret.

Neutropenia

Kineret was commonly associated with neutropenia (ANC < 1.5 x 10

/L) in placebo-controlled studies

in RA and cases of neutropenia have been observed in CAPS patients. For more information on

neutropenia see section 4.8.

Kineret treatment should not be initiated in patients with neutropenia (ANC < 1.5 x 10

/l). It is

recommended that neutrophil counts be assessed prior to initiating Kineret treatment, and while

receiving Kineret, monthly during the first 6 months of treatment and quarterly hereafter. In patients

who become neutropenic (ANC < 1.5 x 10

/l) the ANC should be monitored closely and Kineret

treatment should be discontinued. The safety and efficacy of Kineret in patients with neutropenia

have not been evaluated.

Immunosuppression

The impact of treatment with Kineret on pre-existing malignancy has not been studied. Therefore the

use of Kineret in patients with pre-existing malignancy is not recommended.

Vaccinations

In a placebo-controlled clinical trial (n = 126), no difference was detected in anti-tetanus antibody

response between the Kineret and placebo treatment groups when a tetanus/diphtheria toxoid

vaccine was administered concurrently with Kineret. No data are available on the effects of

vaccination with other inactivated antigens in patients receiving Kineret.

No data are available on either the effects of live vaccination or on the secondary transmission of

infection by live vaccines in patients receiving Kineret. Therefore, live vaccines should not be given

concurrently with Kineret.

Elderly population (≥ 65 years)

A total of 752 RA patients

65 years of age, including 163 patients

75 years of age, were studied in

clinical trials. No overall differences in safety or effectiveness were observed between these patients

and younger patients. There is limited experience in treating elderly CAPS patients. Because there is a

higher incidence of infections in the elderly population in general, caution should be used in treating

elderly patients.

Concurrent Kineret and TNF antagonist treatment

Concurrent administration of Kineret and etanercept has been associated with an increased risk of

serious infections and neutropenia compared to etanercept alone in RA patients. This treatment

combination has not demonstrated increased clinical benefit.

The concurrent administration of Kineret and etanercept or other TNF antagonists is not

recommended (see section 4.5).

This medicinal product contains less than 1 mmol sodium (23 mg) per 100 mg dose, i.e. essentially

‘sodium-free’.

4.5

Interaction with other medicinal products and other forms of interaction

Interactions between Kineret and other medicinal products have not been investigated in formal

studies. In clinical trials, interactions between Kineret and other medicinal products (including

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nonsteroidal anti-inflammatory medicinal products, corticosteroids, and DMARDs) have not been

observed.

Concurrent Kineret and TNF antagonist treatment

In a clinical trial with RA patients receiving background methotrexate, patients treated with Kineret

and etanercept were observed to have a higher rate of serious infections (7%) and neutropenia than

patients treated with etanercept alone and higher than observed in previous trials where Kineret was

used alone. Concurrent Kineret and etanercept treatment has not demonstrated increased clinical

benefit.

The concurrent use of Kineret with etanercept or any other TNF antagonist is not recommended (see

section 4.4).

Cytochrome P450 Substrates

The formation of CYP450 enzymes is suppressed by increased levels of cytokines (e.g., IL-1) during

chronic inflammation. Thus, it may be expected that for an IL-1 receptor antagonist, such as

anakinra, the formation of CYP450 enzymes could be normalized during treatment. This would be

clinically

relevant

CYP450

substrates

with

narrow

therapeutic

index

(e.g.

warfarin

phenytoin). Upon start or end of Kineret treatment in patients on these types of medicinal products,

it may be relevant to consider therapeutic monitoring of the effect or concentration of these

products and the individual dose of the medicinal product may need to be adjusted.

For information on vaccinations see section 4.4.

4.6 Fertility, pregnancy and lactation

There are limited amount of data from the use of anakinra in pregnant women. However,

reproductive studies have been conducted with Kineret on rats and rabbits at doses up to 100 times

the human RA dose and have revealed no evidence of impaired fertility or harm to the foetus.

Kineret is not recommended during pregnancy and in women of childbearing potential not using

contraception.

It is unknown whether anakinra/metabolites are excreted in human milk. A risk to the newborns/

infants cannot be excluded. Breast-feeding should be discontinued during treatment with Kineret.

4.7

Effects on ability to drive and use machines

Not relevant.

4.8

Undesirable effects

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 site

reaction. 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

patients receiving placebo (1.8% vs. 0.7%). Neutrophil decreases occurred more frequently in

patients receiving Kineret compared with placebo.

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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 patient

years. During the 5-year study 14 patients (32.6%) reported 24 serious events. Eleven serious events

in 4 (9.3%) patients were considered related to Kineret. No patient withdrew from Kineret treatment

due to adverse reactions. There are no indications either from this study or from post marketing

adverse reaction reports that the overall safety profile in CAPS patients is different from that in RA

patients. The adverse reactions table below therefore applies to Kineret treatment both in RA and

CAPS patients.

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 frequency

grouping, 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

disorders

Common (

1/100 to < 1/10)

Neutropenia

Thrombocytopenia

Immune system disorders

Uncommon (

1/1,000 to < 1/100)

Allergic reactions including

anaphylactic reactions,

angioedema, urticaria and

pruritus

Nervous system disorders

Very common (

1/10)

Headache

Hepatobiliary system

Uncommon (

1/1,000 to < 1/100)

Hepatic enzyme increased

Not known

(cannot be estimated from the

available data)

Non-infectious hepatitis

Skin and subcutaneous

tissue disorders

Very common (

1/10)

Injection site reaction

Uncommon (

1/1,000 to < 1/100)

Rash

Investigations

Very common (≥1/10)

Blood cholesterol increased

Serious infections

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 to

3 years, the serious infection rate remained stable over time. The infections observed consisted

primarily of bacterial events such as cellulitis, pneumonia, and bone and joint infections. Most

patients continued on study medicinal product after the infection resolved.

In 43 CAPS patients followed for up to 5 years the frequency of serious infections was 0.1/year, the

most common being pneumonia and gastroenteritis. Kineret was temporarily stopped in one patient,

all other patients continued Kineret treatment during the infections.

There were no deaths due to serious infections in RA or CAPS studies.

In clinical RA studies and post-marketing experience, rare cases of opportunistic infections have been

observed and included fungal, mycobacterial, bacterial, and viral pathogens. Infections have been

noted in all organ systems and have been reported in patients receiving Kineret alone or in

combination with immunosuppressive agents.

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Neutropenia

In placebo-controlled RA studies with Kineret, treatment was associated with small reductions in the

mean values for total white blood count and absolute neutrophil count (ANC). Neutropenia

(ANC < 1.5 x 10

/l) was reported in 2.4% patients receiving Kineret compared with 0.4% of placebo

patients. None of these patients had serious infections associated with the neutropenia.

In 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.

Thrombocytopenia

In clinical studies in RA patients, thrombocytopenia has been reported in 1.9% of treated patients

compared to 0.3% in the placebo group. The thrombocytopenias have been mild, i.e. platelet counts

have 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

case reports indicating severe thrombocytopenia (i.e. platelet counts <10 x109/L).

Malignancies

RA patients may be at a higher risk (on average 2-3 fold) for the development of lymphoma. In

clinical trials, whilst patients treated with Kineret had a higher incidence of lymphoma than the

expected rate in the general population, this rate is consistent with rates reported in general for RA

patients.

In clinical trials, the crude incidence rate of malignancy was the same in the Kineret-treated patients

and 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.

Allergic reactions

Allergic reactions including anaphylactic reactions, angioedema, urticaria, rash, and pruritus have

been reported uncommonly with Kineret. The majority of these reactions were maculopapular or

urticarial rashes.

In 43 CAPS patients followed for up to 5 years, no allergic event was serious and no event required

discontinuation of Kineret treatment.

Immunogenicity

In clinical trials in RA, up to 3% of adult patients tested seropositive at least once during the study for

antibodies capable of neutralising the biologic effects of anakinra. The occurrence of antibodies was

typically transient and not associated with clinical adverse reactions or diminished efficacy. In

addition, in a clinical trial 6% of paediatric patients tested seropositive at least once during the study

for antibodies capable of neutralising the biologic effects of anakinra.

The majority of CAPS patients in Study 03-AR-0298 developed anakinra anti-drug antibodies. This was

not associated with any clinically significant effects on pharmacokinetics, efficacy, or safety.

Hepatic Events

In clinical studies in RA and CAPS patients, transient elevations of liver enzymes have been seen

uncommonly. These elevations have not been associated with signs or symptoms of hepatocellular

damage. During post-marketing use isolated case reports indicating non-infectious hepatitis have

been received. Hepatic events during post marketing use have mainly been reported in patients with

predisposing factors, e.g a history of transaminase elevations before start of Kineret treatment.

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Injection site reactions

In RA patients the most common and consistently reported treatment-related adverse reactions

associated 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 to

28% of the placebo treated patients. In 43 CAPS patients followed for up to 5 years no patient

permanently or temporarily discontinued Kineret treatment due to injection site reactions.

ISRs typically appear within 2 weeks’ 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 of

therapy.

Blood cholesterol increase

In clinical studies of RA, 775 patients treated with daily Kineret doses of 30mg, 75mg, 150mg, 1mg/kg

or 2mg/kg, there was an increase of 2.4% to 5.3% in total cholesterol levels 2 weeks after start of

Kineret treatment, without a dose-response relationship. A similar pattern was seen after 24 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 HDL cholesterol.

Paediatric population

Kineret has been studied in 36 CAPS patients aged 8 months to < 18 years, for up to 5 years. With the

exception of infections and related symptoms that were more frequently reported in patients <2

years of age, the safety profile was similar in all paediatric age groups. The safety profile in paediatric

patients was similar to that seen in adult populations and no clinically relevant new adverse reactions

were seen.

Reporting of Adverse events reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It

allows continued monitoring of the benefit/risk balance of the medicinal product.

Any suspected adverse events should be reported to the Ministry of Health according to the National

Regulation by using an online form

http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic@moh.

gov.il

4.9 Overdose

No dose-limiting toxicities were observed during clinical trials in RA or CAPS patients.

In studies of sepsis, 1015 patients received Kineret at doses up to 2 mg/kg/hour i.v. (~35 times the

recommended dose in RA) over a 72 hour treatment period. The adverse event profile from these

studies show no overall difference from that seen in the rheumatoid arthritis studies.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

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

Anakinra neutralises the biologic activity of interleukin-1α (IL-1α) and interleukin-1β (IL-1β) by

competitively inhibiting their binding to interleukin-1 type I receptor (IL-1RI). Interleukin-1 (IL-1) is a

pivotal pro-inflammatory cytokine mediating many cellular responses including those important in

synovial inflammation.

IL-1 is found in the plasma and synovial fluid of patients with rheumatoid arthritis, and a correlation

has been reported between IL-1 concentrations in the plasma and the activity of the disease.

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Anakinra inhibits responses elicited by IL-1 in vitro, including the induction of nitric oxide and

prostaglandin E

and/or collagenase production by synovial cells, fibroblasts, and chondrocytes.

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 activated

inflammasome results in proteolytic maturation and secretion of IL-1β, which has a broad range of

effects 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 in

the acute phase reactants and a decrease in IL-6 expression level has been observed. Decreased

acute phase protein levels are noted within the first weeks of treatment.

Clinical efficacy and safety in RA

The safety and efficacy of anakinra in combination with methotrexate have been demonstrated in

1790 RA patients

18 years of age patients with varying degrees of disease severity.

A clinical response to anakinra generally appeared within 2 weeks of initiation of treatment and was

sustained with continued administration of anakinra. Maximal clinical response was generally seen

within 12 weeks after starting treatment.

Combined anakinra and methotrexate treatment demonstrates a statistically and clinically significant

reduction in the severity of the signs and symptoms of rheumatoid arthritis in patients who have had

an inadequate response to methotrexate alone (38% vs. 22% responders as measured by ACR

criteria). Significant improvements are seen in the pain, tender joint count, physical function (HAQ

score), acute phase reactants 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 no

deleterious effect on joint cartilage.

Clinical efficacy and safety in CAPS

The safety and efficacy of Kineret have been demonstrated in CAPS patients with varying degrees of

disease severity. In a clinical study including 43 adult and paediatric patients (36 patients aged 8

months to < 18 years) with severe CAPS (NOMID/CINCA and MWS), a clinical response to anakinra

was seen within 10 days after initiation of treatment in all patients and was sustained for up to 5

years with the continued administration of Kineret.

Kineret treatment significantly decreases the manifestations of CAPS, including a reduction in

frequently occurring symptoms as fever, rash, joint pain, headache, fatigue, and eye redness. A rapid

and 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 of

inflammatory hematological changes are seen. In the severe form of CAPS, long-term treatment

improves the systemic inflammatory organ manifestations of the eye, inner ear, and CNS. Hearing

and visual acuity did not deteriorate further during anakinra treatment.

Analysis of treatment-emergent AEs classified by presence of CIAS1 mutation showed that there

were no major differences between the CIAS1 and non-CIAS1 groups in overall AE reporting rates, 7.4

and 9.2, respectively. Similar rates were obtained for the groups on the SOC level, except for eye

disorders with 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).

Paediatric population

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

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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 for

information on paediatric use).

Safety in pediatric RA (JIA) patients

Kineret was studied in a single randomized, blinded multi-center trial in 86 patients with polyarticular

course Juvenile Rheumatoid Arthritis (JRA; ages 2-17 years) receiving a dose of 1 mg/kg

subcutaneously daily, up to a maximum 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 for an additional 16 weeks. A subset of these patients continued open-

label treatment with Kineret for up to 1 year in a companion extension study. An adverse event

profile similar to that seen in adult RA patients was observed in these studies. These study data are

insufficient to demonstrate efficacy and, therefore, Kineret is not recommended for pediatric use in

Juvenile Rheumatoid Arthritis.

Immunogenicity

See section 4.8.

5.2

Pharmacokinetic properties

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

anakinra from the plasma after subcutaneous injection. In subjects with RA, maximum plasma

concentrations of anakinra occurred at 3 to 7 hours after subcutaneous administration of anakinra at

clinically relevant doses (1 to 2 mg/kg; n = 18). The plasma concentration decreased with no

discernible distribution phase and the terminal half-life ranged from 4 to 6 hours. In RA patients, no

unexpected accumulation of anakinra was observed after daily subcutaneous doses for up to 24

weeks. Mean (SD) estimates of clearance (CL/F) and volume of distribution (Vd/F) by population

analysis of data from two PK studies in 35 RA patients were 105(27) mL/min and 18.5(11) L,

respectively. Human and animal data demonstrated that the kidney is the major organ responsible

for elimination of anakinra. The clearance of anakinra in RA patients increased with increasing

creatinine clearance.

The influence of demographic covariates on the pharmacokinetics of anakinra was studied using

population pharmacokinetic analysis encompassing 341 patients receiving daily subcutaneous

injection of anakinra at doses of 30, 75, and 150 mg for up to 24 weeks. The estimated anakinra

clearance increased with increasing creatinine clearance and body weight. Population

pharmacokinetic analysis demonstrated that the mean plasma clearance value after subcutaneous

bolus administration was 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 body weight, gender and age were not significant factors for mean plasma clearance.

No dose adjustment is required based on age or gender.

In general the pharmacokinetics in CAPS patients is similar to that in RA patients. In CAPS patients

approximate 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 from

8 months of age, and when started at the recommended daily dose of 1-2 mg/kg, no safety concerns

have been identified. Pharmacokinetic data are lacking in older CAPS patients. Distribution into the

cerebrospinal fluid has been demonstrated.

Hepatic impairment

A study including 12 patients with hepatic dysfunction (Child-Pugh Class B) given a single 1mg/kg

intravenous dose has been performed. Pharmacokinetic parameters were not substantially different

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from healthy volunteers, other than a decrease in clearance of approximately 30% in comparison

with data from a study with healthy volunteers. A corresponding decrease in creatinine clearance

was seen in the hepatic failure population. Accordingly, the decrease in clearance is most likely

explained by a decrease in renal function in this population. These data support that no dose

adjustment is required for patients with hepatic dysfunction of Child-Pugh Class B. See section 4.2.

Renal impairment

The mean plasma clearance of Kineret in subjects with mild (creatinine clearance 50-80 mL/min) and

moderate (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 the

administered dose of Kineret was removed by hemodialysis or continuous ambulatory peritoneal

dialysis. 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.

5.3

Preclinical safety data

Anakinra had no observed effect on the fertility, early development, embryo-foetal development, or

peri- and postnatal development in the rat at doses up to 100 times the human dose. No effects 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 not

induce bacterial or mammalian cell gene mutations. Neither did anakinra increase the incidence of

chromosomal abnormalities or micronuclei in bone marrow cells in mice. Long-term studies have not

been 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 Kineret

alters the toxicologic or pharmacokinetic profile of methotrexate.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Citric acid anhydrous

Sodium chloride

Disodium edentate dehydrate

Polysorbate 80

Sodium hydroxide

Water for injections

6.2

Incompatibilities

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

medicinal products.

6.3

Shelf life

3 years.

Page

from

6.4

Special precautions for storage

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 removed from the refrigerator for 12 hours at

temperature not above 25 °C, without exceeding the expiry date. At the end of this period, the

product must not be put back in the refrigerator and must be disposed of.

6.5 Nature and contents of container

0.67 ml of solution for injection in a graduated pre-filled syringe (Type I glass) with a plunger stopper

(bromobutyl rubber). The pre-filled syringe has an outer rigid plastic needle shield attached to a grey

inner needle cover. None of the syringe or needle shield components are made with natural rubber

latex.

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

Not all pack sizes may be marketed.

6.6

Special precautions for disposal and other handling

Kineret is a sterile unpreserved 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. Only

clear, colourless-to-white solutions that may contain some product-related translucent-to-white

amorphous 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 local

requirements.

7.

MARKETING AUTHORISATION HOLDER

Swedish Orphan Biovitrum AB (SOBI)

SE-112 76 Stockholm

Sweden

8.

MARKETING AUTHORISATION NUMBER(S)

145-79-33059-00

10.

LOCAL LICENSE HOLDER

Megapharm Ltd., P.O.Box 519, Hod-Hasharon 4510501

The format of this leaflet was determained by the ministry of health and its content was checked

and approved in August 2016.

KIN SPC 082016 P.1

Page

from

רשוא

61

.

8

______ ךיראת

692702/761

_________________

תילגנאב רישכת םש

for injection

Kineret 100mg solution

יר רפסמ _______םוש

145-79-33059-00

________________

םושירה לעב םש

:

___

מ"עב םראפאגמ

__________

םי/שקובמה םי/יונישה לע םיטרפ

ןולעב קרפ

יחכונ טסקט

שדח טסקט

יאוול תועפות שומישה ,הפורת לכל ומכ

טרניק

.םישמתשמהמ קלחב יאוול תועפותל םורגל לולע .ןהמ תחא ףאמ לובסת אלו ןכתי .יאוולה תועפות תמישר ארקמל להבית לא

:תואבה יאוול תועפותה ןמ תחא ךלצא העיפומו הדימב ,דימ אפורה םע ץעייתה

םירומח םימוהיז

רועב םימוהיז וא )המישנה יכרדב םוהיז( תואיר תקלד ןוגכ הל םילוכי לופיטה ןמזב עיפו

טרניק לש העפוה לולכל םילולע םינימסתה . תוחיכש( רועב תושיגרו תוימומדא וא לועיש ,םוח

)תובורק םיתעל

תורומח היגרלא תועפות

לולע םיאבה םינימסתהמ דחא לכ םלוא ,תוצופנ ןניא ל תיגרלא העפות לע עיבצהל טרניק הרזע תלבקל ידיימ ןפואב תונפל שי ןכלו , פר תקרזהב ךישמהל אלו תיאו טרניק :םיעיפומו הדימב ,

ןורגב וא ןושלב ,םינפב תוחיפנ

המישנב וא העילבב תויעב

שומישה ,הפורת לכל ומכ

טרניק

לא .םישמתשמהמ קלחב יאוול תועפותל םורגל לולע .ןהמ תחא ףאמ לובסת אלו ןכתי .יאוולה תועפות תמישר ארקמל להבית

:תואבה יאוול תועפותה ןמ תחא ךלצא העיפומו הדימב ,דימ אפורה םע ץעייתה

םירומח םימוהיז

תקלד ןוגכ

םילוכי רועב םימוהיז וא )המישנה יכרדב םוהיז( תואיר לופיטה ןמזב עיפוהל

טרניק וא לועיש ,םוח לש העפוה לולכל םילולע םינימסתה . תוחיכש( רועב תושיגרו תוימומדא

)תובורק םיתעל

תורומח היגרלא תועפות

עיבצהל לולע םיאבה םינימסתהמ דחא לכ םלוא ,תוצופנ ןניא ל תיגרלא העפות לע טרניק אלו תיאופר הרזע תלבקל ידיימ ןפואב תונפל שי ןכלו , תקרזהב ךישמהל טרניק :םיעיפומו הדימב ,

ןורגב וא ןושלב ,םינפב תוחיפנ

המישנב וא העילבב תויעב

העזה וא ריהמ קפוד לש תימואתפ העפוה

החירפ וא רועב דרג

:תובורק דואמ םיתיעל תועיפומ

ללכ ךרדב ולא םינימסת .הקרזהה רתאב דרג וא תולבח ,תוחיפנ ,תוימומדא לופיטה תליחתב רתוי םיצופנו תינוניב וא הנותמ הרוצב םיעיפומ

שאר יבאכ

:תובורק םיתיעל תועיפומ

תקידב תועצמאב תנחבואמה )םינבל םד יאת לש הכומנ הריפס( הינפורטיונ םוהיז לש םינימסת .םוהיזב תוקלל ןוכיסה תא לידגהל לולע הז יאופר בצמ ,םד רג באכו םוח לולכל םילולע ןו

:תוקוחר םיתיעל תועיפומ

םדב דבכה ימיזנא תומרב היילע

:העודי הניאש תורידתב תועיפומ

ןתש ,ןובאית ןדבוא ,תוליחב ,תובוהצ םייניעו רוע ומכ דבכב תוערפהל םינמיס האוצו ההכ

הריהב

אלש יאוול תעפותמ לבוס התא רשאכ וא ,הרימחמ יאוולה תועפותמ תחא םא ,ןולעב הרכזוה .אפורה םע ץעייתהל ךילע

העזה וא ריהמ קפוד לש תימואתפ העפוה

דרג

החירפ וא רועב

:תובורק דואמ םיתיעל תועיפומ

םיעיפומ ללכ ךרדב ולא םינימסת .הקרזהה רתאב דרג וא תולבח ,תוחיפנ ,תוימומדא לופיטה תליחתב רתוי םיצופנו תינוניב וא הנותמ הרוצב

שאר יבאכ

םדב לורטסלוכה תומרב הילע

:תובורק םיתיעל תועיפומ

הריפס( הינפורטיונ בצמ ,םד תקידב תועצמאב תנחבואמה )םינבל םד יאת לש הכומנ םוח לולכל םילולע םוהיז לש םינימסת .םוהיזב תוקלל ןוכיסה תא לידגהל לולע הז יאופר ןורג באכו

( תואיר תקלד ןוגכ םירומח םימוהיז רועב םימוהיז וא )המישנה יכרדב םוהיז

םיכרע( הינפוטיצובמורט כומנ םי

)םד תויסט לש םדב

:תוקוחר םיתיעל תועיפומ

םדב דבכה ימיזנא תומרב היילע

:העודי הניאש תורידתב תועיפומ

האוצו ההכ ןתש ,ןובאית ןדבוא ,תוליחב ,תובוהצ םייניעו רוע ומכ דבכב תוערפהל םינמיס

הריהב

אלש יאוול תעפותמ לבוס התא רשאכ וא ,הרימחמ יאוולה תועפותמ תחא םא ,ןולעב הרכזוה .אפורה םע ץעייתהל ךילע

םי/שקובמה םי/יונישה לע םיטרפ

ןולעב קרפ

יחכונ טסקט

שדח טסקט

Undesirable effects

Serious infections

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-

Serious infections

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

to 3 years, the serious infection rate remained stable over time.

treated patients. In observations up to 3 years, the serious

infection rate remained stable over time. The infections

observed consisted primarily of bacterial events such as

cellulitis, pneumonia, and bone and joint infections. Most

patients continued on study medicinal product after the

infection resolved.

In 43 CAPS patients followed for up to 5 years the

frequency of serious infections was 0.1/year, the most

common being pneumonia and gastroenteritis. Kineret

was temporarily stopped in one patient, all other patients

continued Kineret treatment during the infections.

There were no deaths due to serious infections in RA or

CAPS studies.

In clinical RA studies and post-marketing experience, rare

cases of opportunistic infections have been observed and

included fungal, mycobacterial, bacterial, and viral

pathogens. Infections have been noted in all organ

systems and have been reported in patients receiving

Kineret alone or in combination with immunosuppressive

agents.

Neutropenia

In placebo-controlled RA studies with Kineret, treatment

was associated with small reductions in the mean values

for total white blood count and absolute neutrophil count

(ANC). Neutropenia (ANC < 1.5 x 10

/l) was reported in

2.4% patients receiving Kineret compared with 0.4% of

placebo patients. None of these patients had serious

infections associated with the neutropenia.

The infections observed consisted primarily of bacterial events

such as cellulitis, pneumonia, and bone and joint infections. Most

patients continued on study medicinal product after the infection

resolved.

In 43 CAPS patients followed for up to 5 years the frequency of

serious infections was 0.1/year, the most common being

pneumonia and gastroenteritis. Kineret was temporarily stopped

in one patient, all other patients continued Kineret treatment

during the infections.

There were no deaths due to serious infections in RA or CAPS

studies.

In clinical RA studies and post-marketing experience, rare cases

of opportunistic infections have been observed and included

fungal, mycobacterial, bacterial, and viral pathogens. Infections

have been noted in all organ systems and have been reported in

patients receiving Kineret alone or in combination with

immunosuppressive agents.

Neutropenia

In placebo-controlled RA studies with Kineret, treatment was

associated with small reductions in the mean values for total

white blood count and absolute neutrophil count (ANC).

Neutropenia (ANC < 1.5 x 10

/l) was reported in 2.4% patients

receiving Kineret compared with 0.4% of placebo patients. None

of these patients had serious infections associated with the

neutropenia.

In 43 CAPS patients followed for up to 5 years neutropenia was

reported in 2 patients. Both episodes of neutropenia resolved

In 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.

Malignancies

RA patients may be at a higher risk (on average 2-3 fold)

for the development of lymphoma. In clinical trials, whilst

patients treated with Kineret had a higher incidence of

lymphoma than the expected rate in the general

population, this rate is consistent with rates reported in

general for RA patients.

In clinical trials, the crude incidence rate of malignancy

was the same in the Kineret-treated patients and 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.

Allergic reactions

Allergic reactions including anaphylactic reactions,

angioedema, urticaria, rash, and pruritus have been reported

uncommonly with Kineret. The majority of these reactions

were maculopapular or urticarial rashes.

In 43 CAPS patients followed for up to 5 years, no allergic

event was serious and no event required discontinuation of

Kineret treatment.

over time with continued Kineret treatment.

Thrombocytopenia

In clinical studies in RA patients, thrombocytopenia has been reported

in 1.9% of treated patients compared to 0.3% in the placebo group. The

thrombocytopenias have been mild, i.e. platelet counts have been >75

/L. Mild thrombocytopenia has also been observed in CAPS

patients.

During post-marketing use of Kineret, thrombocytopenia has been

reported, including occasional case reports indicating severe

thrombocytopenia (i.e. platelet counts <10 x10

/L).

Malignancies

RA patients may be at a higher risk (on average 2-3 fold) for the

development of lymphoma. In clinical trials, whilst patients

treated with Kineret had a higher incidence of lymphoma than

the expected rate in the general population, this rate is consistent

with rates reported in general for RA patients.

In clinical trials, the crude incidence rate of malignancy was the

same in the Kineret-treated patients and 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.

Allergic reactions

Allergic reactions including anaphylactic reactions, angioedema,

urticaria, rash, and pruritus have been reported uncommonly with

Kineret. The majority of these reactions were maculopapular or

urticarial rashes.

In 43 CAPS patients followed for up to 5 years, no allergic event was

serious and no event required discontinuation of Kineret treatment.

Immunogenicity

In clinical trials in RA, up to 3% of adult patients tested

seropositive at least once during the study for antibodies

capable of neutralising the biologic effects of anakinra. The

occurrence of antibodies was typically transient and not

associated with clinical adverse reactions or diminished

efficacy. In addition, in a clinical trial 6% of paediatric patients

tested seropositive at least once during the study for antibodies

capable of neutralising the biologic effects of anakinra.

The majority of CAPS patients in Study 03-AR-0298

developed anakinra anti-drug antibodies. This was not

associated with any clinically significant effects on

pharmacokinetics, efficacy, or safety.

Hepatic Events

In clinical studies in RA and CAPS patients, transient

elevations of liver enzymes have been seen uncommonly.

These elevations have not been associated with signs or

symptoms of hepatocellular damage. During post-

marketing use isolated case reports indicating non-

infectious hepatitis have been received. Hepatic events

during post marketing use have mainly been reported in

patients with predisposing factors, e.g a history of

transaminase elevations before start of Kineret treatment.

Injection site reactions

In RA patients the most common and consistently

reported treatment-related adverse reactions associated

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

Immunogenicity

In clinical trials in RA, up to 3% of adult patients tested seropositive at

least once during the study for antibodies capable of neutralising the

biologic effects of anakinra. The occurrence of antibodies was typically

transient and not associated with clinical adverse reactions or

diminished efficacy. In addition, in a clinical trial 6% of paediatric

patients tested seropositive at least once during the study for antibodies

capable of neutralising the biologic effects of anakinra.

The majority of CAPS patients in Study 03-AR-0298 developed

anakinra anti-drug antibodies. This was not associated with any

clinically significant effects on pharmacokinetics, efficacy, or safety.

Hepatic Events

In clinical studies in RA and CAPS patients, transient elevations

of liver enzymes have been seen uncommonly. These elevations

have not been associated with signs or symptoms of

hepatocellular damage. During post-marketing use isolated case

reports indicating non-infectious hepatitis have been received.

Hepatic events during post marketing use have mainly been

reported in patients with predisposing factors, e.g a history of

transaminase elevations before start of Kineret treatment.

Injection site reactions

In RA patients the most common and consistently reported

treatment-related adverse reactions associated 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 to 28% of the placebo treated patients. In 43 CAPS

patients followed for up to 5 years no patient permanently or

temporarily discontinued Kineret treatment due to injection site

compared to 28% of the placebo treated patients. In 43

CAPS patients followed for up to 5 years no patient

permanently or temporarily discontinued Kineret

treatment due to injection site reactions.

ISRs typically appear within 2 weeks’ 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 of therapy.

Paediatric population

Kineret has been studied in 36 CAPS patients aged 8

months to < 18 years, for up to 5 years. With the

exception of infections and related symptoms that were

more frequently reported in patients <2 years of age, the

safety profile was similar in all paediatric age groups. The

safety profile in paediatric patients was similar to that

seen in adult populations and no clinically relevant new

adverse reactions were seen.

reactions.

ISRs typically appear within 2 weeks’ 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 of therapy.

Blood cholesterol increase

In clinical studies of RA, 775 patients treated with daily Kineret doses

of 30mg, 75mg, 150mg, 1mg/kg or 2mg/kg, there was an increase of

2.4% to 5.3% in total cholesterol levels 2 weeks after start of Kineret

treatment, without a dose-response relationship. A similar pattern was

seen after 24 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 HDL

cholesterol.

Paediatric population

Kineret has been studied in 36 CAPS patients aged 8 months to <

18 years, for up to 5 years. With the exception of infections and

related symptoms that were more frequently reported in patients

<2 years of age, the safety profile was similar in all paediatric

age groups. The safety profile in paediatric patients was similar

to that seen in adult populations and no clinically relevant new

adverse reactions were seen.

צמ

"

ב

ןולעה

,

ובש

תונמוסמ

תורמחהה

תושקובמה

לע

עקר

בוהצ

.

םייוניש

םניאש

רדגב

תורמחה

ונמוס

ןולעב

עבצב

זיקרוט

רבעוה

ראודב

ינורטקלא

ךיראתב

:

6

/02/

7

/2

/1

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