Summary of medicine characteristics - IDACIO 40 MG / 0.8 ML SOLUTION FOR INJECTION FOR PAEDIATRIC USE
This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.
1 NAME OF THE MEDICINAL PRODUCT
Idacio 40 mg/0.8 ml solution for injection for paediatric use
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each 0.8 ml single dose vial contains 40 mg of adalimumab.
Adalimumab is a recombinant human monoclonal antibody produced in Chinese Hamster Ovary cells.
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Solution for injection (injection).
Clear, colourless solution.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Juvenile idiopathic arthritis
Polyarticular juvenile idiopathic arthritis
Idacio in combination with methotrexate is indicated for the treatment of active polyarticular juvenile idiopathic arthritis, in patients from the age of 2 years who have had an inadequate response to one or more disease-modifying anti-rheumatic drugs (DMARDs). Idacio can be given as monotherapy in case of intolerance to methotrexate or when continued treatment with methotrexate is inappropriate (for the efficacy in monotherapy see section 5.1).
Adalimumab has not been studied in patients aged less than 2 years.
Enthesitis-related arthritis
Idacio is indicated for the treatment of active enthesitis-related arthritis in patients, 6 years of age and older, who have had an inadequate response to, or who are intolerant of, conventional therapy (see section 5.1).
Paediatric plaque psoriasis
Idacio is indicated for the treatment of severe chronic plaque psoriasis in children and adolescents from 4 years of age who have had an inadequate response to or are inappropriate candidates for topical therapy and phototherapies.
Adolescent hidradenitis suppurativa
Idacio is indicated for the treatment of active moderate to severe hidradenitis suppurativa (acne inversa) in adolescents from 12 years of age with an inadequate response to conventional systemic HS therapy (see sections 5.1 and 5.2).
Paediatric Crohn's disease
Idacio is indicated for the treatment of moderately to severely active Crohn's disease in paediatric patients (from 6 years of age) who have had an inadequate response to conventional therapy including primary nutrition therapy and a corticosteroid and/or an immunomodulator, or who are intolerant to or have contraindications for such therapies.
Paediatric ulcerative colitis
Idacio is indicated for the treatment of moderately to severely active ulcerative colitis in paediatric patients (from 6 years of age) who have had an inadequate response to conventional therapy including corticosteroids and/or 6-mercaptopurine (6-MP) or azathioprine (AZA), or who are intolerant to or have medical contraindications for such therapies.
Paediatric Uveitis
Idacio is indicated for the treatment of paediatric chronic non-infectious anterior uveitis in patients from 2 years of age who have had an inadequate response to or are intolerant to conventional therapy, or in whom conventional therapy is inappropriate.
4.2 Posology and method of administration
Idacio treatment should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of conditions for which Idacio is indicated. Ophthalmologists are advised to consult with an appropriate specialist before initiation of treatment with Idacio (see section 4.4). Patients treated with Idacio should be given the patient reminder card.
After proper training in injection technique, patients may self-inject with Idacio if their physician determines that it is appropriate and with medical follow-up as necessary.
During treatment with Idacio, other concomitant therapies (e.g. corticosteroids and/or immunomodulatory agents) should be optimised.
Posology
Paediatric population
Juvenile idiopathic arthritis
Polyarticular , juvenile idiopathic arthritis from 2 years of age
The recommended dose of Idacio for patients with polyarticular juvenile idiopathic arthritis from 2 years of age is based on body weight (Table 1). Idacio is administered every other week via subcutaneous injection.
Table 1. Idacio dose for patients with polyarticular juvenile idiopathic arthrtis
| Patient weight | Dosing regimen |
| 10 kg to < 30 kg | 20 mg every other week |
| > 30 kg | 40 mg every other week |
Available data suggest that clinical response is usually achieved within 12 weeks of treatment. Continued therapy should be carefully reconsidered in a patient not responding within this time period.
There is no relevant use of adalimumab in patients aged less than 2 years for this indication.
Idacio may be available in other presentations depending on the individual treatment needs.
Enthesitis-related arthritis
The recommended dose of Idacio for patients with enthesitis-related arthritis from 6 years of age is based on body weight (Table 2). Idacio is administered every other week via subcutaneous injection.
Table 2. Idacio dose for patients with enthesitis-related arthritis
| Patient weight | Dosing regimen |
| 15 kg to < 30 kg | 20 mg every other week |
| > 30 kg | 40 mg every other week |
Adalimumab has not been studied in patients with enthesitis-related arthritis aged less than 6 years.
Idacio may be available in other presentations depending on the individual treatment needs.
Paediatric plaque psoriasis
The recommended Idacio dose for patients with plaque psoriasis from 4 to 17 years of age is based on body weight (Table 3). Idacio is administered via subcutaneous injection.
Table 3. Idacio dose for paediatric patients with plaque psoriasis
| Patient weight | Dosing regimen |
| 15 kg to < 30 kg | Initial dose of 20 mg, followed by 20 mg given every other week starting one week after the initial dose |
| > 30 kg | Initial dose of 40 mg, followed by 40 mg given every other week starting one week after the initial dose |
Continued therapy beyond 16 weeks should be carefully considered in a patient not responding within this time period.
If retreatment with Idacio is indicated, the above guidance on dose and treatment duration should be followed.
The safety of adalimumab in paediatric patients with plaque psoriasis has been assessed for a mean of 13 months.
There is no relevant use of adalimumab in children aged less than 4 years for this indication.
Idacio may be available in other presentations depending on the individual treatment needs.
Adolescent hidradenitis suppurativa (from 12 years of age, weighing at least 30 kg)
There are no clinical trials with adalimumab in adolescent patients with HS. The posology of adalimumab in these patients has been determined from pharmacokinetic modelling and simulation (see section 5.2).
The recommended Idacio dose is 80 mg at week 0 followed by 40 mg every other week starting at week 1 via subcutaneous injection.
In adolescent patients with inadequate response to Idacio 40 mg every other week, an increase in dosage to 40 mg every week or 80 mg every other week may be considered.
Antibiotics may be continued during treatment with Idacio if necessary. It is recommended that the patient should use a topical antiseptic wash on their HS lesions on a daily basis during treatment with Idacio.
Continued therapy beyond 12 weeks should be carefully reconsidered in a patient with no improvement within this time period.
Should treatment be interrupted, Idacio may be re-introduced as appropriate.
The benefit and risk of continued long-term treatment should be periodically evaluated (see adult data in section 5.1)
There is no relevant use of adalimumab in children aged less than 12 years in this indication.
Idacio may be available in other presentations depending on the individual treatment needs.
Paediatric Crohn's disease
The recommended dose of Idacio for patients with Crohn’s disease from 6 to 17 years of age is based on body weight (Table 4). Idacio is administered via subcutaneous injection.
Table 4. Idacio dose for paediatric patients with Crohn’s disease
| Patient weight | Induction dose | Maintenance dose starting at week 4 |
| < 40 kg | 40 mg at week 0 and 20 mg at week 2 In case there is a need for a more rapid response to therapy with the awareness that the risk for adverse events may be higher with use of the higher induction dose, the following dose may be used: 80 mg at week 0 and 40 mg at week 2 | 20 mg every other week |
| > 40 kg | 80 mg at week 0 and 40 mg at week 2 In case there is a need for a more rapid response to therapy with the awareness that the risk for adverse events may be higher with use of the higher induction dose, the following dose may be used: 160 mg at week 0 and 80 mg at week 2 | 40 mg every other week |
Patients who experience insufficient response may benefit from an increase in dosage:
< 40 kg: 20 mg every week
> 40 kg: 40 mg every week or 80 mg every other week
Continued therapy should be carefully considered in a subject not responding by week 12.
There is no relevant use of adalimumab in children aged less than 6 years for this indication.
Idacio may be available in other presentations depending on the individual treatment needs.
Paediatric ulcerative colitis
The recommended dose of Idacio for patients from 6 to 17 years of age with ulcerative colitis
is based on body weight (Table 5). Idacio is administered via subcutaneous injection.
Table 5. Idacio dose for paediatric patients with ulcerative colitis
| Patient weight | Induction dose | Maintenance dose starting at week 4* |
| < 40 kg | 80 mg at week 0 (given as two 40 mg injections in one day) and 40 mg at week 2 (given as one 40 mg injection) | 40 mg every other week |
| 4 40 kg | 160 mg at week 0 (given as four 40 mg injections in one day or two 40 mg injections per day for two consecutive days) and 80 mg at week 2 (given as two 40 mg injections in one day) | 80 mg every other week |
*Paediatric patients who turn 18 years of age while on Idacio should continue their prescribed maintenance dose.
Continued therapy beyond 8 weeks should be carefully considered in patients not showing signs of response within this time period.
There is no relevant use of adalimumab in children less than 6 years in this indication.
Idacio may be available in different presentations depending on the individual treatment needs.
Paediatric Uveitis
The recommended dose of Idacio for paediatric patients with uveitis from 2 years of age is based on body weight (Table 6). Idacio is administered via subcutaneous injection.
In paediatric uveitis, there is no experience in the treatment with adalimumab without concomitant treatment with methotrexate.
Table 6. Idacio dose for paediatric patients with uveitis
| Patient weight | Dosing regimen |
| < 30 kg | 20 mg every other week in combination with methotrexate |
| > 30 kg | 40 mg every other week in combination with methotrexate |
When Idacio therapy is initiated, a loading dose of 40 mg for patients < 30 kg or 80 mg for patients > 30 kg may be administered one week prior to the start of maintenance therapy. No clinical data are available on the use of an adalimumab loading dose in children < 6 years of age (see section 5.2).
There is no relevant use of Idacio in children aged less than 2 years in this indication.
It is recommended that the benefit and risk of continued long-term treatment should be evaluated on a yearly basis (see section 5.1).
Idacio may be available in other presentations depending on the individual treatment needs.
Renal and/or hepatic impairment
Adalimumab has not been studied in these patient populations. No dose recommendations can be made.
Method of administration
Idacio is administered by subcutaneous injection. Full instructions for use are provided in the package leaflet.
Idacio is available in other presentations.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Active tuberculosis or other severe infections such as sepsis, and opportunistic infections (see section 4.4).
Moderate to severe heart failure (NYHA class III/IV) (see section 4.4).
4.4 Special warnings and precautions for use
Traceability
In order to improve traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
Infections
Patients taking TNF-antagonists are more susceptible to serious infections. Impaired lung function may increase the risk for developing infections. Patients must therefore be monitored closely for infections, including tuberculosis, before, during and after treatment with Idacio. Because the elimination of adalimumab may take up to four months, monitoring should be continued throughout this period.
Treatment with Idacio should not be initiated in patients with active infections including chronic or localised infections until infections are controlled. In patients who have been exposed to tuberculosis and patients who have travelled in areas of high risk of tuberculosis or endemic mycoses, such as histoplasmosis, coccidioidomycosis, or blastomycosis, the risk and benefits of treatment with Idacio should be considered prior to initiating therapy (see Other opportunistic infections).
Patients who develop a new infection while undergoing treatment with Idacio, should be monitored closely and undergo a complete diagnostic evaluation. Administration of Idacio should be discontinued if a patient develops a new serious infection or sepsis, and appropriate antimicrobial or antifungal therapy should be initiated until the infection is controlled. Physicians should exercise caution when considering the use of Idacio in patients with a history of recurring infection or with underlying conditions which may predispose patients to infections, including the use of concomitant immunosuppressive medications.
Serious infections
Serious infections including sepsis, due to bacterial, mycobacterial, invasive fungal, parasitic, viral, or other opportunistic infections such as listeriosis, legionellosis and pneumocystis have been reported in patients receiving adalimumab.
Other serious infections seen in clinical trials include pneumonia, pyelonephritis, septic arthritis and septicaemia. Hospitalisation or fatal outcomes associated with infections have been reported.
Tuberculosis
Tuberculosis, including reactivation and new onset of tuberculosis, has been reported in patients receiving adalimumab. Reports included cases of pulmonary and extra-pulmonary (i.e. disseminated) tuberculosis.
Before initiation of therapy with Idacio, all patients must be evaluated for both active or inactive (“latent”) tuberculosis infection. This evaluation should include a detailed medical assessment of patient history of tuberculosis or possible previous exposure to people with active tuberculosis and previous and/or current immunosuppressive therapy. Appropriate screening tests (i.e. tuberculin skin test and chest X-ray) should be performed in all patients (local recommendations may apply). It is recommended that the conduct and results of these tests are recorded in the patient reminder card. Prescribers are reminded of the risk of false negative tuberculin skin test results, especially in patients who are severely ill or immunocompromised.
If active tuberculosis is diagnosed, Idacio therapy must not be initiated (see section 4.3).
In all situations described below, the benefit/risk balance of therapy should be very carefully considered.
If latent tuberculosis is suspected, a physician with expertise in the treatment of tuberculosis should be consulted.
If latent tuberculosis is diagnosed, appropriate treatment must be started with anti-tuberculosis prophylaxis treatment before the initiation of Idacio, and in accordance with local recommendations.
Use of anti-tuberculosis prophylaxis treatment should also be considered before the initiation of Idacio in patients with several or significant risk factors for tuberculosis despite a negative test for tuberculosis and in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed.
Despite prophylactic treatment for tuberculosis, cases of reactivated tuberculosis have occurred in patients treated with adalimumab Some patients who have been successfully treated for active tuberculosis have redeveloped tuberculosis while being treated with adalimumab.
Patients should be instructed to seek medical advice if signs/symptoms suggestive of a tuberculosis infection (e.g. persistent cough, wasting/weight loss, low grade fever, listlessness) occur during or after therapy with Idacio.
Other opportunistic infections
Opportunistic infections, including invasive fungal infections have been observed in patients receiving adalimumab. These infections have not consistently been recognised in patients taking TNF- antagonists and this has resulted in delays in appropriate treatment, sometimes resulting in fatal outcomes.
For patients who develop the signs and symptoms such as fever, malaise, weight loss, sweats, cough, dyspnea, and/or pulmonary infiltrates or other serious systemic illness with or without concomitant shock an invasive fungal infection should be suspected and administration of Idacio should be promptly discontinued. Diagnosis and administration of empiric antifungal therapy in these patients should be made in consultation with a physician with expertise in the care of patients with invasive fungal infections.
Hepatitis B reactivation
Reactivation of hepatitis B has occurred in patients receiving a TNF-antagonist including adalimumab, who are chronic carriers of this virus (i.e. surface antigen positive). Some cases have had a fatal outcome. Patients should be tested for HBV infection before initiating treatment with Idacio. For patients who test positive for hepatitis B infection, consultation with a physician with expertise in the treatment of hepatitis B is recommended.
Carriers of HBV who require treatment with Idacio should be closely monitored for signs and symptoms of active HBV infection throughout therapy and for several months following termination of therapy. Adequate data from treating patients who are carriers of HBV with anti-viral therapy in conjunction with TNF-antagonist therapy to prevent HBV reactivation are not available. In patients who develop HBV reactivation, Idacio should be stopped and effective anti-viral therapy with appropriate supportive treatment should be initiated.
Neurological events
TNF-antagonists including adalimumab have been associated in rare instances with new onset or exacerbation of clinical symptoms and/or radiographic evidence of central nervous system demyelinating disease including multiple sclerosis and optic neuritis, and peripheral demyelinating disease, including Guillain-Barré syndrome. Prescribers should exercise caution in considering the use of Idacio in patients with pre-existing or recent-onset central or peripheral nervous system demyelinating disorders; discontinuation of Idacio should be considered if any of these disorders develop. There is a known association between intermediate uveitis and central demyelinating disorders. Neurologic evaluation should be performed in patients with non-infectious intermediate uveitis prior to the initiation of Idacio therapy and regularly during treatment to assess for pre-existing or developing central demyelinating disorders.
Allergic reactions
Serious allergic reactions associated with adalimumab were rare during clinical trials. Non-serious allergic reactions associated with adalimumab were uncommon during clinical trials.Reports of serious allergic reactions including anaphylaxis have been received following adalimumab administration. If an anaphylactic reaction or other serious allergic reaction occurs, administration of Idacio should be discontinued immediately and appropriate therapy initiated.
Immunosuppression
In a study of 64 patients with rheumatoid arthritis that were treated with adalimumab, there was no evidence of depression of delayed-type hypersensitivity, depression of immunoglobulin levels, or change in enumeration of effector T-, B -, NK-cells, monocyte/macrophages, and neutrophils.
Malignancies and lymphoproliferative disorders
In the controlled portions of clinical trials of TNF-antagonists, more cases of malignancies including lymphoma have been observed among patients receiving a TNF-antagonist compared with control patients. However, the occurrence was rare. In the post marketing setting, cases of leukaemia have been reported in patients treated with a TNF-antagonist. There is an increased background risk for lymphoma and leukaemia in rheumatoid arthritis patients with long-standing, highly active, inflammatory disease, which complicates the risk estimation. With the current knowledge, a possible risk for the development of lymphomas, leukaemia, and other malignancies in patients treated with a TNF-antagonist cannot be excluded.
Malignancies, some fatal, have been reported among children, adolescents and young adults (up to 22 years of age) treated with TNF-antagonists (initiation of therapy < 18 years of age), including adalimumab in the post marketing setting. Approximately half the cases were lymphomas. The other cases represented a variety of different malignancies and included rare malignancies usually associated with immunosuppression. A risk for the development of malignancies in children and adolescents treated with TNF-antagonists cannot be excluded.
Rare postmarketing cases of hepatosplenic T-cell lymphoma have been identified in patients treated with adalimumab. This rare type of T-cell lymphoma has a very aggressive disease course and is usually fatal. Some of these hepatosplenic T-cell lymphomas with adalimumab have occurred in young adult patients on concomitant treatment with azathioprine or 6-mercaptopurine used for inflammatory bowel disease. The potential risk with the combination of azathioprine or 6-mercaptopurine and adalimumab should be carefully considered. A risk for the development of hepatosplenic T-cell lymphoma in patients treated with Idacio cannot be excluded (see section 4.8).
No studies have been conducted that include patients with a history of malignancy or in whom treatment with adalimumab is continued following development of malignancy. Thus, additional caution should be exercised in considering Idacio treatment of these patients (see section 4.8).
All patients, and in particular patients with a medical history of extensive immunosuppressant therapy or psoriasis patients with a history of PUVA treatment should be examined for the presence of non- melanoma skin cancer prior to and during treatment with Idacio. Melanoma and Merkel cell carcinoma have also been reported in patients treated with TNF-antagonists including adalimumab (see section 4.8).
In an exploratory clinical trial evaluating the use of another TNF-antagonist, infliximab, in patients with moderate to severe chronic obstructive pulmonary disease (COPD), more malignancies, mostly in the lung or head and neck, were reported in infliximab-treated patients compared with control patients. All patients had a history of heavy smoking. Therefore, caution should be exercised when using any TNF-antagonist in COPD patients, as well as in patients with increased risk for malignancy due to heavy smoking.
With current data it is not known if adalimumab treatment influences the risk for developing dysplasia or colon cancer. All patients with ulcerative colitis who are at increased risk for dysplasia or colon carcinoma (for example, patients with long-standing ulcerative colitis or primary sclerosing cholangitis), or who had a prior history of dysplasia or colon carcinoma should be screened for dysplasia at regular intervals before therapy and throughout their disease course. This evaluation should include colonoscopy and biopsies per local recommendations.
Haematologic reactions
Rare reports of pancytopenia including aplastic anaemia have been reported with TNF-antagonists. Adverse events of the haematologic system, including medically significant cytopenia (e.g. thrombocytopenia, leucopenia) have been reported with adalimumab. All patients should be advised to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias (e.g. persistent fever, bruising, bleeding, pallor) while on Idacio. Discontinuation of Idacio therapy should be considered in patients with confirmed significant haematologic abnormalities.
Vaccinations
Similar antibody responses to the standard 23-valent pneumococcal vaccine and the influenza trivalent virus vaccination were observed in a study in 226 adult subjects with rheumatoid arthritis who were treated with adalimumab or placebo. No data are available on the secondary transmission of infection by live vaccines in patients receiving adalimumab.
It is recommended that paediatric patients, if possible, be brought up to date with all immunisations in agreement with current immunisation guidelines prior to initiating adalimumab therapy.
Patients on adalimumab may receive concurrent vaccinations, except for live vaccines. Administration of live vaccines (e.g., BCG vaccine) to infants exposed to adalimumab in utero is not recommended for 5 months following the mother’s last adalimumab injection during pregnancy.
Congestive heart failure
In a clinical trial with another TNF-antagonist worsening congestive heart failure and increased mortality due to congestive heart failure have been observed. Cases of worsening congestive heart failure have also been reported in patients receiving adalimumab. Idacio should be used with caution in patients with mild heart failure (NYHA class I/II). Idacio is contraindicated in moderate to severe heart failure (see section 4.3). Treatment with Idacio must be discontinued in patients who develop new or worsening symptoms of congestive heart failure.
Autoimmune processes
Treatment with Idacio may result in the formation of autoimmune antibodies. The impact of long- term treatment with adalimumab on the development of autoimmune diseases is unknown. If a patient develops symptoms suggestive of a lupus-like syndrome following treatment with Idacio and is positive for antibodies against double-stranded DNA, further treatment with Idacio should not be given (see section 4.8).
Concurrent administration of biologic DMARDs or TNF-antagonists
Serious infections were seen in clinical studies with concurrent use of anakinra and another TNF-antagonist, etanercept, with no added clinical benefit compared to etanercept alone. Because of the nature of the adverse events seen with the combination of etanercept and anakinra therapy, similar toxicities may also result from the combination of anakinra and other TNF-antagonists. Therefore, the combination of adalimumab and anakinra is not recommended. (See section 4.5).
Concomitant administration of adalimumab with other biologic DMARDs (e.g, anakinra and abatacept) or other TNF-antagonists is not recommended based upon the possible increased risk for infections, including serious infections and other potential pharmacological interactions. (See section 4.5).
Surgery
There is limited safety experience of surgical procedures in patients treated with adalimumab. The long half-life of adalimumab should be taken into consideration if a surgical procedure is planned. A patient who requires surgery while on Idacio should be closely monitored for infections, and appropriate actions should be taken. There is limited safety experience in patients undergoing arthroplasty while receiving adalimumab.
Small bowel obstruction
Failure to respond to treatment for Crohn’s disease may indicate the presence of fixed fibrotic stricture that may require surgical treatment. Available data suggest that adalimumab does not worsen or cause strictures.
Elderly
The frequency of serious infections among adalimumab treated subjects over 65 years of age (3.7%) was higher than for those under 65 years of age (1.5%). Some of those had a fatal outcome. Particular attention regarding the risk for infection should be paid when treating the elderly.
Paediatric population
See Vaccinations above.
Excipients with known effects
This medicinal product contains less than 1 mmol of sodium (23 mg) per 0.8 ml dose, i.e. essentially ‚sodium-free‘.
4.5 Interaction with other medicinal products and other forms of interaction
Adalimumab has been studied in rheumatoid arthritis, polyarticular juvenile idiopathic arthritis and psoriatic arthritis patients taking adalimumab as monotherapy and those taking concomitant methotrexate. Antibody formation was lower when adalimumab was given together with methotrexate in comparison with use as monotherapy. Administration of adalimumab without methotrexate resulted in increased formation of antibodies, increased clearance and reduced efficacy of adalimumab (see section 5.1).
The combination of Idacio and anakinra is not recommended (see section 4.4 “Concurrent administration of biologic DMARDs or TNF-antagonists”).
The combination of Idacio and abatacept is not recommended (see section 4.4 “Concurrent administration of biologic DMARDs or TNF-antagonists”).
4.6 Fertility, pregnancy and lactation
Women of childbearing potential
Women of childbearing potential should consider the use of adequate contraception to prevent pregnancy and continue its use for at least five months after the last Idacio treatment.
Pregnancy
A large number (approximately 2100) of prospectively collected pregnancies exposed to adalimumab resulting in live birth with known outcomes, including more than 1500 exposed during the first trimester, does not indicate an increase in the rate of malformation in the newborn.
In a prospective cohort registry, 257 women with rheumatoid arthritis (RA) or Crohn’s disease (CD) treated with adalimumab at least during the first trimester and 120 women with RA or CD not treated with adalimumab were enrolled. The primary endpoint was the birth prevalence of major birth defects. The rate of pregnancies ending with at least one live born infant with a major birth defect was 6/69 (8.7%) in the adalimumab-treated women with RA and 5/74 (6.8%) in the untreated women with RA (unadjusted OR 1.31, 95% CI 0.38–4.52) and 16/152 (10.5%) in the adalimumab-treated women with CD and 3/32 (9.4%) in the untreated women with CD (unadjusted OR 1.14, 95% CI 0.31–4.16). The adjusted OR (accounting for baseline differences) was 1.10 (95% CI 0.45–2.73) with RA and CD combined. There were no distinct differences between adalimumab-treated and untreated women for the secondary endpoints spontaneous abortions, minor birth defects, preterm delivery, birth size and serious or opportunistic infections and no stillbirths or malignancies were reported. The interpretation of data may be impacted due to methodological limitations of the study, including small sample size and non-randomized design.
In a developmental toxicity study conducted in monkeys, there was no indication of maternal toxicity, embryotoxicity or teratogenicity. Preclinical data on postnatal toxicity of adalimumab are not available (see section 5.3).
Due to its inhibition of TNFa, adalimumab administered during pregnancy could affect normal immune responses in the newborn. Adalimumab should only be used during pregnancy if clearly needed.
Adalimumab may cross the placenta into the serum of infants born to women treated with adalimumab during pregnancy. Consequently, these infants may be at increased risk for infection. Administration of live vaccines (e.g., BCG vaccine) to infants exposed to adalimumab in utero is not recommended for 5 months following the mother’s last adalimumab injection during pregnancy.
Breast-feeding
Limited information from the published literature indicates that adalimumab is excreted in breast milk at very low concentrations with the presence of adalimumab in human milk at concentrations of 0.1% to 1% of the maternal serum level. Given orally, immunoglobulin G proteins undergo intestinal proteolysis and have poor bioavailability. No effects on the breastfed newborns/infants are anticipated. Consequently, Idacio can be used during breastfeeding.
Fertility
Preclinical data on fertility effects of adalimumab are not available.
4.7 Effects on ability to drive and use machines
Idacio may have a minor influence on the ability to drive and use machines.
Vertigo and visual impairment may occur following administration of Idacio (see section 4.8).
4.8 Undesirable effects
Summary of the safety profile
Adalimumab was studied in 9,506 patients in pivotal controlled and open label trials for up to 60 months or more. These trials included rheumatoid arthritis patients with short term and long standing disease, juvenile idiopathic arthritis (polyarticular juvenile idiopathic arthritis and enthesitis-related arthritis) as well as axial spondyloarthritis (ankylosing spondylitis and axial spondyloarthritis without radiographic evidence of AS), psoriatic arthritis, Crohn’s disease, ulcerative colitis, psoriasis, hidradenitis suppurativa and uveitis patients. The pivotal controlled studies involved 6,089 patients receiving adalimumab and 3,801 patients receiving placebo or active comparator during the controlled period.
The proportion of patients who discontinued treatment due to adverse events during the double-blind, controlled portion of pivotal studies was 5.9% for patients taking adalimumab and 5.4% for control treated patients.
The most commonly reported adverse reactions are infections (such as nasopharyngitis, upper respiratory tract infection and sinusitis), injection site reactions (erythema, itching, haemorrhage, pain or swelling), headache and musculoskeletal pain.
Serious adverse reactions have been reported for adalimumab. TNF-antagonists, such as adalimumab affect the immune system and their use may affect the body’s defence against infection and cancer.
Fatal and life-threatening infections (including sepsis, opportunistic infections and TB), HBV reactivation and various malignancies (including leukaemia, lymphoma and HSTCL) have also been reported with use of adalimumab.
Serious haematological, neurological and autoimmune reactions have also been reported. These include rare reports of pancytopenia, aplastic anaemia, central and peripheral demyelinating events and reports of lupus, lupus-related conditions and Stevens-Johnson syndrome.
Paediatric population
In general, the adverse events in paediatric patients were similar in frequency and type to those seen in adult patients.
Tabulated list of adverse reactions
The following list of adverse reactions is based on experience from clinical trials and on postmarketing experience and are displayed by system organ class and frequency in Table 7 below:
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); and not known (cannot be estimated from the available data).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. The highest frequency seen among the various indications has been included. An asterisk () appears in the System Organ Class (SOC) column if further information is found elsewhere in sections 4.3, 4.4 and 4.8.
Table 7 Undesirable effects
| System Organ Class | Frequency | Adverse reaction |
| Infections and infestations | Very common | Respiratory tract infections (including lower and upper respiratory tract infection, pneumonia, sinusitis, pharyngitis, nasopharyngitis and pneumonia herpes viral) |
| Common | Systemic infections (including sepsis, candidiasis and influenza), intestinal infections (including gastroenteritis viral), skin and soft tissue infections (including paronychia, cellulitis, impetigo, necrotising fasciitis and herpes zoster), ear infections, oral infections (including herpes simplex, oral herpes and tooth infections), reproductive tract infections (including vulvovaginal mycotic infection), urinary tract infections (including pyelonephritis), fungal infections, joint infections | |
| Uncommon | Neurological infections (including viral meningitis), opportunistic infections and tuberculosis (including coccidioidomycosis, histoplasmosis and mycobacterium avium complex infection), bacterial infections, eye infections, diverticulitis 1) | |
| Neoplasms benign, | Common | Skin cancer excluding melanoma (including |
| System Organ Class | Frequency | Adverse reaction |
| malignant and unspecified (including cysts and polyps) | basal cell carcinoma and squamous cell carcinoma), benign neoplasm | |
| Uncommon | Lymphoma, solid organ neoplasm (including breast cancer, lung neoplasm and thyroid neoplasm), melanoma | |
| Rare | Leukaemia1) | |
| Not known | Hepatosplenic T-cell lymphoma1), Merkel cell carcinoma (neuroendocrine carcinoma of the skin)1) Kaposi’s sarcoma | |
| Blood and lymphatic system disorders | Very common | Leucopaenia (including neutropaenia and agranulocytosis), Anaemia |
| Common | Leucocytosis, thrombocytopenia | |
| Uncommon | Idiopathic thrombocytopenic purpura | |
| Rare | Pancytopenia | |
| Immune system disorders* | Common | Hypersensitivity, allergies (including seasonal allergy) |
| Uncommon | Sarcoidosis1), vasculitis | |
| Rare | Anaphylaxis1) | |
| Metabolism and nutrition disorders | Very common | Lipids increased |
| Common | Hypokalaemia, uric acid increased, blood sodium abnormal, hypocalcaemia, hyperglycaemia, hypophosphataemia, |
| System Organ Class | Frequency | Adverse reaction |
| dehydration | ||
| Psychiatric disorders | Common | Mood alterations (including depression), anxiety, insomnia |
| Nervous system disorders* | Very common | Headache |
| Common | Paraesthesias (including hypoaesthesia), migraine, nerve root compression | |
| Uncommon | Cerebrovascular accident1), tremor, neuropathy | |
| Rare | Multiple sclerosis, demyelinating disorders (e.g. optic neuritis, Guillain-Barre syndrome) 1) | |
| Eye disorders | Common | Visual impairment, conjunctivitis, blepharitis, eye swelling |
| Uncommon | Diplopia | |
| Ear and labyrinth disorders | Common | Vertigo |
| Uncommon | Deafness, tinnitus | |
| Cardiac disorders* | Common | Tachycardia |
| Uncommon | Myocardial infarction1), arrhythmia, congestive heart failure | |
| Rare | Cardiac arrest | |
| Vascular disorders | Common | Hypertension, flushing, haematoma |
| System Organ Class | Frequency | Adverse reaction |
| Uncommon | Aortic aneurysm, vascular arterial occlusion, thrombophlebitis | |
| Respiratory, thoracic and mediastinal disorders* | Common | Asthma, dyspnoea, cough |
| Uncommon | Pulmonary embolism1), interstitial lung disease, chronic obstructive pulmonary disease, pneumonitis, pleural effusion1) | |
| Rare | Pulmonary fibrosis1) | |
| Gastrointestinal disorders | Very common | Abdominal pain, nausea and vomiting |
| Common | GI haemorrhage, dyspepsia, gastroesophageal reflux disease, sicca syndrome | |
| Uncommon | Pancreatitis, dysphagia, face oedema | |
| Rare | Intestinal perforation1) | |
| Hepatobiliary disorders* | Very Common | Elevated liver enzymes |
| Uncommon | Cholecystitis and cholelithiasis, hepatic steatosis, bilirubin increased | |
| Rare | Hepatitis, reactivation of hepatitis B1), autoimmune hepatitis1) | |
| Not known | Liver failure1) | |
| Skin and subcutaneous | Very Common | Rash (including exfoliative rash) |
| System Organ Class | Frequency | Adverse reaction |
| tissue disorders | Common | Worsening or new onset of psoriasis (including palmoplantar pustular psoriasis) 1), urticaria, bruising (including purpura), dermatitis (including eczema), onychoclasis, hyperhidrosis, alopecia1), pruritus |
| Uncommon | Night sweats, scar | |
| Rare | Erythema multiforme1), Stevens-Johnson syndrome1), angioedema1), cutaneous vasculitis1), lichenoid skin reaction1) | |
| Not known | Worsening of symptoms of dermatomyositis1) | |
| Musculoskeletal and connective tissue disorders | Very common | Musculoskeletal pain |
| Common | Muscle spasms (including blood creatine phosphokinase increased) | |
| Uncommon | Rhabdomyolysis, systemic lupus erythematosus | |
| Rare | Lupus-like syndrome1) | |
| Renal and urinary disorders | Common | Renal impairment, haematuria |
| Uncommon | Nocturia | |
| Reproductive system and breast disorders | Uncommon | Erectile dysfunction |
| General disorders and administration site conditions* | Very Common | Injection site reaction (including injection site erythema) |
| Common | Chest pain, oedema, |
| System Organ Class | Frequency | Adverse reaction |
| pyrexia1) | ||
| Uncommon | Inflammation | |
| Investigations* | Common | Coagulation and bleeding disorders (including activated partial thromboplastin time prolonged), autoantibody test positive (including double stranded DNA antibody), blood lactate dehydrogenase increased |
| Not known | Weight increased2) | |
| Injury, poisoning and procedural complications | Common | Impaired healing |
* further information is found elsewhere in sections 4.3, 4.4 and 4.8
* * including open label extension studies
1) including spontaneous reporting data
2) The mean weight change from baseline for adalimumab ranged from 0.3 kg to 1.0 kg across adult indications compared to (minus) –0.4 kg to 0.4 kg for placebo over a treatment period of 4–6 months. Weight increase of 5–6 kg has also been observed in long-term extension studies with mean exposures of approximately 1–2 years without control group, particularly in patients with Crohn’s disease and ulcerative colitis. The mechanism behind this effect is unclear but could be associated with the anti-inflammatory effect of adalimumab.
Hidradenitis suppurativa
The safety profile for patients with HS treated with adalimumab weekly was consistent with the known safety profile of adalimumab.
Uveitis
The safety profile for patients with uveitis treated with adalimumab every other week was consistent with the known safety profile of adalimumab.
Description of selected adverse reactions
Injection site reactions
In the pivotal controlled trials in adults and children, 12.9% of patients treated with adalimumab developed injection site reactions (erythema and/or itching, haemorrhage, pain or swelling), compared to 7.2% of patients receiving placebo or active control. Injection site reactions generally did not necessitate discontinuation of the medicinal product.
Infections
In the pivotal controlled trials in adults and children, the rate of infection was 1.51 per patient year in the adalimumab treated patients and 1.46 per patient year in the placebo and active control-treated patients. The infections consisted primarily of nasopharyngitis, upper respiratory tract infection, and sinusitis. Most patients continued on adalimumab after the infection resolved.
The incidence of serious infections was 0.04 per patient year in adalimumab treated patients and 0.03 per patient year in placebo and active control – treated patients.
In controlled and open label adult and paediatric studies with adalimumab, serious infections (including fatal infections, which occurred rarely) have been reported, which include reports of tuberculosis (including miliary and extra-pulmonary locations) and invasive opportunistic infections (e.g. disseminated or extrapulmonary histoplasmosis, ,blastomycosis, coccidioidomycosis, pneumocystis, candidiasis, aspergillosis and listeriosis). Most of the cases of tuberculosis occurred within the first eight months after initiation of therapy and may reflect recrudescence of latent disease.
Malignancies and lymphoproliferative disorders
No malignancies were observed in 249 paediatric patients with an exposure of 655.6 patient years during adalimumab trials in patients with juvenile idiopathic arthritis (polyarticular juvenile idiopathic arthritis and enthesitis-related arthritis). In addition, no malignancies were observed in 192 paediatric patients with an exposure of 498.1 patient years during adalimumab trials in paediatric patients with Crohn’s disease. No malignancies were observed in 77 paediatric patients with an exposure of 80.0 patient years during a adalimumab trial in paediatric patients with chronic plaque psoriasis. No malignancies were observed in 93 paediatric patients with an exposure of 65.3 patient years during an adalimumab trial in paediatric patients with ulcerative colitis. No malignancies were observed in 60 paediatric patients with an exposure of 58.4 patient years during an adalimumab trial in paediatric patients with uveitis.
During the controlled portions of pivotal adalimumab trials in adults of at least 12 weeks in duration in patients with moderately to severely active rheumatoid arthritis, ankylosing spondylitis, axial spondyloarthritis without radiographic evidence of AS, psoriatic arthritis, psoriasis, hidradenitis suppurativa, Crohn’s disease, ulcerative colitis and uveitis, malignancies, other than lymphoma and non-melanoma skin cancer, were observed at a rate (95% confidence interval) of 6.8 (4.4, 10.5) per 1,000 patient-years among 5,291 adalimumab treated patients versus a rate of 6.3 (3.4, 11.8) per 1,000 patient-years among 3,444 control patients (median duration of treatment was 4.0 months for adalimumab and 3.8 months for control-treated patients). The rate (95% confidence interval) of non-melanoma skin cancers was 8.8 (6.0, 13.0) per 1,000 patient-years among adalimumab-treated patients and 3.2 (1.3, 7.6) per 1,000 patient-years among control patients. Of these skin cancers, squamous cell carcinomas occurred at rates (95% confidence interval) of 2.7 (1.4, 5.4) per 1,000 patientyears among adalimumab- treated patients and 0.6 (0.1, 4.5) per 1,000 patient-years among control patients. The rate (95% confidence interval) of lymphomas was 0.7 (0.2, 2.7) per 1,000 patient-years among adalimumab-treated patients and 0.6 (0.1, 4.5) per 1,000 patientyears among control patients.
When combining controlled portions of these trials and ongoing and completed open label extension studies with a median duration of approximately 3.3 years including 6,427 patients and over 26,439 patient-years of therapy, the observed rate of malignancies, other than lymphoma and non-melanoma skin cancers is approximately 8.5 per 1,000 patient years. The observed rate of non-melanoma skin cancers is approximately 9.6 per 1,000 patient years, and the observed rate of lymphomas is approximately 1.3 per 1,000 patient years.
In post-marketing experience from January 2003 to December 2010, predominantly in patients with rheumatoid arthritis, the reported rate of malignancies is approximately 2.7 per 1,000 patient treatment years. The reported rates for non-melanoma skin cancers and lymphomas are approximately 0.2 and 0.3 per 1,000 patient treatment years, respectively (see section 4.4).
Rare post-marketing cases of hepatosplenic T-cell lymphoma have been reported in patients treated with adalimumab (see section 4.4).
Autoantibodies
Patients had serum samples tested for autoantibodies at multiple time points in rheumatoid arthritis studies I – V. In these trials, 11.9% of patients treated with adalimumab and 8.1% of placebo and active control – treated patients that had negative baseline anti-nuclear antibody titres reported positive titres at week 24. Two patients out of 3,441 treated with adalimumab in all rheumatoid arthritis and psoriatic arthritis studies developed clinical signs suggestive of new-onset lupus-like syndrome. The patients improved following discontinuation of therapy. No patients developed lupus nephritis or central nervous system symptoms.
Hepato-biliary events
In controlled Phase 3 trials of adalimumab in patients with rheumatoid arthritis and psoriatic arthritis with a control period duration ranging from 4 to 104 weeks, ALT elevations > 3 x ULN occurred in3.7% of adalimumab-treated patients and 1.6% of control-treated patients.
In controlled Phase 3 trials of adalimumab in patients with polyarticular juvenile idiopathic arthritis who were 4 to 17 years and enthesitis-related arthritis who were 6 to 17 years, ALT elevations > 3 x ULN occurred in 6.1% of adalimumab-treated patients and 1.3% of control-treated patients. Most ALT elevations occurred with concomitant methotrexate use. No ALT elevations > 3 x ULN occurred in the Phase 3 trial of adalimumab in patients with polyarticular juvenile idiopathic arthritis who were 2 to <4 years.
In controlled Phase 3 trials of adalimumab in patients with Crohn’s disease and ulcerative colitis with a control period ranging from 4 to 52 weeks. ALT elevations > 3 x ULN occurred in 0.9% of adalimumab- treated patients and 0.9% of controlled-treated patients.
In the Phase 3 trial of adalimumab in patients with paediatric Crohn’s disease which evaluated efficacy and safety of two body weight adjusted maintenance dose regimens following body weight adjusted induction therapy up to 52 weeks of treatment, ALT elevations > 3 x ULN occurred in 2.6% (5/192) of patients of whom 4 were receiving concomitant immunosuppressants at baseline.
In controlled Phase 3 trials of adalimumab in patients with plaque psoriasis with a control period duration ranging from 12 to 24 weeks, ALT elevations > 3 x ULN occurred in 1.8% of adalimumab-treated patients and 1.8% of control-treated patients.
No ALT elevations >3 X ULN occurred in the Phase 3 trial of adalimumab in paediatric patients with plaque psoriasis.
In controlled trials of adalimumab (initial doses of 160 mg at week 0 and 80 mg at week 2, followed by 40 mg every week starting at week 4), in patients with hidradenitis suppurativa with a control period duration ranging from 12 to 16 weeks, ALT elevations > 3 x ULN occurred in 0.3% of adalimumab-treated patients and 0.6% of control-treated patients.
In controlled trials of adalimumab (initial doses of 80 mg at week 0 followed by 40 mg every other week starting at week 1) in adult patients with uveitis up to 80 weeks with a median exposure of 166.5 days and 105.0 days in Adalimumab-treated and control-treated patients, respectively, ALT elevations > 3 x ULN occurred in 2.4% of adalimumab-treated patients and 2.4% of control-treated patients.
In the controlled Phase 3 trial of an adalimumab in patients with paediatric ulcerative colitis (N=93) which evaluated efficacy and safety of a maintenance dose of 0.6 mg/kg (maximum of 40 mg) every other week (N=31) and a maintenance dose of 0.6 mg/kg (maximum of 40 mg) every Week (N=32), following body weight adjusted induction dosing of 2.4 mg/kg (maximum of 160 mg) at Week 0 and Week 1, and 1.2 mg/kg (maximum of 80 mg) at Week 2 (N=63), or an induction dose of 2.4 mg/kg (maximum of 160 mg) at Week 0, placebo at Week 1, and 1.2 mg/kg (maximum of 80 mg) at Week 2 (N=30), ALT elevations > 3 X ULN occurred in 1.1% (1/93) of patients.
Across all indications in clinical trials patients with raised ALT were asymptomatic and in most cases elevations were transient and resolved on continued treatment. However, there have also been post- marketing reports of liver failure as well as less severe liver disorders that may precede liver failure, such as hepatitis including autoimmune hepatitis in patients receiving adalimumab.
Concurrent treatment with azathioprine/6-mercaptopurine
In adult Crohn’s disease studies, higher incidences of malignant and serious infection-related adverse events were seen with the combination of adalimumab and azathioprine/6-mercaptopurine compared with adalimumab alone.
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 Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store
4.9 Overdose
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
5.2 Pharmacokinetic properties
Absorption and distribution
Following the administration of 24 mg/m2 (maximum of 40 mg) subcutaneously every other week to patients with polyarticular juvenile idiopathic arthritis (JIA) who were 4 to 17 years the mean trough steady-state (values measured from week 20 to 48) serum adalimumab concentration was 5.6 ± 5.6 ^g/ml (102% CV) for adalimumab without concomitant methotrexate and 10.9 ± 5.2 ^g/ml (47.7% CV) with concomitant methotrexate.
In patients with polyarticular JIA who were 2 to <4 years old or aged 4 and above weighing <15 kg dosed with adalimumab 24 mg/m2 , the mean trough steady-state serum adalimumab concentrations was 6.0 ± 6.1 ^g/ml (101% CV) for adalimumab without concomitant methotrexate and 7.9 ± 5.6 ^g/ml (71.2% CV) with concomitant methotrexate.
Following the administration of 24 mg/m2 (maximum of 40 mg) subcutaneously every other week to patients with enthesitis-related arthritis who were 6 to 17 years, the mean trough steady-state (values measured at week 24) serum adalimumab concentrations were 8.8 ± 6.6 jig/ml for adalimumab without concomitant methotrexate and 11.8 ± 4.3 jig/ml with concomitant methotrexate.
Following the administration of 0.8 mg/kg (maximum of 40 mg) subcutaneously every other week to paediatric patients with chronic plaque psoriasis, the mean ± SD steady-state adalimumab trough concentration was approximately 7.4 ± 5.8 ^g/ml (79% CV).
Adalimumab exposure in adolescent HS patients was predicted using population pharmacokinetic modelling and simulation based on cross-indication pharmacokinetics in other paediatric patients (paediatric psoriasis, juvenile idiopathic arthritis, paediatric Crohn's disease, and enthesitis-related arthritis). The recommended adolescent HS dosing schedule is 40 mg every other week. Since exposure to adalimumab can be affected by body size, adolescents with higher body weight and inadequate response may benefit from receiving the recommended adult dose of 40 mg every week.
In paediatric patients with moderate to severe CD, the open-label adalimumab induction dose was 160/80 mg or 80/40 mg at weeks 0 and 2, respectively, dependent on a body weight cutoff of 40 kg. At week 4, patients were randomised 1:1 to either the Standard Dose (40/20 mg eow) or Low Dose (20/10 mg eow) maintenance treatment groups based on their body weight. The mean (±SD) serum adalimumab trough concentrations achieved at week 4 were 15.7±6.6 ^g/ml for patients > 40 kg (160/80 mg) and 10.6±6.1 ^g/ml for patients < 40 kg (80/40 mg).
For patients who stayed on their randomised therapy, the mean (±SD) adalimumab trough concentrations at week 52 were 9.5±5.6 ^g/ml for the Standard Dose group and 3.5±2.2 ng/ml for the Low Dose group. The mean trough concentrations were maintained in patients who continued to receive adalimumab treatment eow for 52 weeks. For patients who dose escalated from eow to weekly regimen, the mean (±SD) serum concentrations of adalimumab at week 52 were 15.3±11.4 jig/ml (40/20 mg, weekly) and 6.7±3.5 jig/ml (20/10 mg, weekly).
Adalimumab exposure in paediatric uveitis patients was predicted using population pharmacokinetic modelling and simulation based on cross-indication pharmacokinetics in other paediatric patients (paediatric psoriasis, juvenile idiopathic arthritis, paediatric Crohn’s disease, and enthesitis-related arthritis). No clinical exposure data are available on the use of a loading dose in children < 6 years. The predicted exposures indicate that in the absence of methotrexate, a loading dose may lead to an initial increase in systemic exposure.
Exposure-response relationship in paediatric population
On the basis of clinical trial data in patients with JIA (pJIA and ERA), an exposureresponse relationship was established between plasma concentrations and PedACR 50 response. The apparent adalimumab plasma concentration that produces half the maximum probability of PedACR 50 response (EC50) was 3 jig/ml (95% CI: 1–6 jig/ml).
Exposure-response relationships between adalimumab concentration and efficacy in paediatric patients with severe chronic plaque psoriasis were established for PASI 75 and PGA clear or minimal, respectively. PASI 75 and PGA clear or minimal increased with increasing adalimumab concentrations, both with a similar apparent EC50 of approximately 4.5 jig/ml (95% CI 0.4–47.6 and 1.9–10.5, respectively).
Adults
After subcutaneous administration of a single 40 mg dose, absorption and distribution of adalimumab was slow, with peak serum concentrations being reached about 5 days after administration. The average absolute bioavailability of adalimumab estimated from three studies following a single 40 mg subcutaneous dose was 64%. After single intravenous doses ranging from 0.25 to 10 mg/kg, concentrations were dose proportional. After doses of 0.5 mg/kg (~40 mg), clearances ranged from 11 to 15 ml/hour, the distribution volume (Vss) ranged from 5 to 6 litres and the mean terminal phase half-life was approximately two weeks. Adalimumab concentrations in the synovial fluid from several rheumatoid arthritis patients ranged from 31–96% of those in serum.
Following subcutaneous administration of 40 mg of adalimumab every other week in adult rheumatoid arthritis (RA) patients the mean steady-state trough concentrations were approximately 5 ^g/ml (without concomitant methotrexate) and 8 to 9 ^g/ml (with concomitant methotrexate), respectively. The serum adalimumab trough levels at steady-state increased roughly proportionally with dose following 20, 40 and 80 mg subcutaneous dosing every other week and every week.
In adult patients with psoriasis, the mean steady-state trough concentration was 5 ^g/ml during adalimumab 40 mg every other week monotherapy treatment.
In adult patients with hidradenitis suppurativa, a dose of 160 mg adalimumab on week 0 followed by 80 mg on week 2 achieved serum adalimumab trough concentrations of approximately 7 to 8 jig/ml at week 2 and week 4. The mean steady-state trough concentration at week 12 through week 36 were approximately 8 to 10 jig/ml during adalimumab 40 mg every week treatment.
In patients with Crohn’s disease, the loading dose of 80 mg adalimumab on week 0 followed by 40 mg adalimumab on week 2 achieves serum adalimumab trough concentrations of approximately 5.5 ^g/ml during the induction period. A loading dose of 160 mg adalimumab on week 0 followed by 80 mg adalimumab on week 2 achieves serum adalimumab trough concentrations of approximately 12 ^g/ml during the induction period. Mean steady-state trough levels of approximately 7 ^g/ml were observed in Crohn’s disease patients who received a maintenance dose of 40 mg adalimumab every other week.
Following the subcutaneous administration of body weight-based dosing of 0.6 mg/kg (maximum of 40 mg) every other week to paediatric patients with ulcerative colitis, the mean trough steady-state serum adalimumab concentration was 5.01±3.28 jig/ml at Week 52. For patients who received 0.6 mg/kg (maximum of 40 mg) every week, the mean (±SD) trough steady-state serum adalimumab concentration was 15.7±5.60 jig/ml at Week 52.
In adult patients with uveitis, a loading dose of 80 mg adalimumab on week 0 followed by 40 mg adalimumab every other week starting at week 1, resulted in mean steady-state concentrations of approximately 8 to 10 ^g/ml.
Population pharmacokinetic and pharmacokinetic/pharmacodynamic modelling and simulation predicted comparable adalimumab exposure and efficacy in patients treated with 80 mg every other week when compared with 40 mg every week (including adult patients with RA, HS, UC, CD or Ps, patients with adolescent HS, and paediatric patients > 40 kg with CD and UC).
Elimination
Population pharmacokinetic analyses with data from over 1300 RA patients revealed a trend toward higher apparent clearance of adalimumab with increasing body weight. After adjustment for weight differences, gender and age appeared to have a minimal effect on adalimumab clearance. The serum levels of free adalimumab (not bound to anti-adalimumab antibodies, AAA) were observed to be lower in patients with measurable AAA.
Hepatic or renal impairment
Adalimumab has not been studied in patients with hepatic or renal impairment.
5.3 Preclinical safety data
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Sodium dihydrogen phosphate dihydrate
Disodium phosphate dihydrate
Mannitol
Sodium chloride
Citric acid monohydrate
Sodium citrate
Polysorbate 80
Sodium hydroxide (for pH adjustment)
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
2 years
6.4 Special precautions for storage
Idacio 40 mg/0.8 ml solution for injection for paediatric use in single-use vial
0.8 ml solution in vial (type I glass) with a rubber stopper (synthetic rubber) and aluminium crimp seal.
Each box contains 1 vial, 1 sterile injection syringe, 1 sterile needle, 1 vial adaptor and 2 alcohol pads.
6.5 Nature and contents of container
Idacio 40 mg/0.8 ml solution for injection for paediatric use in single-use vial
0.8 ml solution in vial (type I glass) with a rubber stopper (synthetic rubber) and aluminium crimp seal.
Each box contains 1 vial, 1 sterile injection syringe, 1 sterile needle, 1 vial adaptor and 2 alcohol pads.
6.6 Special precautions for disposal
6.6 Special precautions for disposalAny unused medicinal product or waste material should be disposed of in accordance with local requirements.