What Factors Affect Humira Dosage?

Adalimumab injection, this product is used: 1. Rheumatoid arthritis This product is combined with methotrexate for the treatment of: · Antirheumatic drugs (DMARDs), including methotrexate, which are not effective in improving the condition Of adults with moderate to severe active rheumatoid arthritis. This product in combination with methotrexate can slow the progression of joint injuries in patients (X-ray display) and improve physical function. 2. Ankylosing spondylitis is used in adult patients with severe active ankylosing spondylitis with poor conventional treatment. 3. Psoriasis is used in adults who require systemic or phototherapy and are not sensitive to other systemic treatments (including cyclosporine, methotrexate, or photochemotherapy), have contraindications, or cannot tolerate chronic severe adulthood. Patients with plaque psoriasis. This product should only be given to patients who will be closely monitored and regularly followed by a physician.

Drug Name: Adalimumab injection

Hanyu Pinyin: A Da Mu Dan Kang Zhu She Ye

Adalimumab injection warnings

Warning: Risk of serious infection. Among patients receiving this product, tuberculosis (usually disseminated or extrapulmonary clinically), invasive fungal infections, and other opportunistic infections have developed. Some infections are fatal. Antituberculosis treatment of latent tuberculosis in patients who are going to receive this product can reduce the risk of tuberculosis activation in patients. However, those patients who have received negative screening for latent tuberculosis infection treated with this product may also progress to active tuberculosis.
Before and during treatment with this product, patients need to be evaluated for TB risk factors and tested for latent TB infection. Before starting treatment with this product, latent tuberculosis infection needs to be treated. Clinicians need to monitor the signs and symptoms of active tuberculosis in patients receiving this product (including patients with a negative initial test for latent tuberculosis).

Adalimumab injection ingredients

Active ingredient: Adalimumab, a recombinant fully humanized tumor necrosis factor alpha monoclonal antibody expressed in Chinese hamster ovary cells.
Molecular weight: 148, 108 ± 8Da
Excipients: Mannitol citric acid monohydrate, sodium citrate, sodium dihydrogen phosphate, dihydrate, disodium hydrogen phosphate, dihydrate, sodium chloride, polysorbate 80
Sodium hydroxide water for injection

Adalimumab injection properties

This product is a clear liquid pre-filled in a syringe.

Indications for adalimumab injection

Rheumatoid arthritis < br This product is used in combination with methotrexate to treat:
Anti-rheumatic drugs (DMARDs) for improving the condition, including adult patients with moderate to severe active rheumatoid arthritis, who have poor efficacy with methotrexate.
This product in combination with methotrexate can slow the progression of joint injuries in patients (X-ray display) and improve physical function.
Ankylosing spondylitis < br For adults with severe active ankylosing spondylitis who are not well treated by conventional treatment.
Psoriasis < br is used in adults who require systemic or phototherapy and are not sensitive to other systemic treatments, including cyclosporine, methotrexate, or photochemotherapy, or have contraindications or intolerance Patients with severe chronic plaque psoriasis.
This product should only be given to patients who will be closely monitored and regularly followed by a physician.

Adalimumab injection specifications

40mg / 0.8ml

Adalimumab injection usage and dosage

The treatment of this product should be carried out under the supervision of a specialist with experience in diagnosis and treatment of the relevant indications.
Patients who are deemed appropriate by the treating physician and who can perform medical follow-up if necessary, can be self-administered after being trained in proper injection techniques.
This product can be left at room temperature for about 15 to 30 minutes before injection. Do not remove the needle cap until it reaches room temperature. Before injection, carefully check the injection solution in the prefilled syringe for particles or discoloration. Do not use if particulate matter or discoloration is found. This product contains no preservatives, so discard any unused medicine left in the syringe.
It should be injected in the front of the thigh or in the lower abdomen. Choose a different site for each injection. Do not inject in areas of pain, bruising, redness, stiffness, scarring or stretch marks. If you have psoriasis, do not inject into any areas that are raised, thickened, red, or scaly.
During the treatment with this product, other combination therapies (eg, glucocorticoids and / or immunomodulators) need to be optimized.
Adult rheumatoid arthritis For adult patients with rheumatoid arthritis, the recommended dosage is 40 mg of adalimumab, given as a single subcutaneous injection every two weeks. Methotrexate should be continued during the treatment of this product.
During the course of this product, you can continue to use glucocorticoids, salicylic acid drugs, non-steroidal anti-inflammatory drugs or analgesics. For combined use with other anti-rheumatic drugs (DMARDs) other than methotrexate, please see the [Caution] section.
In the case of single drug treatment, if some patients experience a decrease in treatment effect, the dosage can be increased to 40 mg of adalimumab per week to improve the efficacy.
Available data indicate that a clinical response is usually obtained within 12 weeks of treatment, and that patients who have not had a clinical response during that treatment period should carefully consider whether to continue treatment.
Discontinuation of administration If surgery or severe infection occurs, it may be necessary to discontinue administration.
Available data indicate that re-use of this product after an interval of 70 days or more will achieve the same level of clinical response and similar safety as before the discontinuation of dosing.
Ankylosing spondylitis For adult patients with ankylosing spondylitis, the recommended dosage is 40 mg of adalimumab, given as a single subcutaneous injection every two weeks.
Available data indicate that a clinical response is usually obtained within 12 weeks of treatment, and that patients who have not had a clinical response during that treatment period should carefully consider whether to continue treatment.
For adult patients with psoriasis, the recommended dosage of this product is 80 mg for the first subcutaneous injection, and then 40 mg for every two weeks from the first week after the first administration.
Patients who do not have a clinical response within 16 weeks of treatment should carefully consider whether to continue treatment.
The safety and effectiveness of this product for more than one year in patients with moderate to severe chronic plaque psoriasis have not been evaluated in controlled clinical trials.
No dosage adjustment is needed for elderly patients.
Patients with hepatic and / or renal dysfunction have not been studied in this patient population and no dose recommendations have been made.

Adalimumab injection adverse reactions

Clinical studies The following adverse reaction data are mainly from clinical studies conducted abroad. Key controlled and open studies of 9,506 patients were conducted for 60 months or more. These patients include patients with short-term and long-term rheumatoid arthritis, juvenile idiopathic arthritis (polyarticular juvenile idiopathic arthritis and attachment-point arthritis), and axial spinal arthritis (ankylosing Spondylitis and radiologically negative axial spinal arthritis), psoriatic arthritis, Crohn's disease, ulcerative colitis, psoriasis, suppurative sweat glanditis, and uveitis. The key controlled study included 6,089 patients receiving this product and 3,801 patients receiving placebo or active control drugs during the control phase.
In the double-blind controlled phase of the key study, the proportion of patients who discontinued treatment due to adverse events was 5.9% and 5.4% in the treatment group and the control group.
Safety summary The most commonly reported adverse reactions are infections (such as nasopharyngitis, upper respiratory infections, and sinusitis), injection site reactions (erythema, itching, bleeding, pain, or swelling), headaches, and musculoskeletal pain.
Serious adverse reactions to this product have been reported. TNF-antagonists including this product can affect the human immune system, and the use of such drugs may affect the body's defense function against infection and cancer. Some cases have reported fatal and life-threatening infections (including sepsis, opportunistic infections, and tuberculosis) caused by the use of this product, recurrence of hepatitis B, and a variety of malignancies (including leukemia, lymphoma, and hepatosplenic T-cell lymphocytes) tumor).
Serious hematological, neurological, and autoimmune reactions have also been reported. These reactions include pancytopenia, aplastic anemia, central and peripheral nerve demyelinating adverse events, and also include lupus, lupus-related symptoms, and Stephen Strong Reports of Stevens-Johnson syndrome.
In Table 1, according to the classification and frequency of human organs (very common 1 / 10; common 1 / 100 to <1/10; rare 1 / 1000 to <1/100, rare 1 / 10000 to <1 / 1000, unknown: cannot be estimated based on available data) lists adverse reactions after clinical studies and after marketing.
In the following groups divided by frequency, adverse reactions are listed in descending order according to severity. The table has included the highest frequency of adverse reactions observed in each indication. The asterisk (*) in the human organ classification column indicates that for more related information, see [Contraindications], [Cautions], and [Adverse Reactions].

Injection site reactions < br In a key adult controlled clinical trial study, 12.9% of patients receiving this product experienced injection site reactions (redness and / or itching, bleeding, pain, or swelling) and received placebo Or active control drugs, the above response accounted for 7.2%. In general, there is no need to discontinue medication due to injection site reactions.
Infection In a key adult controlled clinical study, the infection rate was 1.51 / patient-years in patients receiving this product, compared with 1.46 / patient-years in patients receiving placebo and active control. Infections are mainly nasopharyngeal inflammation, upper respiratory tract infections, and urinary tract infections. The vast majority of patients continue to receive this product after recovery.
The incidence of severe infections was 0.04 per patient-year in patients receiving this product, and 0.03 per patient-year in patients receiving placebo and active control drugs.
Cases of severe infections (including fatal infections but rarely occurring) are reported in controlled and open studies. These reports include tuberculosis (including miliary and extrapulmonary tuberculosis) and aggressive opportunistic infections (such as disseminated or Extrapulmonary histoplasmosis, blastomycosis, coccidiosis, pneumocystis, candidiasis, aspergillosis, and listeriosis). The vast majority of tuberculosis occurs in the first eight months after treatment and can reflect the recurrence of latent disease.
Malignant disease and abnormal lymphocytic hyperplasia The key controlled trial phase of this product is for patients with moderate to severe active rheumatoid arthritis, ankylosing spondylitis, radionegative axial spinal arthritis, psoriatic arthritis, Adult patients with psoriasis, suppurative sweat glanditis, Crohn's disease, ulcerative colitis, and uveitis were studied for at least 12 weeks, and malignancies (lymphoma and non-melanin skin) were received in 5,291 patients receiving this product Excluding cancer) The incidence rate was 6.8 (4.4, 10.5) / 1000 patient years (95% confidence interval), and the corresponding data for 3444 control patients was 6.3 (3.4, 11.8) / 1000 patient years (95% confidence interval) (this The median treatment time for the product was 4.0 months, and the control median treatment time was 3.8 months. Among patients treated with this product, the incidence of non-melanin skin cancer was 8.8 (6.0, 13.0) per 1000 patient years (95% confidence interval), and the control patient was 3.2 (1.3, 7.6) per 1000 patient years (95% confidence interval). ). Among the above skin cancers, the incidence of squamous cell carcinoma in patients treated with this product was 2.7 (1.4, 5.4) per 1000 patient years (95% confidence interval), while the corresponding data in the control group was 0.6 (0.1, 4.5) per 1000 patients. year. The incidence of lymphoma in patients treated with this product was 0.7 (0.2, 2.7) per 1000 patient years (95% confidence interval), and the corresponding data in the control group was 0.6 (0.1, 4.5) per 1000 patient years.
Combining the control portion of the study with ongoing and completed open-ended extension studies with a median observation time of approximately 3.3 years, including treatment of 6,427 patients over 26439 patient years, and observed lymphoma removal The incidence of malignant lesions other than non-melanoma skin cancer is 8.5 / 1000 patient years. The incidence of non-melanoma skin cancer is approximately 9.6 / 1000 patient-years, and lymphoma is approximately 1.3 / 1000 patient-years.
Post-marketing experience from January 2003 to December 2010 showed that (mainly rheumatoid arthritis patients) the reported incidence of malignancies is approximately 2.7 / 1000 patient years. The reported incidence of non-melanin skin cancer and lymphoma is approximately 0.2 / 1000 patient years and 0.3 / 1000 patient years, respectively (see the [Precautions] section).
After marketing, there are few reports of adverse reactions in liver and spleen T-cell lymphoma (see the [Precautions] section).
The formation of immunogenic anti-adalimumab antibodies is associated with increased drug clearance and decreased efficacy of adalimumab. There was no significant correlation between anti-adalimumab antibodies and adverse reactions.
Anti-adalimumab antibodies were tested at multiple time points within 6 to 12 months of rheumatoid arthritis study I, II, and III. In a pivotal clinical trial study, adalimumab antibodies were detected in 58 (5.5%) of 1,053 patients treated with adalimumab compared to 2/370 (0.5%) in the placebo group. . Among patients without methotrexate, the ratio was 12.4%; when adalimumab was used in combination with methotrexate, the ratio was 0.6%.
Among patients with ankylosing spondylitis, the detection rate of anti-adalimumab antibodies in patients receiving adalimumab was 8.3% (17/204). In patients without methotrexate, the detection rate was 8.6% (16/185), compared with 5.3% (1/19) of methotrexate plus adalimumab.
Among patients with psoriasis, the detection rate of anti-adalimumab antibodies was 8.4% (77/920) in patients receiving adalimumab monotherapy.
In patients with plaque psoriasis who have been treated with adalimumab monotherapy for a long time after adding discontinuation and re-use studies, the detection rate of anti-adalimumab antibodies after adalimumab retreatment was 2.3% (11 / 482), similar to 1.9% (11/590) before discontinuation.
Because immunogenicity analysis is product specific, it is not advisable to compare the proportion of antibodies present with other products.
Autoantibodies In rheumatoid arthritis research I to V, serum samples were taken from patients at multiple time points to detect autoantibodies. In these studies, patients with negative antinuclear antibody at baseline showed a positive titer after 24 weeks. The proportion of patients receiving this product and receiving placebo and active control treatment were 11.9% and 8.1%, respectively. Of all the 3,441 patients with rheumatoid arthritis and psoriatic arthritis treated with this product, two patients had clinical manifestations supporting the diagnosis of lupus-like syndrome. After stopping treatment, the patient's symptoms improved. No patient developed lupus nephritis or had central nervous symptoms.
Hepatobiliary adverse eventsIn the controlled phase III clinical study of rheumatoid arthritis and psoriatic arthritis of this product, the medication period was 4 to 104 weeks. The incidence of ALT elevation 3 x ULN in patients treated with this product %, The incidence rate in the control group was 1.6%. In the phase III clinical study of this product in controlled plaque psoriasis, the medication period was 12 to 24 weeks. The incidence of ALT elevation 3 x ULN in patients treated with this product was 1.8%, and the incidence rate in the control group. 1.8%.
In clinical studies of all indications, patients with elevated ALT are asymptomatic, and the increase in most cases is transient and can be resolved with subsequent treatment. However, there have been reports of liver failure in patients receiving this product and a few severe liver diseases that can lead to liver failure, such as hepatitis, including autoimmune hepatitis, after marketing.
In combination with imidazolethiopurine / 6-thiopurine in adult Crohn's disease studies, the incidence of malignant and severe infection-related adverse events was higher when adalimumab and imidazolethiopurine / 6-thiopurine were used Use adalimumab.

Adalimumab injection contraindications

People who are allergic to this product or other ingredients in the preparation.
Active tuberculosis or other serious infectious diseases, such as sepsis and opportunistic infections (see the [Precautions] section).
Patients with moderate to severe heart failure (NYHA classification III / IV) (see the [Caution] section).

Precautions for adalimumab injection

Patients infected with TNF antagonists are more likely to develop severe infections. Impaired lung function may increase the risk of infection.
Patients must be closely monitored for infection, including tuberculosis, before, during, and after use of this product. Since the elimination of adalimumab may take up to 4 months, monitoring should be continued during this period.
Regardless of chronic active or focal active infection, treatment with this product should not be started until the infection is not controlled. Before starting treatment with this product in patients with a history of tuberculosis exposure and in patients traveling in areas at high risk of tuberculosis or endemic mycosis (such as histoplasmosis, coccidiosis, or blastomycosis), Risk and benefit assessment (see Opportunistic infections).
Patients who develop infections during treatment should be closely monitored and a comprehensive diagnostic evaluation performed. When the patient develops a new severe infection or sepsis, the treatment of this product should be interrupted and treated with appropriate antibacterial or antifungal drugs until the infection is controlled. For patients with a history of recurrence of infection, or those who are susceptible to infection, including the use of immunosuppressants, doctors should be careful when considering the use of this product in these patients.
Severe infection:
Treatment with this product may increase the patient's risk of serious infections involving various organ systems and parts, and such conditions may lead to hospitalization or death (see the [Black Box Warning] section). Patients using TNF antagonists have reported opportunistic infections caused by bacteria, mycobacteria, invasive fungi, viruses, parasites, or other conditional pathogens, including aspergillosis, blastomycosis, candidiasis, bulbs Sporellosis, Histoplasmosis, Legionella, Listeria, Pneumocystis, and Tuberculosis. These patients often develop disseminated rather than localized diseases. Other serious infections were also found in clinical trials, including pneumonia, pyelonephritis, septic arthritis, and sepsis.
The use of TNF antagonists in combination with abascept or anakinra in patients with rheumatoid arthritis (RA) is associated with a higher risk of serious infections; therefore, the combination of this product and these biologics is not recommended for RA.
This product should not be used in patients with active infections, including local infections. Patients older than 65 years, with comorbidities, and / or concurrent use of immunosuppressants (such as corticosteroids or methotrexate) may have a greater risk of infection. Consider the risks and benefits of treatment before starting treatment for the following patients:
Have a chronic or recurrent infection;
· Previous exposure to tuberculosis;
Have a history of sexually transmitted infections;
· Have lived or traveled to an area with endemic tuberculosis or endemic fungal disease, such as histoplasmosis, coccidioidosis, or blastomycosis;
· Or there is a potential risk factor for infection.
tuberculosis:
TB reactivation and new cases of TB have been reported in patients treated with this product, including latent or active TB patients who have been treated. The emergence of TB includes tuberculosis and extrapulmonary tuberculosis (ie disseminated tuberculosis ). Patients should be evaluated for tuberculosis risk factors and regularly tested for latent tuberculosis infection before and during treatment with this product. The assessment should include the patient's detailed history of TB, previous contact with active TB population, and previous and / or current immunosuppressive therapy. All patients must be screened appropriately, that is, a tuberculin skin test and a chest radiograph (should comply with local guidelines). It is also recommended to record the test results in the patient's medical history. Prescribers should consider the possibility of false negative tuberculin skin tests, especially those with severe illness or who are using immunosuppressants.
If the patient is diagnosed with active tuberculosis, the use of this product is prohibited.
Treatment of latent tuberculosis infection before treatment with a TNF antagonist has been shown to reduce the risk of tuberculosis reactivation during treatment. Before starting treatment with this product, assess whether latent tuberculosis needs treatment; consider positive tuberculin skin test results of induration 5 mm, and even treat patients who have previously been vaccinated with BCG.
In the following situations, doctors must carefully weigh the pros and cons of treatment.
If you suspect a latent TB infection, you must consult a physician with experience in treating TB. If latent tuberculosis is diagnosed, appropriate preventive anti-TB treatment must be performed according to local treatment recommendations before using this product for treatment.
For those patients who have multiple or significant risk factors for TB infection, but have negative TB screening and have a history of latent or active TB infection, but cannot be sure that they have received sufficient courses of treatment, before taking this product, Consideration should be given to appropriate preventive anti-TB treatment. Even with prophylactic antituberculosis treatment, cases of reactivation of tuberculosis still occur with this product. Some patients with active tuberculosis who have been successfully cured have recurrence of tuberculosis during the treatment of this product. Consultation with a tuberculosis treatment specialist is recommended to help determine the suitability of individual patients for antituberculosis treatment.
If during or after the treatment of this product, patients have signs / symptoms of tuberculosis infection (for example, persistent cough, wasting / weight loss, low fever, and malaise), the patient should be advised to see a doctor immediately.
It is strongly recommended that patients with new infections during the treatment of this product consider TB in the differential diagnosis, especially if the patient has been to or has recently been in a country with a high incidence of TB, or has been in close contact with patients with active TB.
Surveillance During the treatment of this product and after treatment, the development of patient infection symptoms and signs should be closely monitored, including the possible occurrence of tuberculosis in patients who have a negative test result for latent tuberculosis infection before starting treatment. When using this product, latent tuberculosis infection may also be false negative.
If patients have severe infections or sepsis during treatment, this product should be discontinued. For a patient who has a new infection during the treatment with this product, close monitoring should be performed, and appropriate prompt and comprehensive diagnostic tests should be performed on patients with low immune function, and appropriate antibacterial treatment should be taken.
Opportunistic infections such as invasive fungal infections:
Opportunistic infections including invasive fungal infections have been observed in patients receiving this product. Delays in proper treatment because such infections are not recognized in patients who have previously used TNF antagonists can have fatal consequences.
If the patient has a severe systemic disease or lives or travels in an area where mycosis is endemic, invasive fungal infections need to be considered in the differential diagnosis. Patients who have signs or symptoms of fever, discomfort, weight loss, sweating, coughing, dyspnea and / or pulmonary infiltration or other serious systemic diseases (with or without accompanying shock) should be suspected of having an invasive fungal infection, And immediately stop using this product. Histoplasmosis and antibodies may be negative in some patients with active infection. When conducting diagnostic tests, appropriate empirical antifungal treatment should be considered, taking into account both the risk of severe fungal infections and the risk of antifungal treatment. Consult with a physician who has experience in the diagnosis and treatment of invasive fungal infections to diagnose and implement antifungal treatment for these patients.
Malignant tumors At present, there are no studies on the use of this product in patients with malignant tumors, or in patients who have developed malignant tumors. Therefore, in patients with known malignancies (except for patients who have successfully cured non-melanoma skin cancer (NMSC)), when starting treatment with TNF antagonists including this product, or in patients with malignant tumors When continuing with TNF antagonist therapy, due consideration should be given to its risks and benefits.
Adult malignancies In the control phase of clinical trials of certain TNF antagonists, including this product, compared with adult patients treated with control, more cases of malignant tumors can be observed in adult patients treated with TNF antagonists. In rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), Crohn's disease (CD), ulcerative colitis (UC), plaque psoriasis (Ps ), 39 controlled clinical trials of this product in global clinical trials performed in adult patients with suppurative sweat glanditis (HS) and uveitis (UV), except for melanoma (basal and squamous cell) skin cancer, malignant tumors The incidence was 0.7 / 100 patient years [0.48, 1.03 (95% confidence interval)] in 7973 patients treated with this product, and 0.7 / 100 patient years [0.41, 1.17 (95%) in 4848 patients treated with control Confidence interval)] (median treatment time for patients treated with this product and patients treated with control were 4 months). Among the 52 global controlled and uncontrolled clinical trials of this product in adult patients with RA, PsA, AS, CD, UC, Ps, HS and UV, except lymphoma and non-melanoma skin cancer (NMSC), the most common The observed malignancies were breast cancer, colon cancer, prostate cancer, lung cancer, and melanoma. The type and number of malignancies in patients treated with this product in the control and non-control phases of these studies were similar in type and number to those expected across the U.S. population based on the SEER database (by age, gender, and ethnicity) Correction). Three control trials of this product-controlled clinical trial in Chinese adults with rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriasis (Ps), in 809 patients treated with this product or 262 No malignant tumor was observed in the control-treated patients (median treatment time was 3 months in patients treated with this product and in patients treated with control). In the open-label extension phase of 3 controlled clinical trials of this product and 1 non-controlled clinical trial in adult patients with RA, AS, and Ps in China, in 1090 patients treated with this product (median treatment time: 6 months) The Chinese Communist Party observed three cases of malignant tumors, namely endometrial cancer, gastric cancer and lung tumors. The incidence of malignant tumors was 0.43 per 100 patient-years [0.10, 1.30 (95% confidence interval)].
Controlled trials of other TNF antagonists in adult patients with a higher risk of malignancy (ie, patients with chronic obstructive pulmonary disease (COPD) with a significant history of smoking, and patients with Wegener's granulomatosis treated with cyclophosphamide) Compared with the control group, the incidence of malignant tumors was higher in the TNF antagonist group.
Based on available data, it is unclear whether adalimumab has an effect on the risk of atypical hyperplasia or colon cancer. All patients with ulcerative colitis with atypical hyperplasia or increased risk of colon cancer (for example, patients with long-term ulcerative colitis or primary sclerosing cholangitis), or patients with a history of atypical hyperplasia or colon cancer Screen for atypical hyperplasia before administration and throughout the course of the disease. Evaluation can be based on local treatment guidelines and should include at least colonoscopy and tissue biopsy.
39 items of non-melanoma skin cancer Non-melanoma skin cancer in adult patients treated with RA, PsA, AS, CD, UC, Ps, HS, and UV. NMSC) occurred at a rate of 0.8 / 100 patient-years [0.52, 1.09 (95% confidence interval)] and 0.2 / 100 patient-years [0.10, 0.59 (95% confidence interval)] in patients treated with control. Before and during treatment with this product, all patients should be checked for the presence of NMSC, especially patients with a long history of immunosuppressive therapy or patients with psoriasis with a history of PUVA treatment.
Lymphoma and leukemia In the control phase of adult clinical trials of all TNF antagonists, more cases of lymphoma can be observed in patients in the TNF antagonist treatment group than in the control treatment group. In the control phase of 39 global clinical trials of this product in adult patients with RA, PsA, AS, CD, UC, Ps, HS, and UV, 2 lymphomas occurred in 7973 patients treated with this product, and in 4848 patients One patient had lymphoma in the control group. Among 52 global controlled and uncontrolled clinical trials (median treatment time of about 0.7 years) of this product in adult patients with RA, PsA, AS, CD, UC, Ps, HS and UV, 24605 patients treated with this product For example, over 40215 patient years, the observed incidence of lymphoma is about 0.11 / 100 patient years. This is approximately three times higher than the expected incidence (adjusted for age, gender, and ethnicity) among the entire U.S. population based on the SEER database. The incidence of lymphoma in this product's clinical trials cannot be compared with that of other TNF antagonists in clinical trials, and the incidence in a wider patient population cannot be predicted. Even without TNF antagonist treatment, patients with RA and other chronic inflammatory diseases, especially those with highly active disease and / or chronic exposure to immunosuppressant therapy, may have a higher incidence of lymphoma than the general population. The risk is higher (up to several times higher). For RA and other indications, post-marketing cases of acute and chronic leukemia have been reported to be associated with the use of TNF antagonists. Even without TNF antagonist treatment, patients with RA may be at a higher risk (approximately 2 times) than the general population to develop leukemia.
Malignancies in children and young patients have been reported in TNF antagonists, including children, adolescents, and young adults treated with this product (primary treatment age 18 years), some of which are fatal. About half of the cases are lymphomas, including Hodgkin and non-Hodgkin's lymphoma. The remaining cases are a variety of different malignancies, including rare malignancies that are not commonly seen in children and adolescents and are usually associated with immunosuppressive and malignant diseases. Malignant tumors occur after a median treatment time of 30 months (1 to 84 months). Most patients are receiving immunosuppressive therapy at the same time. These post-market reported cases come from a variety of sources, including registration databases and spontaneous post-market reports.
Post-marketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have occurred in patients treated with TNF antagonists, including this product. These cases have progressed rapidly and have died. Most of these reported cases occurred in patients with Crohn's disease or ulcerative colitis, and most were adolescents or young adult men. Almost all of these patients have been treated with immunosuppressants azathioprine or 6-mercaptopurine (6-MP) in combination with TNF antagonists at or before diagnosis. It is unclear whether the occurrence of HSTCL is related to the use of TNF antagonists or other immunosuppressants in combination with TNF antagonists. The potential risks of combining this product with azathioprine or 6-mercaptopurine should be carefully considered.
Allergic reactions have been reported after treatment with this product allergic reactions and angioedema. If an allergic reaction or other severe allergic reaction occurs, the administration of this product should be stopped immediately and appropriate treatment given. In adult clinical trials of this product, allergic reactions (eg, allergic rash, allergic reactions, fixed drug reactions, non-specific drug reactions, urticaria) have been observed.
Hepatitis B virus reactivation The use of TNF antagonists, including this product, may increase the risk of virus reactivation in carriers of chronic hepatitis B virus (HBV) (ie, surface antigen positive). Some cases have already resulted in deaths. Most of these reports have occurred in patients who are also receiving other drugs that suppress the immune system, which may also contribute to HBV reactivation.
Patients should be tested for HBV infection before starting TNF antagonist therapy. Evidence of previous HBV infection in patients at risk for HBV infection should be assessed. For patients with positive hepatitis B virus test results, it is recommended to consult a relevant professional doctor with experience in treating hepatitis B. Caution should be exercised in prescribing TNF antagonists to patients identified as carriers of hepatitis B virus. At present, the safety and effectiveness of HBV carriers receiving antiviral therapy at the same time as TNF antagonists to prevent HBV reactivation have not been fully proven. Carriers of hepatitis B virus that require TNF antagonist therapy should be closely monitored for clinical and laboratory signs of active HBV infection throughout the treatment period and months after treatment termination. If HBV reactivation occurs in patients, treatment with this product should be discontinued and effective antiviral treatment should be taken with appropriate supportive care. The safety of restarting TNF antagonist therapy after HBV reactivation is controlled is not clear. Therefore, in this case, special care should be taken when resuming treatment with this product, and patients need to be closely monitored.
Nervous system response The use of TNF antagonists including this product is associated with new or worsening clinical symptoms and / or imaging manifestations of some rare cases of central nervous system demyelinating diseases, including multiple sclerosis (MS) and Optic neuritis, as well as peripheral demyelinating diseases, including Guillain-Barre syndrome. For patients with previous or recent onset of demyelination of the central and peripheral nervous system, doctors should exercise extreme caution when administering this product. If any of these diseases occur, consideration should be given to discontinuing this product.
Immunosuppression In the 64 patients with rheumatoid arthritis who studied this product, there is no evidence that this product inhibits delayed allergic reactions, immunoglobulin levels, and does not change T cells, B cells, NK (natural Killer) cells, monocytes / macrophages and neutrophils.
Hematological reactions In cases where TNF antagonists are used, reports of whole blood cells including aplastic anemia are rare. A few reports of adverse hematological reactions when using this product include clinically significant reductions in blood cells (eg, thrombocytopenia, leukopenia). The causal relationship between these cases and the use of this product is unknown. If the patient develops signs and symptoms of cachexia (for example, persistent fever, bruises, bleeding, pale skin), they should be treated immediately. For patients who have been diagnosed with a hematological abnormality, the use of this product should be stopped immediately.
Immunization In a placebo-controlled clinical trial in patients with RA, when this product was used concurrently with pneumococcal polysaccharide vaccine and influenza vaccine, patients' anti-pneumococcal antibody responses were Difference detected. A similar proportion of patients treated with this product and the placebo group produced protective levels of anti-influenza antibodies; however, the total influenza titer of patients treated with this product was slightly lower, and its clinical significance is unknown. Patients treated with this product can receive vaccinations in addition to live vaccines. There have been no reports of secondary infection transmission from live vaccines in patients treated with this product.
For infants who have been exposed to this product in the womb, the safety of administering a live or attenuated live vaccine is unknown. The risks and benefits of these infants should be carefully considered before immunizing them. It is not recommended to give live vaccinations to infants within 5 months after the last injection of this product during pregnancy.
Congestive heart failure has been reported with exacerbation of congestive heart failure (CHF) and new episodes of CHF after treatment with TNF antagonists. Cases of worsening congestive heart failure have also been reported in patients receiving this product. This product has not been formally studied in patients with CHF; however, a higher incidence of CHF-related serious adverse reactions has been observed in clinical trials of another TNF antagonist. In a clinical study using another TNF antagonist, an increase in mortality due to congestive heart failure was observed. For patients with mild heart failure (NYHA Class I / II), this product should be used with extreme caution and closely monitored. Moderate to severe heart failure (see the [Contraindications] section) is a contraindication for this product. If you have symptoms of congestive heart failure, or if your symptoms have worsened in the past, you should stop using this product.
Autoimmune process The drug treatment of this product will lead to the formation of autoantibodies. The effect of long-term treatment with this product on autoimmune diseases is unclear. If after treatment with this product, the patient develops symptoms of lupus-like syndrome and the double-stranded DNA antibody is positive, the treatment with this product should be stopped immediately (see section [Adverse reactions]).
Simultaneous use of biological anti-rheumatic drugs and TNF antagonists In clinical studies of the simultaneous use of anakinra and another TNF antagonist, etanercept, severe infections have been observed, and compared with the use of etanercept alone Compared with nascept, it cannot improve the clinical effect. According to the characteristics of adverse reactions in the combined use of etanercept and anakinin, similar toxicity may also occur when anakinin is used in combination with other TNF antagonists. Therefore, the combined use of this product and anakinin is not recommended (see section [Drug Interactions]).
It is not recommended to use this product together with other biological anti-rheumatic drugs (such as anakinra and abatacept) or other TNF-antagonists, as this increases the risk of infections including severe infections and other potential drug interactions (see [Drug Interactions] section).
Surgery Experience on the safety of surgery in patients receiving this product is limited. When planning surgery for patients, consider the long half-life of adalimumab. When patients receiving this product need surgery, they should pay close attention to the patient's infection and take appropriate measures. Arthroplasty safety experience in patients receiving this product is also limited.
Small bowel obstruction is ineffective for Crohn's disease, which means that there may be fixed fibrous stenosis in the intestinal lumen and surgery is needed. Existing data show that this product will not cause intestinal stenosis or cause it to worsen.
The elderly group of patients over the age of 65 who received this product have more serious infections and malignancies than those under 65 years of age. Some of them have fatal consequences. Therefore, the treatment of elderly patients should pay special attention to the risk of infection.
Impact on the ability to drive and operate the machine This product has a slight impact on driving and operating the machine. Treatment with this product may cause dizziness (including dizziness, visual impairment and fatigue) (see section [Adverse reactions]).

Adalimumab injection for pregnant and lactating women

Pregnancy risk summary Clinical data obtained from this product's pregnancy registry are limited. Excluding lost follow-up patients, data from the registry report that the rate of major birth defects in pregnant women with rheumatoid arthritis (RA) who used adalimumab in the first trimester was 5.6%. The disease matched the control and non-disease The incidence of major birth defects in the control group was 7.8% and 5.5%, respectively. In the third trimester, adalimumab can pass through the placenta and may affect the immune response of infants exposed in the womb (see the [Cautions] section). In an embryo-fetal perinatal development study in cynomolgus monkeys, adalimumab was injected intravenously during organogenesis and subsequent pregnancy (days 20 to 97 of pregnancy) at a dose that produced Up to about 373 times the maximum human recommended dose (MRHD), which is 40 mg subcutaneously, without methotrexate, resulting in exposure (based on AUC of maternal intravenous doses up to 100 mg / kg / week). Adalimumab did not cause damage or deformity to the fetus. The estimated background risk of major birth defects and miscarriages in specific populations is unknown.
Clinical Precautions Fetal / Newborn Adverse Reactions As pregnancy progresses, monoclonal antibodies gradually increase through the placenta, with the largest amount of metastasis in late pregnancy. For infants who have been exposed to this product in the womb, the risks and benefits should be considered before giving live or attenuated vaccines.
Data Human data In a prospective pregnancy exposure registry cohort study conducted in the United States and Canada between 2004 and 2013, a total of 74 women with RA who were treated with adalimumab at least in the first trimester were included, 80 One female RA patient not receiving adalimumab, and 218 females without RA (non-disease control). Excluding missing patients, the incidence of major birth defects in the adalimumab-exposed pregnancy group (N = 72), disease-matched control group (N = 77), and non-disease control group (N = 201) were 5.6%, respectively. , 7.8% and 5.5%. However, this study cannot be concluded without any risks, because its research method has the limitations of small sample size and non-random study design. The Crohn's disease portion of the study is currently in the follow-up phase and data analysis is ongoing.
In an independent clinical study in 10 pregnant women with inflammatory bowel disease treated with this product, the serum of mothers and umbilical cord blood (N = 10) and the serum of infants born at birth (N = 8) were measured ) Concentration of adalimumab. The last dose of this product was given between 1 and 56 days before delivery. The concentrations of adalimumab in umbilical cord blood, infant serum, and mother serum were 0.16-19.7 g / mL, 4.28-17.7 g / mL, and 0-16.1 g / mL, respectively. In all but one case, the level of adalimumab in umbilical cord blood was higher than that in maternal serum, indicating that adalimumab can pass through the placenta. In addition, there was an infant's serum adalimumab levels at the following time points: week 6 (1.94 g / mL), week 7 (1.31 g / mL), week 8 (0.93 g / mL), and 11 weeks (0.53 g / mL), which indicates that babies exposed in the womb can still detect adalimumab in serum for at least 3 months after birth.
Summary of breastfeeding risks There are only limited case reports in the published literature showing the presence of adalimumab in breast milk at doses ranging from 0.1% to 1% of maternal serum levels in infants. There were no reports of adverse reactions of adalimumab to breast-fed infants, and adalimumab had no effect on milk production.
It is unclear whether adalimumab can be passed into breast milk or if it is absorbed by the body.
However, because human immunoglobulin is secreted in milk, female patients cannot breastfeed for at least 5 months after the end of treatment.
There are no preclinical data on the effects of this product on fertility.
Females of childbearing potential are given contraceptive measures.
It is recommended that female patients with childbearing potential use appropriate contraceptive methods to avoid pregnancy, and continue to use this method for at least 5 months after ending the treatment with this product.

Adalimumab injection for children

There are no data on safety and efficacy studies of this product in pediatric patients.

Adalimumab injection for the elderly

See [Usage and Dosage] and [Precautions].

Adalimumab injection drug interactions

Methotrexate was studied as a single drug and in combination with methotrexate in patients with rheumatoid arthritis, juvenile idiopathic arthritis and psoriatic arthritis. Compared with monotherapy, this product produces lower antibodies when used together with methotrexate. Not using methotrexate will increase antibody formation, speed up clearance, and reduce the efficacy of adalimumab. Although methotrexate reduces the apparent clearance of adalimumab, based on current evidence, it is not recommended to adjust the dose of this product or methotrexate.
Biologics are not recommended for combination with anakinin (see the [Precautions] section).
Combination use of this product and abatacept is not recommended (see the [Caution] section).
A higher incidence of severe infections has been observed in RA patients treated with rituximab and subsequently with a TNF antagonist. There is insufficient information on the simultaneous use of this product and other biological agents in the treatment of RA, PsA, AS, CD, UC, Ps, HS and UV patients.
This product is not recommended in combination with other biological anti-rheumatic drugs or other TNF antagonists, as this may increase the risk of infection and other potential drug interactions.
Avoid using this product with a live vaccine at the same time (see the [Precautions] section).
Elevated levels of cytokines (such as TNF, IL-6) of cytochrome P450 substrates during chronic inflammation may inhibit the production of CYP450 enzymes. Molecules that antagonize cytokine activity, such as adalimumab, may affect CYP450 enzyme production. For patients who are being treated with a CYP450 substrate with a narrow therapeutic index, it is recommended to monitor the treatment effect (such as warfarin) or drug concentration (such as cyclosporine or theophylline) and the individual dose of the drug since starting or stopping treatment Can be adjusted as needed.
Drug compatibility Due to no drug compatibility studies, this product cannot be mixed with other drugs.

Adalimumab injection overdose

No dose limiting toxicity has been observed in clinical studies. The maximum multiple intravenous dose evaluated was 10 mg / kg, approximately 15 times the recommended dose.

Pharmacology and toxicology of adalimumab injection

Pharmacological effects Adalimumab specifically binds to TNF, and eliminates its biological function by blocking the interaction of TNF with TNF receptors on the surface of p55 and p75 cells.
Adalimumab can also modulate biological effects mediated or regulated by TNF, including changes in the levels of adhesion molecules that play an important role in leukocyte migration (ELAM-1, VCAM-1 and ICAM-1, half inhibitory concentration (0.1 ~ 0.2nM).
In patients with rheumatoid arthritis, the levels of inflammatory reactants (C-reactive protein (CRP), erythrocyte sedimentation rate (ESR)), and serum cytokine (IL-6) decreased rapidly compared with baseline levels after receiving this product. . Serum levels of matrix metalloproteinases (MMP-1 and MMP-3), which cause tissue remodeling and cartilage destruction, also decline. Patients receiving this product usually show improved hematological indicators of chronic inflammation.
Toxicity studies genotoxicity: Genetic toxicity tests have not found that adalimumab may cause special harm to the human body.
Reproductive toxicity: In the study of cynomolgus monkey embryo-fetal development / perinatal developmental toxicity, when adalimumab dose reached 30 and 100 mg / kg (9-17 monkeys per group), it did not harm the fetus.

Pharmacokinetics of adalimumab injection

After a single subcutaneous injection of 40 mg of this product, the absorption and distribution of adalimumab was slow, and peak serum concentrations were reached 5 days after administration. In three groups of studies, the absolute bioavailability of adalimumab was an average of 64% after a single dose of 40 mg. After a single dose of intravenous injection at a concentration range of 0.25 to 10 mg / kg, the concentration is dose-dependent. After injection at a dose of 0.5 mg / kg (~ 40mg), the clearance range is from 11 to 15 ml / hour, the steady-state apparent volume of distribution (Vss) is 5-6 liters, and the average terminal phase clearance half-life is about 2 weeks. In several patients with rheumatoid arthritis, the concentration of adalimumab in synovial fluid was 31 to 96% of the concentration in serum.
After subcutaneous injection of 40 mg of this product every two weeks, the average concentrations of rheumatoid arthritis patients at steady state were 5 g / ml (without methotrexate) and 8-9 g / ml (with methotrexate). The steady-state concentration of adalimumab in serum increased proportionally with 20, 40, and 80 mg biweekly and weekly subcutaneous injections.
Data from the overall pharmacokinetic analysis were obtained from 1300 patients with rheumatoid arthritis, and trends indicate that clearance of adalimumab increases as patients gain weight. In patients with measurable AAA (anti-adalimumab antibody), serum free adalimumab (without binding to AAA) had lower levels. This study was not performed on pediatric patients or patients with liver and kidney dysfunction.
A pharmacokinetic study of 24 Chinese subjects with mild rheumatoid arthritis evaluated the pharmacokinetic characteristics (40 mg and 80 mg) of single-dose subcutaneous injections of adalimumab and Comparison of Pharmacokinetic Results in Caucasians. The study showed that the blood concentration-time curve and other pharmacokinetic parameters of adalimumab in Chinese subjects were similar to those of Caucasians. The peak concentration (Cmax) and area under the curve (AUC) were tested in China. Those who are slightly higher. No blood samples were detected for positive anti-adalimumab antibodies (AAA).

Adalimumab injection storage

Store in a refrigerator (2 ~ 8 ° C). Syringes or medicines should be stored in the box, and should not be frozen.

Adalimumab injection packaging

A prefilled syringe with a needle cover is filled with a solution for injection containing 40 mg of this product (adalimumab).
The blister pack contains a pre-filled syringe (0.8ml sterile solution) with a needle sleeve and an alcohol wipe.
Packaging specifications: 1) 1 stick / box, 2) 2 sticks / box.
Pre-filled syringe; 40mg / 0.8ml

Validity of adalimumab injection

24 months.

Adalimumab injection standard

JS20120034

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