Hyrimoz

Hyrimoz

adalimumab

Manufacturer:

Sandoz

Distributor:

Zuellig Pharma

Marketer:

Zuellig Pharma
Full Prescribing Info
Contents
Adalimumab.
Description
Each 0.8 ml solution for injection contains 40 mg adalimumab.
Excipients/Inactive Ingredients: Adipic acid, Citric acid monohydrate, Sodium chloride, Mannitol, Polysorbate 80, Hydrochloric acid, Sodium hydroxide, Water for injections.
Action
Pharmacotherapeutic group: Immunosuppressants, immunosuppressants tumour necrosis factor alpha (TNF-α) inhibitors. ATC code: L04AB04.
Pharmacology: Pharmacodynamics: Hyrimoz (Adalimumab) is a medicinal product biosimilar to Humira.
Mechanism of action: Adalimumab binds specifically to TNF and neutralises the biological function of TNF by blocking its interaction with the p55 and p75 cell surface TNF receptors.
Adalimumab also modulates biological responses that are induced or regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 0.1-0.2 nM).
Pharmacodynamic effects: After treatment with adalimumab, a rapid decrease in levels of acute phase reactants of inflammation (C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)) and serum cytokines (IL-6) was observed, compared to baseline in patients with rheumatoid arthritis. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that produce tissue remodelling responsible for cartilage destruction were also decreased after adalimumab administration. Patients treated with adalimumab usually experienced improvement in haematological signs of chronic inflammation.
A rapid decrease in CRP levels was also observed in patients with polyarticular juvenile idiopathic arthritis, Crohn's disease, ulcerative colitis and hidradenitis suppurativa after treatment with adalimumab. In patients with Crohn's disease, a reduction of the number of cells expressing inflammatory markers in the colon including a significant reduction of expression of TNF-α was seen. Endoscopic studies in intestinal mucosa have shown evidence of mucosal healing in adalimumab treated patients.
Toxicology: Preclinical safety data: Non-clinical data reveal no special hazard for humans based on studies of single dose toxicity, repeated dose toxicity, and genotoxicity.
An embryo-foetal developmental toxicity/perinatal developmental study has been performed in cynomolgus monkeys at 0, 30 and 100 mg/kg (9-17 monkeys/group) and has revealed no evidence of harm to the foetuses due to adalimumab. Neither carcinogenicity studies, nor a standard assessment of fertility and postnatal toxicity, were performed with adalimumab due to the lack of appropriate models for an antibody with limited cross-reactivity to rodent TNF and to the development of neutralising antibodies in rodents.
Indications/Uses
Rheumatoid arthritis: Adalimumab in combination with methotrexate, is indicated for: the treatment of moderate to severe, active rheumatoid arthritis in adult patients when the response to disease-modifying anti-rheumatic drugs including methotrexate has been inadequate; the treatment of severe, active and progressive rheumatoid arthritis in adults not previously treated with methotrexate.
Adalimumab can be given as monotherapy in case of intolerance to methotrexate or when continued treatment with methotrexate is inappropriate.
Adalimumab has been shown to reduce the rate of progression of joint damage as measured by X-ray and to improve physical function, when given in combination with methotrexate.
Juvenile idiopathic arthritis: Polyarticular juvenile idiopathic arthritis: Adalimumab 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). Adalimumab 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 Pharmacology: Pharmacodynamics under Actions). Adalimumab has not been studied in patients aged less than 2 years.
Enthesitis-related arthritis: Adalimumab 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 Pharmacology: Pharmacodynamics under Actions).
Axial spondyloarthritis: Ankylosing spondylitis (AS): Adalimumab is indicated for the treatment of adults with severe active ankylosing spondylitis who have had an inadequate response to conventional therapy.
Axial spondyloarthritis without radiographic evidence of AS: Adalimumab is indicated for the treatment of adults with severe axial spondyloarthritis without radiographic evidence of AS but with objective signs of inflammation by elevated CRP and/or MRI, who have had an inadequate response to, or are intolerant to nonsteroidal anti-inflammatory drugs.
Psoriatic arthritis: Adalimumab is indicated for the treatment of active and progressive psoriatic arthritis in adults when the response to previous disease-modifying anti-rheumatic drug therapy has been inadequate.
Adalimumab has been shown to reduce the rate of progression of peripheral joint damage as measured by X-ray in patients with polyarticular symmetrical subtypes of the disease (see Pharmacology: Pharmacodynamics under Actions) and to improve physical function.
Psoriasis: Adalimumab is indicated for the treatment of moderate to severe chronic plaque psoriasis in adult patients who are candidates for systemic therapy.
Paediatric plaque psoriasis: Adalimumab 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.
Hidradenitis suppurativa (HS): Adalimumab is indicated for the treatment of active moderate to severe hidradenitis suppurativa (acne inversa) in adults and adolescents from 12 years of age with an inadequate response to conventional systemic HS therapy (see Pharmacology: Pharmacodynamics under Actions).
Crohn's disease: Adalimumab is indicated for treatment of moderately to severely active Crohn's disease in adult patients who have not responded despite a full and adequate course of therapy with a corticosteroid and/or an immunosuppressant; or who are intolerant to or have medical contraindications for such therapies.
Paediatric Crohn's disease: Adalimumab 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.
Ulcerative colitis: Adalimumab is indicated for treatment of moderately to severely active ulcerative colitis in adult patients who have had an inadequate response to conventional therapy including corticosteroids and 6-mercaptopurine (6-MP) or azathioprine (AZA), or who are intolerant to or have medical contraindications for such therapies.
Uveitis: Adalimumab is indicated for the treatment of non-infectious intermediate, posterior and panuveitis in adult patients who have had an inadequate response to corticosteroids, in patients in need of corticosteroid-sparing, or in whom corticosteroid treatment is inappropriate.
Paediatric uveitis: Adalimumab 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.
Dosage/Direction for Use
Adalimumab treatment should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of conditions for which adalimumab is indicated. Ophthalmologists are advised to consult with an appropriate specialist before initiation of treatment with adalimumab (see Precautions). Patients treated with adalimumab should be given the patient alert card.
After proper training in injection technique, patients may self-inject with adalimumab if their physician determines that it is appropriate and with medical follow-up as necessary.
During treatment with adalimumab, other concomitant therapies (e.g., corticosteroids and/or immunomodulatory agents) should be optimised.
Posology: Rheumatoid arthritis: The recommended dose of adalimumab for adult patients with rheumatoid arthritis is 40 mg adalimumab administered every other week as a single dose via subcutaneous injection.
Methotrexate should be continued during treatment with adalimumab.
Glucocorticoids, salicylates, nonsteroidal anti-inflammatory drugs, or analgesics can be continued during treatment with adalimumab. Regarding combination with disease modifying anti-rheumatic drugs other than methotrexate see Precautions and Pharmacology: Pharmacodynamics under Actions.
In monotherapy, some patients who experience a decrease in their response to adalimumab 40 mg every other week may benefit from an increase in dose to 40 mg adalimumab every week or 80 mg every other week.
Available data suggest that the clinical response is usually achieved within 12 weeks of treatment. Continued therapy should be reconsidered in a patient not responding within this time period.
Adalimumab is only available as 40 mg pre-filled syringe and 40 mg pre-filled pen. Thus, it is not possible to administer adalimumab to patients that require less than a full 40 mg dose.
Dose interruption: There may be a need for dose interruption, for instance before surgery or if a serious infection occurs.
Available data suggest that re-introduction of adalimumab after discontinuation for 70 days or longer resulted in the same magnitudes of clinical response and similar safety profile as before dose interruption.
Ankylosing spondylitis, axial spondyloarthritis without radiographic evidence of AS and psoriatic arthritis: The recommended dose of adalimumab for patients with ankylosing spondylitis, axial spondyloarthritis without radiographic evidence of AS and for patients with psoriatic arthritis is 40 mg adalimumab administered every other week as a single dose via subcutaneous injection.
Available data suggest that the clinical response is usually achieved within 12 weeks of treatment.
Continued therapy should be reconsidered in a patient not responding within this time period.
Psoriasis: The recommended dose of adalimumab for adult patients is an initial dose of 80 mg administered subcutaneously, followed by 40 mg subcutaneously given every other week starting one week after the initial dose.
Continued therapy beyond 16 weeks should be carefully reconsidered in a patient not responding within this time period.
Beyond 16 weeks, patients with inadequate response to adalimumab 40 mg every other week may benefit from an increase in dose to 40 mg every week or 80 mg every other week. The benefits and risks of continued 40 mg weekly or 80 mg every other week therapy should be carefully reconsidered in a patient with an inadequate response after the increase in dose (see Pharmacology: Pharmacodynamics under Actions). If adequate response is achieved with 40 mg every week or 80 mg every other week, the dose may subsequently be reduced to 40 mg every other week.
Adalimumab is only available as 40 mg pre-filled syringe and 40 mg pre-filled pen. Thus, it is not possible to administer adalimumab to patients that require less than a full 40 mg dose.
Hidradenitis suppurativa: The recommended adalimumab dose regimen for adult patients with hidradenitis suppurativa (HS) is 160 mg initially at Day 1 (given as four 40 mg injections in one day or as two 40 mg injections per day for two consecutive days), followed by 80 mg two weeks later at Day 15 (given as two 40 mg injections in one day). Two weeks later (Day 29) continue with a dose of 40 mg every week or 80 mg every other week (given as two 40 mg injections in one day). Antibiotics may be continued during treatment with adalimumab, 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 adalimumab.
Continued therapy beyond 12 weeks should be carefully reconsidered in a patient with no improvement within this time period.
Should treatment be interrupted, adalimumab 40 mg every week or 80 mg every other week may be re-introduced (see Pharmacology: Pharmacodynamics under Actions).
The benefit and risk of continued long-term treatment should be periodically evaluated (see Pharmacology: Pharmacodynamics under Actions).
Adalimumab is only available as 40 mg pre-filled syringe and 40 mg pre-filled pen. Thus, it is not possible to administer adalimumab to patients that require less than a full 40 mg dose.
Crohn's disease: The recommended adalimumab induction dose regimen for adult patients with moderately to severely active Crohn's disease is 80 mg at week 0 followed by 40 mg at week 2. In case there is a need for a more rapid response to therapy, the regimen 160 mg at week 0 (given as four 40 mg injections in one day or as two 40 mg injections per day for two consecutive days), 80 mg at week 2 (given as two 40 mg injections in one day), can be used with the awareness that the risk for adverse events is higher during induction.
After induction treatment, the recommended dose is 40 mg every other week via subcutaneous injection. Alternatively, if a patient has stopped adalimumab and signs and symptoms of disease recur, adalimumab may be re-administered. There is little experience from re-administration after more than 8 weeks since the previous dose.
During maintenance treatment, corticosteroids may be tapered in accordance with clinical practice guidelines.
Some patients who experience decrease in their response to adalimumab 40 mg every other week may benefit from an increase in dose to 40 mg adalimumab every week or 80 mg every other week.
Some patients who have not responded by week 4 may benefit from continued maintenance therapy through week 12. Continued therapy should be carefully reconsidered in a patient not responding within this time period.
Adalimumab is only available as 40 mg pre-filled syringe and 40 mg pre-filled pen. Thus, it is not possible to administer adalimumab to patients that require less than a full 40 mg dose.
Ulcerative colitis: The recommended adalimumab induction dose regimen for adult patients with moderate to severe ulcerative colitis is 160 mg at week 0 (given as four 40 mg injections in one day or as 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). After induction treatment, the recommended dose is 40 mg every other week via subcutaneous injection.
During maintenance treatment, corticosteroids may be tapered in accordance with clinical practice guidelines.
Some patients who experience decrease in their response to adalimumab 40 mg every other week may benefit from an increase in dose to 40 mg adalimumab every week or 80 mg every other week.
Available data suggest that the clinical response is usually achieved within 2-8 weeks of treatment. Adalimumab therapy should not be continued in patients failing to respond within this time period.
Adalimumab is only available as 40 mg pre-filled syringe and 40 mg pre-filled pen. Thus, it is not possible to administer adalimumab to patients that require less than a full 40 mg dose.
Uveitis: The recommended dose of adalimumab for adult patients with uveitis is an initial dose of 80 mg, followed by 40 mg given every other week starting one week after the initial dose. There is limited experience in the initiation of treatment with adalimumab alone. Treatment with adalimumab can be initiated in combination with corticosteroids and/or with other non-biologic immunomodulatory agents. Concomitant corticosteroids may be tapered in accordance with clinical practice starting two weeks after initiating treatment with adalimumab.
It is recommended that the benefit and risk of continued long-term treatment should be evaluated on a yearly basis (see Pharmacology: Pharmacodynamics under Actions).
Adalimumab is only available as 40 mg pre-filled syringe and 40 mg pre-filled pen. Thus, it is not possible to administer adalimumab to patients that require less than a full 40 mg dose.
Special populations: Elderly: No dose adjustment is required.
Renal and/or hepatic impairment: Adalimumab has not been studied in these patient populations. No dose recommendations can be made.
Paediatric population: Adalimumab is only available as 40 mg pre-filled syringe/pre-filled pen. Thus, it is not possible to administer adalimumab to paediatric patients that require less than a full 40 mg dose. If an alternate dose is required, other adalimumab products offering such an option should be used.
Juvenile idiopathic arthritis: Polyarticular juvenile idiopathic arthritis from 2 years of age: The recommended dose of adalimumab for patients with polyarticular juvenile idiopathic arthritis from 2 years of age is based on body weight (table 1). Adalimumab is administered every other week via subcutaneous injection. (See Table 1.)

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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.
Adalimumab is only available as 40 mg pre-filled syringe and 40 mg pre-filled pen. Thus, it is not possible to administer adalimumab to patients that require less than a full 40 mg dose.
Enthesitis-related arthritis: The recommended dose of adalimumab for patients with enthesitis-related arthritis from 6 years of age is based on body weight (table 2). Adalimumab is administered every other week via subcutaneous injection. (See Table 2.)

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Adalimumab has not been studied in patients with enthesitis-related arthritis aged less than 6 years. Adalimumab is only available as 40 mg pre-filled syringe and 40 mg pre-filled pen. Thus, it is not possible to administer adalimumab to patients that require less than a full 40 mg dose.
Paediatric plaque psoriasis: The recommended adalimumab dose for patients with plaque psoriasis from 4 to 17 years of age is based on body weight (table 3). Adalimumab is administered via subcutaneous injection. (See Table 3.)

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Continued therapy beyond 16 weeks should be carefully considered in a patient not responding within this time period.
If re-treatment with adalimumab is indicated, the previously mentioned 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.
Adalimumab is only available as 40 mg pre-filled syringe and 40 mg pre-filled pen. Thus, it is not possible to administer adalimumab to patients that require less than a full 40 mg dose.
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.
The recommended adalimumab 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 adalimumab 40 mg every other week, an increase in dose to 40 mg every week or 80 mg every other week may be considered.
Antibiotics may be continued during treatment with adalimumab 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 adalimumab.
Continued therapy beyond 12 weeks should be carefully reconsidered in a patient with no improvement within this time period.
Should treatment be interrupted, adalimumab may be re-introduced as appropriate.
The benefit and risk of continued long-term treatment should be periodically evaluated (see adult data in Pharmacology: Pharmacodynamics under Actions).
There is no relevant use of adalimumab in children aged less than 12 years in this indication.
Adalimumab is only available as 40 mg pre-filled syringe and 40 mg pre-filled pen. Thus, it is not possible to administer adalimumab to patients that require less than a full 40 mg dose.
Paediatric Crohn's disease: The recommended dose of adalimumab for patients with Crohn's disease from 6 to 17 years of age is based on body weight (table 4). Adalimumab is administered via subcutaneous injection. (See Table 4.)

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Patients who experience insufficient response may benefit from an increase in dose: ≥ 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.
Adalimumab is only available as 40 mg pre-filled syringe and 40 mg pre-filled pen. Thus, it is not possible to administer adalimumab to patients that require less than a full 40 mg dose.
Paediatric uveitis: The recommended dose of adalimumab for paediatric patients with uveitis from 2 years of age is based on body weight (table 5). Adalimumab is administered via subcutaneous injection.
In paediatric uveitis, there is no experience in the treatment with adalimumab without concomitant treatment with methotrexate.
When adalimumab 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.
There is no relevant use of adalimumab in children aged less than 2 years in this indication. (See Table 5.)

Click on icon to see table/diagram/image

It is recommended that the benefit and risk of continued long-term treatment should be evaluated on a yearly basis (see Pharmacology: Pharmacodynamics under Actions).
Adalimumab is only available as 40 mg pre-filled syringe and 40 mg pre-filled pen. Thus, it is not possible to administer adalimumab to patients that require less than a full 40 mg dose.
Paediatric ulcerative colitis: The safety and efficacy of adalimumab in children aged 4-17 years have not yet been established. No data are available.
There is no relevant use of adalimumab in children aged less than 4 years for this indication.
Psoriatic arthritis and axial spondyloarthritis including ankylosing spondylitis: There is no relevant use of adalimumab in the paediatric population for the indications of ankylosing spondylitis and psoriatic arthritis.
Method of administration: Adalimumab is administered by subcutaneous injection.
Full instructions for use are provided in the package leaflet.
Adalimumab is available in other strengths and presentations.
Overdosage
No dose-limiting toxicity was observed during clinical trials. The highest dose level evaluated has been multiple intravenous doses of 10 mg/kg, which is approximately 15 times the recommended dose.
Contraindications
Hypersensitivity to the active substance or to any of the excipients.
Active tuberculosis or other severe infections such as sepsis and opportunistic infections (see Precautions).
Moderate to severe heart failure (NYHA class III/IV) (see Precautions).
Special Precautions
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 adalimumab. Because the elimination of adalimumab may take up to four months, monitoring should be continued throughout this period.
Treatment with adalimumab 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 adalimumab should be considered prior to initiating therapy (see Other opportunistic infections as follows).
Patients who develop a new infection while undergoing treatment with adalimumab should be monitored closely and undergo a complete diagnostic evaluation. Administration of adalimumab 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 adalimumab 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 adalimumab, 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 alert 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, adalimumab therapy must not be initiated (see Contraindications).
In all situations described as follows, 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 adalimumab, and in accordance with local recommendations.
Use of anti-tuberculosis prophylaxis treatment should also be considered before the initiation of adalimumab 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 adalimumab.
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, dyspnoea, and/or pulmonary infiltrates or other serious systemic illness with or without concomitant shock an invasive fungal infection should be suspected and administration of adalimumab 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 adalimumab. 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 adalimumab 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, adalimumab 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 adalimumab in patients with pre-existing or recent-onset central or peripheral nervous system demyelinating disorders; discontinuation of adalimumab 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 adalimumab 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 adalimumab 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 post-marketing 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 adalimumab cannot be excluded (see Adverse Reactions).
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 adalimumab treatment of these patients (see Adverse Reactions).
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 adalimumab. Melanoma and Merkel cell carcinoma have also been reported in patients treated with TNF-antagonists including adalimumab (see Adverse Reactions).
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, leukopenia) 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 adalimumab. Discontinuation of adalimumab 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. Adalimumab should be used with caution in patients with mild heart failure (NYHA class I/II). Adalimumab is contraindicated in moderate to severe heart failure (see Contraindications). Treatment with adalimumab must be discontinued in patients who develop new or worsening symptoms of congestive heart failure.
Autoimmune processes: Treatment with adalimumab 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 adalimumab and is positive for antibodies against double-stranded DNA, further treatment with adalimumab should not be given (see Adverse Reactions).
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 Interactions).
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 Interactions).
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 adalimumab 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.
Effects on ability to drive and use machines: Adalimumab may have a minor influence on the ability to drive and use machines. Vertigo and visual impairment may occur following administration of adalimumab (see Adverse Reactions).
Use in Children: See vaccinations as previously mentioned.
Use in 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.
Use In Pregnancy & Lactation
Women of child bearing 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 adalimumab 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 Pharmacology: Toxicology: Preclinical safety data under Actions).
Due to its inhibition of TNFα, 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, adalimumab can be used during breastfeeding.
Fertility: Preclinical data on fertility effects of adalimumab are not available.
Adverse Reactions
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 defense 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.
List of adverse reactions: The following list of adverse reactions is based on experience from clinical trials and on post-marketing experience and are displayed by system organ class and frequency as follows: 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 SOC column if further information is found elsewhere in Contraindications, Precautions and as follows.
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, diverticulitis1).
Neoplasms benign, malignant and unspecified (including cysts and polyps)*: Common: Skin cancer excluding melanoma (including 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).
Blood and lymphatic system disorders*: Very common: Leukopenia (including neutropenia and agranulocytosis), anaemia.
Common: Leukocytosis, 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, hypophosphatemia, dehydration.
Psychiatric disorders: Common: Mood alterations (including depression), anxiety, insomnia.
Nervous system disorders*: Very common: Headache.
Common: Paraesthesias (including hypoesthesia), migraine, nerve root compression.
Uncommon: Cerebrovascular accident1), tremor, neuropathy.
Rare: Multiple sclerosis, demyelinating disorders (e.g. optic neuritis, Guillain-Barré 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.
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 tissue disorders: Very common: Rash (including exfoliative rash).
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, 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.
Injury, poisoning and procedural complications: Common: Impaired healing.
* further information is found elsewhere in Contraindications, Precautions and in this section.
** including open label extension studies.
1) including spontaneous reporting data.
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 an adalimumab trial in paediatric patients with chronic plaque psoriasis. 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 patient-years 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 patient-years 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 Precautions).
Rare post-marketing cases of hepatosplenic T-cell lymphoma have been reported in patients treated with adalimumab (see Precautions).
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.
Hepatobiliary 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 in 3.7% 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.
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.
Drug Interactions
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 Pharmacology: Pharmacodynamics under Actions).
The combination of adalimumab and anakinra is not recommended (see Concurrent administration of biologic DMARDS or TNF-antagonists under Precautions).
The combination of adalimumab and abatacept is not recommended (see Concurrent administration of biologic DMARDS or TNF-antagonists under Precautions).
Caution For Usage
Incompatibilities: In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
Instructions for use, Special precautions for disposal and other handling: To help avoid possible infections and to ensure that the patient uses the medicine correctly, it is important that the patient follow these instructions.
Be sure to read, understand, and follow these Instructions for Use before injecting Hyrimoz.
The healthcare provider should show how to prepare and inject Hyrimoz properly using the pre-filled syringe before using it for the first time. Talk to the healthcare provider if there are any questions.
It is important that the patient: Does not open the outer box until they are ready to use the syringe.
Does not use the syringe if the seals of the blister are broken, as it may not be safe for use.
Never leave the syringe unattended where others might tamper with it.
Does not shake the syringe.
If the patient drops the syringe, do not use it if it looks damaged, or if they dropped it with the needle cap removed.
Does not remove the needle cap until just before they give the injection.
Be careful not to touch the needle guard wings before use. Touching them may cause the needle guard to be activated too early. Do not remove the finger flange before the injection.
Inject Hyrimoz 15-30 minutes after taking it out of the refrigerator for a more comfortable injection.
Throw away the used syringe right away after use. Do not re-use a syringe. See Disposing of used syringes as follows.
How to store Hyrimoz: Store outer carton of syringes in a refrigerator, between 2°C to 8°C.
When needed (for example when the patient is travelling), Hyrimoz may be stored at room temperature (up to 25°C) for a maximum period of 21 days - be sure to protect it from light. Once removed from the refrigerator for room temperature storage, the pre-filled syringe must be used within 21 days or discarded, even if it is later returned to the refrigerator. The patient should record the date when the pre-filled syringe is first removed from the refrigerator, and the date after which it should be discarded.
Keep the syringes in the original carton until ready to use to protect from light.
Do not store the syringes in extreme heat or cold.
Do not freeze the syringes.
What does the patient need for the injection: Place the following items on a clean, flat surface. Included in the carton is: Hyrimoz pre-filled syringe/s. Each syringe contains 40 mg/0.8 ml of Hyrimoz.
Not included in the carton are: Alcohol wipe, Cotton ball or gauze, Sharps disposal container.
See Disposing of used syringes at the end of these Instructions for Use.
Preparing the syringe: For a more comfortable injection, take the blister containing the syringe out of the refrigerator and leave it unopened on the work surface for about 15 to 30 minutes so that it reaches room temperature.
Take the syringe out of the blister.
Look through the viewing window. The solution should be colourless to slightly yellowish as well as clear to slightly opalescent. Do not use if any particulates and / or discolorations are observed. If the patient is concerned with the appearance of the solution, then contact the pharmacist for assistance.
Do not use the syringe if it is broken or the needle guard is activated. Return the syringe and the package it came in to the pharmacy.
Look at the expiration date (EXP) on the syringe. Do not use the syringe if the expiration date has passed.
Contact the pharmacist if the syringe fails any of the previously mentioned checks.
Choosing the injection site: The recommended injection site is the front of the thighs. The patient may also use the lower abdomen, but not the area 5 cm around the navel (belly button).
Choose a different site each time the patient give themselves an injection.
Do not inject into areas where the skin is tender, bruised, red, scaly, or hard. Avoid areas with scars or stretch marks. If the patient has psoriasis, they should NOT inject directly into areas with psoriasis plaques.
Cleaning the injection site: Wash hands well with soap and water.
Using a circular motion, clean the injection site with an alcohol wipe. Leave it to dry before injecting.
Do not touch the cleaned area before injecting.
Giving the injection: Carefully pull the needle cap straight off to remove it from the syringe.
Discard the needle cap.
The patient may see a drop of liquid at the end of the needle. This is normal.
Gently pinch the skin at the injection site.
Insert the needle into the skin.
Push the needle all the way in to ensure that the medication can be fully administered.
Hold the syringe.
Slowly press down on the plunger as far as it will go, so that the plunger head is completely between the needle guard wings.
Keep the plunger pressed fully down while the patient holds the syringe in place for 5 seconds.
Keep the plunger fully pressed down while carefully lifting the needle straight out from the injection site and let go of the skin.
Slowly release the plunger and allow the needle safety guard to automatically cover the exposed needle.
There may be a small amount of blood at the injection site. The patient can press a cotton ball or gauze onto the injection site and hold it for 10 seconds. Do not rub the injection site. The patient may cover the injection site with a small adhesive bandage, if needed.
Disposing of used syringes: Dispose of the used syringe in a sharps container (closable, puncture-resistant container).
For the safety and health of the patient and others, needles and used syringes must never be re-used.
Do not throw away any medicines via wastewater or household waste. Ask the doctor or pharmacist how to throw away medicines the patient no longer uses.
These measures will help protect the environment.
Any unused product or waste material should be disposed of in accordance with local requirements.
If the patient has any questions, please talk to a doctor, pharmacist or nurse who is familiar with Hyrimoz.
Storage
Store in a refrigerator (2°C-8°C). Do not freeze. Keep the pre-filled syringe in the outer carton in order to protect from light. Do not shake.
A single adalimumab pre-filled syringe may be stored at temperatures up to a maximum of 25°C for a period of up to 21 days. The pre-filled syringe must be protected from light, and discarded if not used within the 21-day period.
Shelf-life: 30 months.
ATC Classification
L04AB04 - adalimumab ; Belongs to the class of tumor necrosis factor alpha (TNF-alpha) inhibitors. Used as immunosuppressants.
Presentation/Packing
Soln for inj (pre-filled syringe) 40 mg/0.8 mL x 1's.
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