Arthritis Treatment- New drug [Adalimumab]

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Basically, Adalimumab [New Drug] is a medication used to treat rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, chronic psoriasis, hidradenitis suppurativa, and juvenile idiopathic arthritis. In rheumatoid arthritis, adalimumab has a response rate similar to methotrexate, and in combination, it nearly doubles the response rate of methotrexate alone.

Adalimumab is a TNF-inhibiting, anti-inflammatory, biologic medication. It binds to tumor necrosis factor-alpha (TNFα), which normally binds to TNFα receptors, leading to the inflammatory response of autoimmune diseases. By binding to TNFα, adalimumab reduces this inflammatory response. Because TNFα is also part of the immune system, which protects the body from infection, treatment with adalimumab may increase the risk of infections.

Name: Adalimumab

Accession Number: DB00051  (BTD00049, BIOD00049)

 Biologic Classification: Protein-Based Therapies Monoclonal antibody (mAb)

 Protein chemical formula: C6428H9912N1694O1987S46

 Metabolism: Most likely removed by opsonization via the reticuloendothelial system.

 Half-life: 10-20 days.

Clearance: 12 mL/hr [RA patients with dose 0.25-10 mg/kg]

Dosage form: Injection & solution

Route of administration: Subcutaneous

History [Adalimumab] [Arthritis] :

Adalimumab was the first fully human monoclonal antibody approved by the U.S. Food and Drug Administration. It was derived from phage display.

Adalimumab was discovered as a result of a collaboration between BASF Bioresearch Corporation and Cambridge Antibody Technology, U.K., itself a collaboration of the government-funded Medical Research Council and three academics, which began in 1993.

Initially named D2E7, it was then further manufactured at BASF Bioresearch Corporation, developed by BASF Knoll (BASF Pharma), and ultimately manufactured and marketed by Abbott Laboratories after Abbott’s acquisition of BASF Pharma. On January 1, 2013, Abbott split into two companies, one retaining the Abbott name and the other named AbbVie. As a result, AbbVie took over the development and marketing of Humira. The brand name Humira stands for “human monoclonal antibody in rheumatoid arthritis”.

adalimumab
adalimumab

It was the third TNF inhibitor, after infliximab and etanercept, to be approved in the United States. It was constructed from a fully human monoclonal antibody, while infliximab is a mouse-human chimeric antibody and etanercept is a TNF receptor-IgG fusion protein.

The drug candidate was discovered initially using CAT’s phage display technology and named D2E7. The key components of the drug were found by guiding the selection of human antibodies from phage display repertoires to a single epitope of an antigen TNF alpha. The ultimate clinical candidate, D2E7, was created and manufactured at BASF Bioresearch Corporation and taken through most of the drug development process by BASF Knoll, then further development, manufacturing and marketing by Abbott Laboratories, after Abbott acquired the pharmaceutical arm of BASF Knoll.

As of 2008, adalimumab had been approved by the FDA for the treatment of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, moderate to severe chronic psoriasis and juvenile idiopathic arthritis. Although only approved for ulcerative colitis from late 2012 by the FDA in the disease’s management, it had been used for several years in cases that have not responded to conventional treatment at standard dosing for Crohn’s disease.

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Mechanism of action:

Adalimumab has long been thought to exert its anti-inflammatory effects through specific binding to Tumor Necrosis Factor-α (TNF α), preventing it from interacting with TNF receptors. Patients with RA have elevated levels of TNF in their synovial fluid, which greatly contribute to inflammation and joint destruction, 2 hallmarks of RA. Declines in levels of serum Interleukin-6 (Il-6) and acute phase reactants of inflammation are observed in RA patients treated with Humira, compared to untreated patients.

A subset of T helper cells, Th17, produces the highly inflammatory cytokine, Il-17 which has been implicated in the pathophysiology of RA and other auto-immune disorders. RA patients have elevated peripheral Th17 cells, which contribute to joint destruction. Il-17 can be produced by regulatory T cells (Treg cells) and displays resistance to Treg cell-mediated suppression of inflammation. During inflammation, Treg cells may become unstable and secrete enhanced levels of Il-17, rendering Il-17 a potential pharmacologic target for inflammatory diseases.

A study from the Ehrenstein Laboratory

A previous study from the Ehrenstein laboratory showed that RA patients treated with adalimumab had higher Treg cell count than untreated patients, allowing for inhibition of Il-17 3. The authors hypothesized that in the absence of adalimumab, TNF could block Treg development. However, etanercept, a soluble TNF receptor as effective as adalimumab in treating RA, did not have the same effect on Treg cell count. This observation prompted researchers to further investigate mechanisms of suppression of Th17 cells by Treg cells in response to adalimumab.

Results from this study indicated that adalimumab, unlike etanercept, enhances TNF’s ability to induce anti-inflammatory T cell formation, by enhancing surface TNF expression on monocytes, and promoting their binding to Treg cells, thus conferring anti-inflammatory properties to T cells.

Pharmacodynamics [Arthritis]:

In vitro and in vivo studies Binding of adalimumab to soluble recombinant human (rh)TNFα was saturable and concentration dependent (Kd 5.8 – 8.7 10-11). Binding to pro-TNFα (transmembrane TNFα), was also demonstrated. Additional in vitro studies showed that adalimumab inhibited the binding of rhTNFα to both TNFα receptors (p55 and p75; IC50 10-9 -10-10M). It also inhibited hTNFα-induced expression of adhesion molecules (IC50 1-2 10-10M). Specificity of adalimumab for rhTNFα was supported by demonstrating binding to human TNFα, but not human TNFβ and a number of different cytokines. In vitro, adalimumab bound to Fc receptors of human cells, indicating that the immunoglobulin effector functions of adalimumab were intact. In vitro, adalimumab is a potent inhibitor of TNFα from human, various primates including cynomolgus monkey, and dog (IC50s 10-10 –10-11 M). Neutralization of murine TNFα was considerably weaker (>2.0 x 10-7), and adalimumab did not bind rat TNFα.

In-vitro Assays

However, in vitro assays revealed staining of structures in the cytoplasm of vascular smooth muscle in human tissues but not in tissues from cynomolgus monkey, which somewhat limits of the monkey as a model for human safety assessment. Due to the low affinity for mouse TNFα as well as the rapid development of murine antihuman antibodies [MAHA], the relevance of mouse as a species for human safety assessment is considered low. Using fresh animal complement source, adalimumab induced lysis of transfected cells over-expressing pro- TNFα. Whether this has any relevance in vivo is unknown.

Animal Studies

No complement –related tissue injuries have been seen in animal studies, which provides some reassurance. In a pharmacology study in the Tg5453 mouse model (expressing a transgene that encodes human pro-TNFα) adalimumab derived variants with and without effector functions were equally potent. However, the ability to activate human complement has not been studied. The relevance of these data for humans with RA is unknown. In vivo, adalimumab inhibited hTNFα-induced lethality in D-galactosamine sensitized mice and hTNFα-induced pyrexia in rabbits.

Transgenic Mouse Models

Moreover, it prevented the development of arthritis in two transgenic mouse models, the Tg197 (expressing a soluble human TNFα transgene) and Tg5453 (expressing a transgene that encodes human pro-TNFα), serving as disease models of polyarthritis. ED50 values were in between 0.1-0.5 mg/kg.

General & Safety Pharmacology

General and safety pharmacology programme A number of general pharmacology/safety pharmacology studies were performed focussing on the CNS, cardiovascular system, GI tract, renal function, female uterus, local anesthesia, and in vitro studies with human blood. Several of these used rats/rat tissues, or guinea pig /tissues. Since adalimumab did not bind rat TNFα, and there are no data on the affinity of adalimumab for guinea pig TNFα, these studies are of limited value. The studies in dogs (CV effects) and with human blood are considered more relevant. There were no findings in these studies that raise any clinical concerns.

arthritis
arthritis

Pharmacokinetics:

Analyses of adalimumab and of anti-adalimumab antibodies (MAHA or primate anti human antibodies [PAHA]) were made by ELISAs. These methods were adequately validated and demonstrated to be sensitive and specific. However, these assays can only detect free adalimumab or free, non-complexed MAHA/PAHA.

Analyses of MAHA/PAHA

Thus, the presence of adalimumab interfered with the analyses of MAHA/PAHA; and vice versa. These assay limitations reduce the reliability of the pharmacokinetic data and the possibility to assess systemic exposure in the toxicity studies. Conventional studies addressing protein binding, metabolism or excretion of adalimumab were not performed.

The Developmental Study in Monkeys

The lack of such studies is acceptable for this type of compound. The placental transfer was demonstrated in the developmental study in monkeys. Data from in vitro human tissue binding studies showed that adalimumab stained with filamentous structures in the cytoplasm of vascular smooth muscle and of other cells with contractile properties, in a number of tissues.

Further Investigations

Further investigations indicated that the staining could be reduced by human TNF or human serum. The Applicant has provided limited support that under physiological conditions the cytoplasm would not be accessible and that no staining was observed in any structure of any human tissue that would be accessible to circulating therapeutic antibodies.

Thus, the in vivo relevance of this finding is uncertain. In mice and monkeys, the pharmacokinetics of adalimumab were linear as long as anti-adalimumab antibodies were absent. However, both MAHA and PAHA developed after single doses and affected the elimination. Moreover, analyses of the biological activity of serum samples showed that PAHA were neutralizing.

Thus, parameters such as clearance and half-life could not be determined with certainty. In general, though, elimination was slow in both species (t1/2 about 14 –21 days in monkeys).

Toxicology:

The toxicology program included studies of single and repeat dose toxicity, genotoxicity, developmental toxicity, and local tolerance. Adalimimab was generally administered via the i.v. the route, while the intended clinical route is s.c. administration. This is not considered to hamper the assessment of toxicity.

  • Single dose toxicity: The data derived from studies performed in mice and rats after i.v. administration show that in rodents, a single dose of Adalimumab appears to be well tolerated up to a dose of almost 2000 times higher than the single human dose, the target organ of toxicity in the rat was the spleen.
  • Repeat dose toxicity: The studies in cynomolgus monkeys are considered most relevant for human safety assessment. Repeat dose toxicity studies of 4 weeks (32 – 157 mg/kg bw) and 39 weeks (32- 215 mg/kg bw) duration were performed. Overall, no major toxicological concerns were identified. As expected, TNFα inhibition resulted in effects on organs of the immune system, including thymus (decreased weight, involution, reduced lymphocytes, cystic transformation) and spleen (reduced activation and cellularity of the follicular center).
  • Immunohistochemical analyses confirmed effects on various immune cells in these organs. In the 39 weeks study, most of these changes were reversible within the 20-week recovery period. In this study, the NOAEL was 32 mg/kg, with an AUC of 304 800 µg*h/ml. There is a vast amount of published literature from preclinical models that demonstrate the role of TNFα in the protective immune responses against various infective agents. There are also data showing that administration of anti-TNFα monoclonal antibodies reduced host defense, which in a number of cases lead to enhancement of infection-induced mortality.
  • The clinical experience with authorized anti-TNF therapies clearly confirms a reduced defense against infections as the main adverse effect of such treatment. After 39 but not 4 weeks, deposition of immune complexes was observed in isolated glomeruli in the kidneys of most animals give 215 mg/kg BW. There were no inflammatory reactions or functional changes observed in association with these deposits.
  • One problem has been identified. In both the 4 and 39 weeks primate studies, low levels of adalimumab were detected in control monkeys. PAHA analyses from samples in the 4 weeks study revealed PAHAs in 7 out of 10 controls. Despite a careful investigation, no evident reason for contamination has been identified; several measures to reassure adequate conduct of the study had been taken. The explanation of the possible contamination may be plausible.
  • The available toxicokinetic data show the exposure of animals to adalimumab during the toxicity studies, in considerable excess of humans given intended therapy. Development of PAHAs could not be determined in these animals due to assay limitations, but cannot be excluded. However, high concentrations of adalimumab were detected in samples from treated animals throughout the study, which supports that PAHAs had not markedly neutralized the adalimumab activity during the study.
  • Genotoxicity: The genotoxic potential of adalimumab was tested in vitro by gene mutations in bacteria and in vivo in the mouse micronucleus test. No genotoxic effects were seen. This is not a complete genotoxicity test battery (see CPMP/ICH/174/95, S2B). However, for a monoclonal antibody, genotoxicity tests are considered to be of limited value and are therefore not needed (CPMP/ICH/302/95, S6).
  • Carcinogenicity: No carcinogenicity study was performed with adalimumab. The lack of such studies is justified because there is no conventional or alternative model available, (i.e adalimumab has low/no affinity for mouse/rat TNFα, and MAHA developed after single doses). Adalimumab had no genotoxic effects, and no atypical tissue changes were seen in the 39 weeks monkey study. It is agreed that there is no indication of a direct carcinogenic effect of an anti-TNFα antibody. However, the consequences of long-term immunosuppression are unknown and an increased risk of poorer control of nascent tumors cannot be ruled out. The lack of carcinogenicity studies has been reflected in the SPC.

Reproduction Toxicity

Effects on male fertility have not been studied. In females, no study beyond the developmental toxicity study in cynomolgus monkey has been performed. Generally, fertility studies are performed in rodents. However, neither the rat nor the mouse is considered as particularly relevant models for human safety assessment.

The human tissue cross-reactivity studies and the histopathological evaluation of male and female reproductive organs in the repeat dose toxicity studies in monkeys revealed no cause for concern. Whether long-term inhibition of TNFα will affect fertility is not known. One developmental/prenatal toxicity study was performed in cynomolgus monkeys (30 or 100 mg/kg/w, days 20-97 post coitum). Cesarean section was performed day 100. Other females were allowed to deliver and the infants were observed for 1 week.

There were no treatment related effects on the maternal animals, gestation, parturition, on fetuses or on the infants. Available data showed that fetuses were exposed to adalimimab, corresponding to 5-10% of the maternal serum levels. Levels in amniotic fluid were 4-17 fold lower than the fetal levels. PAHAs were not measured. Taken together, these data are not sufficient to support the safe use of adalimumab in pregnant women.

The risk of the use of adalimumab in pregnant women is unknown. Based on a large amount of published data, it is evident that TNFα is involved in embryonic development. For instance, although homozygous TNFα deficient mice were viable, fertile and developed normally the immune function of these mice was compromised, and they were highly susceptible to challenges with infectious agents. Thus, inhibition of TNFα may affect the development of the embryo and/ or fetus.

Thus, adalimumab should not be used during pregnancy. Due to the slow elimination of adalimumab, pregnancy should be avoided for an extended period of time after the finalization of treatment. Excretion of adalimumab in breast milk has not been studied in either animals or humans. However, a time period during which pregnancy and breastfeeding should be avoided has been proposed to be 5 months, based on the population PK parameters and their variability, as well as the longest individual half-life observed.

After subcutaneous administration of a single 40 mg dose, absorption and distribution of adalimumab were slow, with peak serum concentrations being reached about 5 days after administration. The average absolute bioavailability of adalimumab estimated from three studies following a single 40 mg subcutaneous dose was 64%. After single intravenous doses ranging from 0.25 to 10 mg/kg, concentrations were dose proportional. After doses of 0.5 mg/kg (~40 mg), clearances ranged from 11 to 15 ml/hour, the distribution volume (Vss) ranged from 5 to 6 liters and the mean terminal phase half life was approximately two weeks. Adalimumab concentrations in the synovial fluid from several rheumatoid arthritis patients ranged from 31-96% of those in serum.

Presence of anti-adalimumab antibodies (AAA) and the effect of AAA on the pharmacokinetics of adalimumab The frequency of AAA positive samples was quite variable among the pharmacokinetic studies (from almost zero up to 33% in a study in healthy volunteers). The variability may be partly due to the fact that there is interference by adalimumab with the antibody analysis. The median CL/F (apparent clearance) was 59 and 17 ml/h in patients with and without AAA, respectively. This may be a true effect, but the results could also be due to assay artifacts caused by possible interference by AAA in the adalimumab analysis. Because immunogenicity analyses are product-specific, comparison of antibody rates with those from other products is not appropriate.

list of active pharmaceutical ingredients

Dose response studies The results of supportive Study DE007 were used to determine the doses for the pivotal studies DE009, DE011, DE019 and DE031. In study DE007, no difference in efficacy was observed between patient groups receiving adalimumab at 20 mg weekly, 40 mg weekly and 80 mg weekly at the 12- week endpoint. Based on this finding, 40 mg every other week (eow) (equivalent to 20 mg weekly) was selected as the middle dose for Study DE009 and the key dose for studies DE019 and DE031.

Study DE011 continued to explore the dose-response relationship in patients not taking concomitant MTX, and is supported by Study DE007. Study DE001/003 further supported the definition of the dose-response curve for patients not taking concomitant MTX by providing information about the plateau of the dose-response curve. Among the trials, study DE009 defined the dose-response relationship in patients taking concomitant MTX.

Therefore, studies DE019 and DE031 did not investigate different dose of intensities. The overall outcome data from the pivotal trials are presented. Overall, it appears reasonably documented that the proposed dose of 40 mg eow provides levels of adalimumab related to a near-maximal response in the majority of patients.

Dose response studies The results of supportive Study DE007 were used to determine the doses for the pivotal studies DE009, DE011, DE019 and DE031. In study DE007, no difference in efficacy was observed between patient groups receiving adalimumab at 20 mg weekly, 40 mg weekly and 80 mg weekly at the 12- week endpoint. Based on this finding, 40 mg every other week (eow) (equivalent to 20 mg weekly) was selected as the middle dose for Study DE009 and the key dose for studies DE019 and DE031. Study DE011 continued to explore the dose-response relationship in patients not taking concomitant MTX, and is supported by Study DE007.

Study DE001/003 further supported the definition of the dose-response curve for patients not taking concomitant MTX by providing information about the plateau of the dose-response curve. Among the trials, study DE009 defined the dose-response relationship in patients taking concomitant MTX. Therefore, studies DE019 and DE031 did not investigate different dose of intensities. The overall outcome data from the pivotal trials are presented. Overall, it appears reasonably documented that the proposed dose of 40 mg eow provides levels of adalimumab related to a near-maximal response in the majority of patients.

Side effects:

Adalimumab suppresses TNFα, which is an important part of the immune system. Therefore, latent infections such as tuberculosis can be reactivated, and the immune system may be unable to fight new infections. This has led to fatal infections in some patients.

After a number of studies and reports of adverse events in patients receiving adalimumab—including serious and sometimes fatal blood disorders; serious infections, including tuberculosis, and infections caused by viruses, fungi, or bacteria; rare reports of lymphoma and solid tissue cancers; rare reports of serious liver injury; rare reports of demyelinating central nervous system disorders; and rare reports of cardiac failure—the U.S. Food and Drug Administration (FDA) issued a black box warning to doctors, which appears in the product labeling of adalimumab and other TNF-inhibiting drugs, instructing them to screen and monitor potential patients more carefully.  Anaphylaxis or other serious allergic reactions may also occur.

 SERIOUS INFECTIONS:

Patients treated with HUMIRA are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressant such as methotrexate or corticosteroids. Discontinue HUMIRA if a patient develops a serious infection or sepsis.

Reported infections include:

  • Active tuberculosis (TB), including reactivation of latent TB. Patients with TB have frequently presented with disseminated or extra pulmonary disease. Test patients for latent TB before HUMIRA use and during therapy. Initiate treatment for latent TB prior to HUMIRA use.
  • Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blast mycosis, and pneumocystis. Patients with histoplasmosis or other invasive fungal infections may present with disseminated, rather than localized, disease. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Consider empiric antifungal therapy in patients at risk for invasive fungal infections who develop a severe systemic illness.
  • Bacterial, viral, and other infections due to opportunistic pathogens, including Legionella and Listeria.

Carefully consider the risks and benefits of treatment with HUMIRA prior to initiating therapy in patients:

1. with chronic or recurrent infection,

2. who have been exposed to TB,

3. with a history of opportunistic infection,

4. who resided in or traveled in regions where mycoses are endemic,

5. with underlying conditions that may predispose them to infection.

Monitor patients closely for the development of signs and symptoms of infection during and after treatment with HUMIRA, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy.

  • Do not start HUMIRA during an active infection, including localized infections.
  • Patients older than 65 years, patients with co-morbid conditions, and/or patients taking concomitant immunosuppressants may be at greater risk of infection.
  • If an infection develops, monitor carefully and initiate appropriate therapy.
  • Drug interactions with biologic products: A higher rate of serious infections has been observed in RA patients treated with rituximab who received subsequent treatment with a TNF blocker. An increased risk of serious infections has been seen with the combination of TNF blockers with anakinra or abatacept, with no demonstrated added benefit in patients with RA.
  • Concomitant administration of HUMIRA with other biologic DMARDs (e.g., anakinra or abatacept) or other TNF blockers is not recommended based on the possible increased risk for infections and other potential pharmacological interactions.

MALIGNANCY:

Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, including HUMIRA. Post marketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers, including HUMIRA. These cases have had a very aggressive disease course and have been fatal. The majority of reported TNF blocker cases have occurred in patients with Crohn’s disease or ulcerative colitis and the majority was in adolescent and young adult males. Almost all of these patients had received treatment with azathioprine or 6-mercaptopurine concomitantly with a TNF blocker at or prior to diagnosis. It is uncertain whether the occurrence of HSTCL is related to the use of a TNF blocker or a TNF blocker in combination with these other immunosuppressants.

  • Consider the risks and benefits of HUMIRA treatment prior to initiating or continuing therapy in a patient with known malignancy.
  • In clinical trials, more cases of malignancies were observed among HUMIRA-treated patients compared to control patients.
  • Non-melanoma skin cancer (NMSC) was reported during clinical trials for HUMIRA-treated patients. Examine all patients, particularly those with a history of prolonged immunosuppressant or PUVA therapy, for the presence of NMSC prior to and during treatment with HUMIRA.
  • In HUMIRA clinical trials, there was an approximate 3-fold higher rate of lymphoma than expected in the general U.S. population. Patients with chronic inflammatory diseases, particularly those with highly active disease and/or chronic exposure to immunosuppressant therapies, may be at higher risk of lymphoma than the general population, even in the absence of TNF blockers.
  • Post marketing cases of acute and chronic leukemia were reported with TNF blocker use. Approximately half of the post marketing cases of malignancies in children, adolescents, and young adults receiving TNF blockers were lymphomas; other cases included rare malignancies associated with immunosuppression and malignancies not usually observed in children and adolescents.

HYPERSENSITIVITY:

Anaphylaxis and angioneurotic edema have been reported following HUMIRA administration. If a serious allergic reaction occurs, stop HUMIRA and institute appropriate therapy.

HEPATITIS B VIRUS REACTIVATION:

  • Use of TNF blockers, including HUMIRA, may increase the risk of reactivation of hepatitis B virus (HBV) in patients who are chronic carriers. Some cases have been fatal.
  • Evaluate patients at risk for HBV infection for prior evidence of HBV infection before initiating TNF blocker therapy.
  • Exercise caution in patients who are carriers of HBV and monitor them during and after HUMIRA treatment.
  • Discontinue HUMIRA and begin antiviral therapy in patients who develop HBV reactivation. Exercise caution when resuming HUMIRA after HBV treatment.

NEUROLOGIC REACTIONS:

 

  • TNF blockers, including HUMIRA, have been associated with rare cases of new onset or exacerbation of central nervous system and peripheral demyelinating diseases, including multiple sclerosis, optic neuritis, and Guillain-Barre syndrome.
  • Exercise caution when considering HUMIRA for patients with these disorders; discontinuation of HUMIRA should be considered if any of these disorders develop.
  • There is a known association between intermediate uveitis and central demyelinating disorders.

HEMATOLOGIC REACTIONS:

 

  • Rare reports of pancytopenia, including aplastic anemia, have been reported with TNF blockers. Medically significant cytopenia has been infrequently reported with HUMIRA.
  • Consider stopping HUMIRA if significant hematologic abnormalities occur.

CONGESTIVE HEART FAILURE:

 

  • Worsening and new onset congestive heart failure (CHF) has been reported with TNF blockers. Cases of worsening CHF have been observed with HUMIRA; exercise caution and monitor carefully.

AUTOIMMUNITY:

 

  • Treatment with HUMIRA may result in the formation of autoantibodies and, rarely, in the development of a lupus-like syndrome. Discontinue treatment if symptoms of a lupus-like syndrome develop.

IMMUNIZATIONS:

 

  • Patients on HUMIRA should not receive live vaccines.
  • Pediatric patients, if possible, should be brought up to date with all immunizations before initiating HUMIRA therapy.
  • Adalimumab is actively transferred across the placenta during the third trimester of pregnancy and may affect the immune response in the underexposed infant. The safety of administering live or live-attenuated vaccines in infants exposed to HUMIRA in utero is unknown. Risks and benefits should be considered prior to vaccinating (live or live-attenuated) exposed to infants.

ADVERSE REACTIONS

 

  • The most common adverse reactions in HUMIRA clinical trials (>10%) were: infections (e.g., upper respiratory, sinusitis), injection site reactions, headache, and rash.

INDICATIONS:

 

  • Rheumatoid Arthritis: 

HUMIRA is indicated, alone or in combination with methotrexate or other non-biologic DMARDs, for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in adult patients with moderately to severely active rheumatoid arthritis.

  • Juvenile Idiopathic Arthritis:

HUMIRA is indicated, alone or in combination with methotrexate, for reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis in patients 2 years of age and older.

  • Psoriatic Arthritis: 

HUMIRA is indicated, alone or in combination with non-biologic DMARDs, for reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in adult patients with active psoriatic arthritis.

  • Ankylosing Spondylitis:

HUMIRA is indicated for reducing signs and symptoms in adult patients with active ankylosing spondylitis.

  • Adult Crohn’s Disease:

HUMIRA is 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, and reducing signs and symptoms and inducing clinical remission in these patients if they have also lost response to or are intolerant to infliximab.

  • Pediatric Crohn’s Disease:

HUMIRA is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients 6 years of age and older with moderately to severely active Crohn’s disease which have had an inadequate response to corticosteroids or immunomodulators such as azathioprine, 6-mercaptopurine, or methotrexate.

  • Ulcerative Colitis:

HUMIRA is indicated for inducing and sustaining clinical remission in adult patients with moderately to severely active ulcerative colitis who have had an inadequate response to immunosuppressants such as corticosteroids, azathioprine, or 6-mercaptopurine. The effectiveness of HUMIRA has not been established in patients who have lost response to or were intolerant to anti-TNF agents.

  • Plaque Psoriasis:

HUMIRA is indicated for the treatment of adult patients with moderate to severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy, and when other systemic therapies are medically less appropriate. HUMIRA should only be administered to patients who will be closely monitored and have regular follow-up visits with a physician.

  • Hidradenitis Suppurativa: 

HUMIRA is indicated for the treatment of adult patients with moderate to severe hidradenitis suppurativa.

  • Uveitis:

HUMIRA is indicated for the treatment of non-infectious intermediate, posterior and panuveitis in adult patients.

Benefit/risk assessment

 Based on the CPMP review of data on quality, safety and efficacy, the CPMP considered by consensus that the benefit/risk profile of Humira was favorable and therefore recommended the granting of the marketing authorization, for the indication: “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. To ensure maximum efficacy, Humira is given in combination with methotrexate. Humira can be given as monotherapy in case of intolerance to methotrexate or when continued treatment with methotrexate is inappropriate.

References:

  1. Kobayashi T, Yokoyama T, Ito S, et al. Periodontal and serum protein profiles in patients with rheumatoid arthritis treated with tumor necrosis factor inhibitor adalimumab. J Periodontol. 2014;85(11):1480-8.
  2. Nguyen DX, Ehrenstein M Anti-TNF drives regulatory T cell expansion by paradoxically promoting membrane   TNF–TNF-RII bindin­­g in rheumatoid arthritis. doi: 10.1084/jem.20151255

Mcgovern JL, Nguyen DX, Notley CA, Mauri C, Isenberg DA, Ehrenstein MR. Th17 cells are restrained by Treg cells via the inhibition of interleukin-6 in patients with rheumatoid arthritis respond to anti-tumor necrosis factor antibody therapy. Arthritis Rheum. 2012;64(10):3129-38.

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