4.1. Therapeutic indications

Periodic fever syndromes

Ilaris is indicated for the treatment of the following autoinflammatory periodic fever syndromes in adults, adolescents and children aged 2 years and older:

Cryopyrin-associated periodic syndromes

Ilaris is indicated for the treatment of cryopyrin-associated periodic syndromes (CAPS) including:

• Muckle-Wells syndrome (MWS),

• Neonatal-onset multisystem inflammatory disease (NOMID) / chronic infantile neurological, cutaneous, articular syndrome (CINCA),

• Severe forms of familial cold autoinflammatory syndrome (FCAS) / familial cold urticaria (FCU) presenting with signs and symptoms beyond cold-induced urticarial skin rash.

Tumour necrosis factor receptor associated periodic syndrome (TRAPS)

Ilaris is indicated for the treatment of tumour necrosis factor (TNF) receptor associated periodic syndrome (TRAPS).

Hyperimmunoglobulin D syndrome (HIDS)/mevalonate kinase deficiency (MKD)

Ilaris is indicated for the treatment of hyperimmunoglobulin D syndrome (HIDS)/mevalonate kinase deficiency (MKD).

Familial Mediterranean fever (FMF)

Ilaris is indicated for the treatment of Familial Mediterranean Fever (FMF). It is recommended that Ilaris be given in combination with colchicine, if appropriate.

Ilaris is also indicated for the treatment of:

Still's disease

Ilaris is indicated for the treatment of active Still's disease including adult-onset Still's disease (AOSD) and systemic juvenile idiopathic arthritis (SJIA) in patients aged 2 years and older who have responded inadequately to previous therapy with non-steroidal anti-inflammatory drugs (NSAIDs) and systemic corticosteroids. Ilaris can be given as monotherapy or in combination with methotrexate.

Gouty arthritis

Ilaris is indicated for the symptomatic treatment of adult patients with frequent gouty arthritis attacks (at least 3 attacks in the previous 12 months) in whom non-steroidal anti-inflammatory drugs (NSAIDs) and colchicine are contraindicated, are not tolerated, or do not provide an adequate response, and in whom repeated courses of corticosteroids are not appropriate (see section 5.1).

4.2. Posology and method of administration

For CAPS, TRAPS, HIDS/MKD, FMF and Still's disease, the treatment is to be initiated and supervised by a specialist physician experienced in the diagnosis and treatment of the relevant indication.

For gouty arthritis, the physician needs to be experienced in the use of biologics and Ilaris is to be administered by a healthcare professional.

Posology

CAPS: Adults, adolescents and children aged 2 years and older

The recommended starting dose of canakinumab for CAPS patients is:

Adults, adolescents and children ≥ 4 years of age:

• 150 mg for patients with body weight > 40 kg

• 2 mg/kg for patients with body weight ≥ 15 kg and ≤ 40 kg

• 4 mg/kg for patients with body weight ≥ 7.5 kg and < 15 kg

Children 2 to < 4 years of age:

• 4 mg/kg for patients with body weight ≥ 7.5 kg

This is administered every eight weeks as a single dose via subcutaneous injection.

For patients with a starting dose of 150 mg or 2 mg/kg, if a satisfactory clinical response (resolution of rash and other generalised inflammatory symptoms) has not been achieved 7 days after treatment start, a second dose of canakinumab at 150 mg or 2 mg/kg can be considered. If a full treatment response is subsequently achieved, the intensified dosing regimen of 300 mg or 4 mg/kg every 8 weeks needs to be maintained. If a satisfactory clinical response has not been achieved 7 days after this increased dose, a third dose of canakinumab at 300 mg or 4 mg/kg can be considered. If a full treatment response is subsequently achieved, maintaining the intensified dosing regimen of 600 mg or 8 mg/kg every 8 weeks is to be considered, based on individual clinical judgement.

For patients with a starting dose of 4 mg/kg, if a satisfactory clinical response has not been achieved 7 days after treatment start, a second dose of canakinumab 4 mg/kg can be considered. If a full treatment response is subsequently achieved, maintaining the intensified dosing regimen of 8 mg/kg every 8 weeks is to be considered, based on individual clinical judgement.

Clinical experience with dosing at intervals of less than 4 weeks or at doses above 600 mg or 8 mg/kg is limited.

TRAPS, HIDS/MKD and FMF: Adults, adolescents and children aged 2 years and older

The recommended starting dose of canakinumab in TRAPS, HIDS/MKD and FMF patients is:

• 150 mg for patients with body weight > 40 kg

• 2 mg/kg for patients with body weight ≥ 7.5 kg and ≤ 40 kg

This is administered every four weeks as a single dose via subcutaneous injection.

If a satisfactory clinical response has not been achieved 7 days after treatment start, a second dose of canakinumab at 150 mg or 2 mg/kg can be considered. If a full treatment response is subsequently achieved, the intensified dosing regimen of 300 mg (or 4 mg/kg for patients weighing ≤ 40 kg) every 4 weeks needs to be maintained.

In patients without clinical improvement, it is recommended that the treating physician reconsiders continued treatment with canakinumab.

Still's disease (SJIA and AOSD)

The recommended dose of canakinumab for patients with Still's disease with body weight ≥ 7.5 kg is 4 mg/kg (up to a maximum of 300 mg) administered every four weeks via subcutaneous injection. In patients without clinical improvement, it is recommended that the treating physician reconsiders continued treatment with canakinumab.

Gouty arthritis

Management of hyperuricaemia with appropriate urate lowering therapy (ULT) needs to be instituted or optimised. Canakinumab needs to be used as an on-demand therapy to treat gouty arthritis attacks.

The recommended dose of canakinumab for adult patients with gouty arthritis is 150 mg administered subcutaneously as a single dose during an attack. For maximum effect, administration of canakinumab as soon as possible after the onset of a gouty arthritis attack is recommended.

It is recommended that patients who do not respond to initial treatment are not re-treated with canakinumab. In patients who respond and require re-treatment, there needs to be an interval of at least 12 weeks before a new dose of canakinumab may be administered (see section 5.2).

Missed doses

If an injection is missed in patients with CAPS, TRAPS, HIDS/MKD, FMF or Still's disease (AOSD or SJIA), it is to be administered as soon as possible without waiting until the next scheduled dose. Subsequent doses are to be administered at the recommended intervals.

Special populations

Paediatric population

CAPS, TRAPS, HIDS/MKD and FMF

The safety and efficacy of canakinumab in CAPS, TRAPS, HIDS/MKD and FMF patients under 2 years of age have not been established. Currently available data are described in sections 4.8, 5.1 and 5.2 but no recommendation on a posology can be made.

SJIA

The safety and efficacy of canakinumab in SJIA patients under 2 years of age have not been established. No data are available.

Gouty arthritis

There is no relevant use of canakinumab in the paediatric population in the indication gouty arthritis.

Elderly

No dose adjustment is required.

Hepatic impairment

Canakinumab has not been studied in patients with hepatic impairment. No recommendation on a posology can be made.

Renal impairment

No dose adjustment is needed in patients with renal impairment. However, clinical experience in such patients is limited.

Patient Card

All prescribers of Ilaris shall be familiar with the SmPC and inform the patients/caregivers about the Patient Card explaining what to do should they experience any symptom of infection or macrophage activation syndrome (MAS), or in case of vaccinations prior to treatment. The physician will provide the Patient Card to each patient/caregiver.

Method of administration

For subcutaneous use.

The following are suitable injection sites: upper thigh, abdomen, upper arm or buttocks. It is recommended to select a different injection site each time the product is injected to avoid soreness. Broken skin and areas which are bruised or covered by a rash must be avoided. Injection into scar tissue must be avoided as this may result in insufficient exposure to canakinumab.

Vial

Each vial is for single use in a single patient, for a single dose.

CAPS, TRAPS, HIDS/MKD, FMF and Still's disease (AOSD and SJIA)

After proper training in the correct injection technique, patients or their caregivers may inject canakinumab if the physician determines that it is appropriate and with medical follow-up as necessary (see section 6.6).

For instructions on administering the medicinal product, see section 6.6.

4.3. Contraindications

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

Active, severe infections (see section 4.4).

4.4. Special warnings and precautions for use

Traceability

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

Infections

Canakinumab is associated with an increased incidence of serious infections. Patients must be monitored carefully for signs and symptoms of infections during and after treatment with canakinumab (see section 4.8). Physicians need to exercise caution when administering canakinumab to patients with infections, a history of recurring infections, or underlying conditions which may predispose them to infections.

Treatment of CAPS, TRAPS, HIDS/MKD, FMF and Still's disease (SJIA and AOSD)

Canakinumab must not be initiated or continued in patients during an active infection requiring medical intervention.

Treatment of gouty arthritis

Canakinumab must not be administered during an active infection.

Concomitant use of canakinumab with tumour necrosis factor (TNF) inhibitors is not recommended because this may increase the risk of serious infections (see section 4.5).

Isolated cases of unusual or opportunistic infections (including aspergillosis, atypical mycobacterial infections, herpes zoster) have been reported during canakinumab treatment. The causal relationship of canakinumab to these events cannot be excluded.

Tuberculosis screening

In approximately 12% of CAPS patients tested with a PPD (purified protein derivative) skin test in clinical trials, follow-up testing yielded a positive test result while treated with canakinumab without clinical evidence of a latent or active tuberculosis infection.

It is unknown whether the use of interleukin-1 (IL-1) inhibitors such as canakinumab increases the risk of reactivation of tuberculosis. Before initiation of therapy, all patients must be evaluated for both active and latent tuberculosis infection. Particularly in adult patients, it is recommended that this evaluation includes a detailed medical history. Appropriate screening tests (e.g. tuberculin skin test, interferon gamma release assay or chest X-ray) are recommended to be performed in all patients (local recommendations may apply). Patients must be monitored closely for signs and symptoms of tuberculosis during and after treatment with canakinumab. All patients are to be instructed to seek medical advice if signs or symptoms suggestive of tuberculosis (e.g. persistent cough, weight loss, subfebrile temperature) appear during canakinumab therapy. In the event of conversion from a negative to a positive PPD test, especially in high-risk patients, alternative means of screening for a tuberculosis infection can be considered.

Neutropenia and leukopenia

Neutropenia (absolute neutrophil count [ANC] < 1.5 x 109/l) and leukopenia have been observed with medicinal products that inhibit IL-1, including canakinumab. Treatment with canakinumab is not to be initiated in patients with neutropenia or leukopenia. It is recommended that white blood cell (WBC) counts including neutrophil counts be assessed prior to initiating treatment and again after 1 to 2 months. For chronic or repeated therapies, it is also recommended to assess WBC counts periodically during treatment. If a patient becomes neutropenic or leukopenic, the WBC counts need to be monitored closely and treatment discontinuation considered.

Malignancies

Malignancy events have been reported in patients treated with canakinumab. The risk for the development of malignancies with anti-interleukin (IL)-1 therapy is unknown.

Hypersensitivity reactions

Hypersensitivity reactions with canakinumab therapy have been reported. The majority of these events were mild in severity. During clinical development of canakinumab in over 2 600 patients, no anaphylactoid or anaphylactic reactions attributable to treatment with canakinumab were reported. However, the risk of severe hypersensitivity reactions, which is not uncommon for injectable proteins, cannot be excluded (see section 4.3).

Hepatic function

Transient and asymptomatic cases of elevations of serum transaminases or bilirubin have been reported in clinical trials (see section 4.8).

Vaccinations

No data are available on the risk of secondary transmission of infection by live (attenuated) vaccines in patients receiving canakinumab. Therefore, live vaccines must not be given concurrently with canakinumab unless the benefits clearly outweigh the risks (see section 4.5).

Prior to initiation of canakinumab therapy it is recommended that adult and paediatric patients receive all vaccinations, as appropriate, including pneumococcal vaccine and inactivated influenza vaccine (see section 4.5).

Mutation in NLRP3 gene in CAPS patients

Clinical experience in CAPS patients without a confirmed mutation in the NLRP3 gene is limited.

Macrophage activation syndrome in patients with Still's disease (SJIA and AOSD)

Macrophage activation syndrome (MAS) is a known, life-threatening disorder that may develop in patients with rheumatic conditions, in particular Still's disease. If MAS occurs, or is suspected, evaluation and treatment need to be started as early as possible. Physicians need to be attentive to symptoms of infection or worsening of Still's disease, as these are known triggers for MAS. Based on clinical trial experience, canakinumab does not appear to increase the incidence of MAS in Still's disease patients, but no definitive conclusion can be made.

Drug reaction with eosinophilia and systemic symptoms (DRESS)

Drug reaction with eosinophilia and systemic symptoms (DRESS) has rarely been reported in patients treated with Ilaris, predominantly in patients with systemic juvenile idiopathic arthritis (sJIA). Patients with DRESS may require hospitalization, as this condition may be fatal. If signs and symptoms of DRESS are present and an alternative aetiology cannot be established, Ilaris must not be re-administered and a different treatment considered.

Polysorbate 80 content

This medicinal product contains 0.4 mg of polysorbate 80 in each 1 ml of solution for injection. Polysorbates may cause allergic reactions. The patient/caregiver needs to be instructed to tell the doctor if they or their child have/has any known allergies.

4.5. Interaction with other medicinal products and other forms of interaction

Interactions between canakinumab and other medicinal products have not been investigated in formal studies.

An increased incidence of serious infections has been associated with administration of another IL-1 blocker in combination with TNF inhibitors. Use of canakinumab with TNF inhibitors is not recommended because this may increase the risk of serious infections.

The expression of hepatic CYP450 enzymes may be suppressed by the cytokines that stimulate chronic inflammation, such as interleukin-1 beta (IL-1 beta). Thus, CYP450 expression may be reversed when potent cytokine inhibitory therapy, such as canakinumab, is introduced. This is clinically relevant for CYP450 substrates with a narrow therapeutic index where the dose is individually adjusted. On initiation of canakinumab in patients being treated with this type of medicinal product, it is recommended that therapeutic monitoring of the effect or of the active substance concentration is performed and the individual dose of the medicinal product adjusted as necessary.

No data are available on either the effects of live vaccination or the secondary transmission of infection by live vaccines in patients receiving canakinumab. Therefore, live vaccines must not be given concurrently with canakinumab unless the benefits clearly outweigh the risks. In case vaccination with live vaccines is indicated after initiation of canakinumab treatment, the recommendation is to wait for at least 3 months after the last canakinumab injection and before the next one (see section 4.4).

The results of a study in healthy adult subjects demonstrated that a single dose of canakinumab 300 mg did not affect the induction and persistence of antibody responses after vaccination with influenza or glycosylated protein based meningococcus vaccines.

The results of a 56-week, open label study in CAPS patients aged 4 years and younger demonstrated that all patients who received non-live, standard of care childhood vaccinations developed protective antibody levels.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential / Contraception in males and females

It is recommended that women use effective contraceptives during treatment with canakinumab and for up to 3 months after the last dose.

Pregnancy

There is a limited amount of data from the use of canakinumab in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). The risk for the foetus/mother is unknown. It is therefore recommended that women who are pregnant or who desire to become pregnant only be treated after a thorough benefit-risk evaluation.

Animal studies indicate that canakinumab crosses the placenta and is detectable in the foetus. No human data are available, but as canakinumab is an immunoglobulin of the G class (IgG1), human transplacental transfer is expected. The clinical impact of this is unknown. However, administration of live vaccines to newborn infants exposed to canakinumab in utero is not recommended for 16 weeks following the mother's last dose of canakinumab before childbirth. It is recommended that women who received canakinumab during pregnancy be instructed to inform the baby's healthcare professional before any vaccinations are given to their newborn infant.

Breast-feeding

It is unknown whether canakinumab is excreted in human milk. It is therefore recommended that the decision whether to breast-feed during canakinumab therapy only be taken after a thorough benefit-risk evaluation.

Animal studies have shown that a murine anti-murine IL-1 beta antibody had no undesirable effects on development in nursing mouse pups and that the antibody was transferred to them (see section 5.3).

Fertility

Formal studies of the potential effect of canakinumab on human fertility have not been conducted. Canakinumab had no effect on male fertility parameters in marmosets (C. jacchus). A murine anti-murine IL-1 beta antibody had no undesirable effects on fertility in male or female mice (see section 5.3).

4.7. Effects on ability to drive and use machines

Ilaris has minor influence on the ability to drive and use machines. Treatment with Ilaris may result in dizziness/vertigo or asthenia (see section 4.8). Patients who experience such symptoms during Ilaris treatment need to wait for this to resolve completely before performing tasks that require judgement or motor skills.

4.8. Undesirable effects

Summary of the safety profile

The most frequent adverse reactions were infections predominantly of the upper respiratory tract. No impact on the type or frequency of adverse reactions was seen with longer-term treatment.

Hypersensitivity reactions have been reported in patients treated with canakinumab (see sections 4.3 and 4.4).

Opportunistic infections have been reported in patients treated with canakinumab (see section 4.4).

Tabulated list of adverse reactions

Adverse reactions are listed according to MedDRA system organ class. Within each system organ class, the adverse reactions are ranked by frequency category with the most common first. 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.

Table 1 Tabulated list of adverse reactions

MedDRA System Organ Class

Indications:

CAPS, TRAPS, HIDS/MKD, FMF, SJIA, gouty arthritis

Infections and infestations

Very common

Respiratory tract infections (including pneumonia, bronchitis, influenza, viral infection, sinusitis, rhinitis, pharyngitis, tonsillitis, nasopharyngitis, upper respiratory tract infection)

Ear infection

Cellulitis

Gastroenteritis

Urinary tract infection

Common

Vulvovaginal candidiasis

Nervous system disorders

Common

Dizziness/vertigo

Gastrointestinal disorders

Very common

Upper abdominal pain 1

Uncommon

Gastro-oesophageal reflux disease 2

Skin and subcutaneous tissue disorders

Very common

Injection site reaction

Musculoskeletal and connective tissue disorders

Very common

Arthralgia 1

Common

Musculoskeletal pain 1

Back pain 2

General disorders and administration site conditions

Common

Fatigue/asthenia 2

Investigations

Very common

Creatinine renal clearance decreased 1,3

Proteinuria 1,4

Leukopenia 1,5

Common

Neutropenia 5

Uncommon

Platelet count decreased 5

1 In SJIA

2 In gouty arthritis

3 Based on estimated creatinine clearance, most were transient

4 Most represented transient trace to 1+ positive urinary protein by dipstick

5 See further information below

Still's Disease (SJIA and AOSD)

SJIA pooled analysis and AOSD

A total of 445 SJIA patients aged 2 to < 20 years received canakinumab in clinical trials, including 321 patients aged 2 to < 12 years, 88 patients aged 12 to < 16 years, and 36 patients aged 16 to < 20 years. A pooled safety analysis of all SJIA patients showed that in the subset of young adult SJIA patients aged 16 to < 20 years, the safety profile of canakinumab was consistent with what was observed in SJIA patients less than 16 years of age. The safety profile of canakinumab in AOSD patients in a randomised, double blind placebo-controlled study (GDE01T) in 36 adult patients (aged 22 to 70 years) was similar to what was observed in SJIA patients.

Description of selected adverse reactions

Long-term data and laboratory abnormalities in CAPS patients

During clinical trials with canakinumab in CAPS patients mean values for haemoglobin increased and those for white blood cell, neutrophils and platelets decreased.

Elevations of transaminases have been observed rarely in CAPS patients.

Asymptomatic and mild elevations of serum bilirubin have been observed in CAPS patients treated with canakinumab without concomitant elevations of transaminases.

In the long-term, open-label studies with dose escalation, events of infections (gastroenteritis, respiratory tract infection, upper respiratory tract infection), vomiting and dizziness were more frequently reported in the 600 mg or 8 mg/kg dose group than in other dose groups.

Laboratory abnormalities in TRAPS, HIDS/MKD and FMF patients

Neutrophils

Although ≥ Grade 2 reductions in neutrophil count occurred in 6.5% of patients (common) and Grade 1 reductions occurred in 9.5% of patients, the reductions are generally transient and neutropenia-associated infection has not been identified as an adverse reaction.

Platelets

Although reductions in platelet count (≥ Grade 2) occurred in 0.6% of patients, bleeding has not been identified as an adverse reaction. Mild and transient Grade 1 reduction in platelets occurred in 15.9% of patients without any associated bleeding adverse events.

Laboratory abnormalities in SJIA patients

Haematology

In the overall SJIA programme, transient decreased white blood cell (WBC) counts ≤ 0.8 x LLN were reported in 33 patients (16.5%).

In the overall SJIA programme, transient decreases in absolute neutrophil count (ANC) to less than 1 x 109/l were reported in 12 patients (6.0%).

In the overall SJIA programme, transient decreases in platelet counts (< LLN) were observed in 19 patients (9.5%).

ALT/AST

In the overall SJIA programme, high ALT and/or AST > 3 x upper limit of normal (ULN) were reported in 19 patients (9.5%).

Laboratory abnormalities in gouty arthritis patients

Haematology

Decreased white blood cell counts (WBC) ≤ 0.8 x lower limit of normal (LLN) were reported in 6.7% of patients treated with canakinumab compared to 1.4% treated with triamcinolone acetonide. Decreases in absolute neutrophil counts (ANC) to less than 1 x 109/l were reported in 2% of patients in the comparative trials. Isolated cases of ANC counts < 0.5 x 109/l were also observed (see section 4.4).

Mild (< LLN and > 75 x 109/l) and transient decreases in platelet counts were observed at a higher incidence (12.7%) with canakinumab in the active-controlled clinical studies versus the comparator (7.7%) in gouty arthritis patients.

Uric acid

Increases in uric acid level (0.7 mg/dl at 12 weeks and 0.5 mg/dl at 24 weeks) were observed after canakinumab treatment in comparative trials in gouty arthritis. In another study, among patients who were starting on ULT, increases in uric acid were not observed. Uric acid increases were not observed in clinical trials in non-gouty arthritis populations (see section 5.1).

ALT/AST

Mean and median increases in alanine transaminase (ALT) of 3.0 U/l and 2.0 U/l, respectively, and in aspartate transaminase (AST) of 2.7 U/l and 2.0 U/l, respectively, from baseline to end of study were seen in the canakinumab-treated groups versus the triamcinolone acetonide-treated group(s), however the incidence of clinically significant changes (≥ 3 x the upper limit of normal) was greater for patients treated with triamcinolone acetonide (2.5% for both AST and ALT) compared with canakinumab-treated patients (1.6% for ALT and 0.8% for AST).

Triglycerides

In active-controlled gouty arthritis trials, there was a mean increase in triglycerides of 33.5 mg/dl in canakinumab-treated patients compared with a modest decrease of ‑3.1 mg/dl with triamcinolone acetonide. The incidence of patients with triglyceride elevations > 5 x upper limit of normal (ULN) was 2.4% with canakinumab and 0.7% with triamcinolone acetonide. The clinical significance of this observation is unknown.

Long term data from observational study

A total of 243 CAPS patients (85 paediatric patients aged ≥ 2 to ≤ 17 years and 158 adult patients aged ≥ 18 years) were treated with canakinumab in routine clinical practice in a long-term registry study (mean of 3.8 years of canakinumab exposure). The safety profile of canakinumab observed following long-term treatment in this setting was consistent with what has been observed in interventional studies in CAPS patients.

Paediatric population

There were 80 paediatric CAPS patients (2‑17 years of age) who received canakinumab in the interventional studies. Overall, there were no clinically meaningful differences in the safety and tolerability profile of canakinumab in paediatric patients compared to the overall CAPS population (comprised of adult and paediatric patients, N=211), including the overall frequency and severity of infectious episodes. Infections of the upper respiratory tract were the most frequently reported infection events.

Additionally, 6 paediatric patients under the age of 2 years were evaluated in a small open-label clinical study. The safety profile of canakinumab appeared similar to that in patients aged 2 years and above.

There were 102 TRAPS, HIDS/MKD and FMF patients (2‑17 years of age) who received canakinumab in a 16-week study. Overall, there were no clinically meaningful differences in the safety and tolerability profile of canakinumab in paediatric patients compared to the overall population.

Elderly population

There is no significant difference in safety profile observed in patients ≥ 65 years of age.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Reported experience with overdose is limited. In early clinical trials, patients and healthy volunteers received doses as high as 10 mg/kg, administered intravenously or subcutaneously, without evidence of acute toxicity.

In case of overdose, it is recommended for the patient to be monitored for any signs or symptoms of adverse reactions, and appropriate symptomatic treatment instituted immediately.