HYRIMOZ

/ Sandoz Pharmaceuticals Israel Ltd

Rheumatoid arthritis
The recommended dose 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.
In monotherapy, some patients who experience a decrease in their response to adalimumab 40 mg every other week may benefit from an increase in dosage to 40 mg adalimumab every week or 80 mg every other week.
Ankylosing spondylitis, axial spondyloarthritis without radiographic evidence of AS and psoriatic arthritis
The recommended dose is 40 mg adalimumab administered every other week as a single dose via subcutaneous injection.
Psoriasis
The recommended dose 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.
Beyond 16 weeks, patients with inadequate response to adalimumab 40 mg every other week may benefit from an increase in dosage 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 dosage. If adequate response is achieved with 40 mg every week or 80 mg every other week, the dosage may subsequently be reduced to 40 mg every other week.
Hidradenitis suppurativa
The recommended dose 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, if necessary. It is recommended that the patient should use a topical antiseptic wash on their HS lesions on a daily basis during treatment.
Crohn’s disease
The recommended induction dose regimen for adult patients with moderately to severely active Crohn’s disease 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), followed by 80 mg at Week 2 (given as two 40 mg injections in one day), followed by a maintenance dose of 40 mg every other week via subcutaneous injection beginning at Week 4.
Aminosalicylates, corticosteriods and/or immunomodulatory agents (e.g. 6-mercaptopurine and azathioprine) may be continued during treatment.
Some patients who experience decrease in their response to adalimumab 40 mg every other week may benefit from an increase in dosage to 40 mg adalimumab every week or 80 mg every other week.
Ulcerative colitis
The recommended 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 dosage to 40 mg adalimumab every week or 80 mg every other week.
Uveitis
The recommended dose 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.
Intestinal Behcet’s disease
The initial dose for adult intestinal Behcet’s disease patients is 160 mg as subcutaneous injection. The initial dose is followed by 80 mg two weeks later. From four weeks after the initial dose, 40mg is administered every other week.
Adalimumab should be used when the signs and symptoms caused by intestinal Behcet’s disease remain clearly even if patients have appropriate treatment with existing drug (steroids or immunomodulator, etc.).
Paediatric population– based on body weight
See prescribing information for full details.

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.
As monotherapy in case of intolerance to methotrexate or when continued treatment with methotrexate is inappropriate.
Juvenile idiopathic arthritis
Polyarticular juvenile idiopathic arthritis
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). As monotherapy in case of intolerance to methotrexate or when continued treatment with methotrexate is inappropriate. Adalimumab has not been studied in patients aged less than 2 years.
Enthesitis-related arthritis
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.
Axial spondyloarthritis
Ankylosing spondylitis (AS)
Treatment of adults with severe active ankylosing spondylitis who have had an
inadequate response to conventional therapy.
Axial spondyloarthritis without radiographic evidence of AS
Treatment of adults with severe axial spondyloarthritis without radiographic
evidence of AS, but with objective signs of inflammation by radiological and/or laboratory tests including MRI and serum CRP levels, who have had an inadequate response to, or are intolerant to, non – steroidal anti-inflammatory drugs.
Psoriatic arthritis
Treatment of active and progressive psoriatic arthritis in adults when the response to previous disease-modifying anti-rheumatic drug therapy has been inadequate.
Psoriasis
Treatment of moderate to severe chronic plaque psoriasis in adult patients who are candidates for systemic therapy.
Paediatric plaque psoriasis
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)
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.
Crohn’s disease
Indicated for reducing signs and symptoms and inducing and maintaining clinical remission in adult patients with moderately to severely active Crohn’s disease who have had an inadequate response to conventional therapy. Adalimumab is indicated for reducing signs and symptoms and inducing clinical remission in these patients if they have also lost response to or are intolerant to infliximab.
Paediatric Crohn’s disease
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 corticosteroid, and/or an immunomodulator, or who are intolerant to or have contraindications for such therapies.
Ulcerative colitis
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.
Paediatric ulcerative colitis
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.
Uveitis
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
Treatment of chronic non-infectious uveitis in paediatric 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.
Intestinal Behcet’s disease
Treatment of intestinal Behcet’s disease in patients who have had an inadequate response to conventional therapy.

* Hypersensitivity to the active substance or to any of the excipients
* Active tuberculosis or other severe infections such as sepsis, and opportunistic infections
* Moderate to severe heart failure (NYHA class III / IV)

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. Because the elimination of adalimumab may take up to four months, monitoring should be continued throughout this period.
Administration 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.
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.
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.
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.
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.
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.
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 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 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. 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.
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.
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.
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.
See prescribing information for full details.

Very common: Respiratory tract infections (including lower and upper respiratory tract infection, pneumonia, sinusitis, pharyngitis, nasopharyngitis and pneumonia herpes viral), Leucopaenia (including neutropaenia and agranulocytosis), anaemia, Lipids increased, Headache, Abdominal pain, nausea and vomiting, Elevated liver enzymes, Rash (including exfoliative rash), Musculoskeletal pain, Injection site reaction (including injection site erythema).
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, Skin cancer excluding melanoma (including basal cell carcinoma and squamous cell carcinoma) benign neoplasm, Leucocytosis, thrombocytopaenia, Hypersensitivity,
allergies (including seasonal allergy), Hypokalaemia, uric acid increased, blood sodium abnormal, hypocalcaemia hyperglycaemia, hypophosphataemia, dehydration, Mood alterations (including depression), anxiety, insomnia, Paraesthesias (including hypoaesthesia), migraine, nerve root compression, Visual impairment, conjunctivitis, blepharitis, eye swelling, Vertigo, Tachycardia, Hypertension, flushing, haematoma, Asthma, dyspnoea, cough, GI haemorrhage, dyspepsia, gastroesophageal reflux disease, sicca syndrome, Worsening or new onset of psoriasis (including
palmoplantar pustular psoriasis), urticaria, bruising (including purpura), dermatitis (including eczema), onychoclasis, hyperhidrosis, alopecia, pruritus, Muscle spasms (including blood creatine phosphokinase increased), Renal impairment, haematuria, Chest pain, oedema, pyrexia, Coagulation and bleeding disorders (including activated partial thromboplastin time prolonged), autoantibody test positive (including double
stranded DNA antibody), blood lactate dehydrogenase increased, Impaired healing.
See prescribing information for full details.

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.
The combination of adalimumab and anakinra is not recommended.
The combination of adalimumab and abatacept is not recommended

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 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.
A study compared pregnant women with rheumatoid arthritis (RA) or Crohn’s disease (CD) who were treated with adalimumab to those who were not. It found no meaningful differences between the groups in the occurrence of major birth defects or other outcomes such as miscarriages, preterm birth, infant size, and infections. After adjusting for baseline differences, there was still no clear association between the treatment and adverse outcomes. However, the findings should be interpreted with caution due to methodological limitations, including a small sample size and a non-randomized design.
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.
Lactation: 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.

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.