Cyltezo

Rheumatoid Arthritis

CYLTEZO is indicated 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. CYLTEZO can be used alone or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs).

Juvenile Idiopathic Arthritis

CYLTEZO is indicated for reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis in patients 4 years of age and older. CYLTEZO can be used alone or in combination with methotrexate.

Psoriatic Arthritis

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

Ankylosing Spondylitis

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

Adult Crohn’s Disease

CYLTEZO 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. CYLTEZO 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.

Ulcerative Colitis

CYLTEZO 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 (6-MP). The effectiveness of CYLTEZO has not been established in patients who have lost response to or were intolerant to TNF blockers .

Plaque Psoriasis

CYLTEZO 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. CYLTEZO should only be administered to patients who will be closely monitored and have regular follow-up visits with a physician .

CYLTEZO is administered by subcutaneous injection.

Rheumatoid Arthritis, Psoriatic Arthritis, And Ankylosing Spondylitis

The recommended dose of CYLTEZO for adult patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), or ankylosing spondylitis (AS) is 40 mg administered every other week. Methotrexate (MTX), other non-biologic DMARDS, glucocorticoids, nonsteroidal anti-inflammatory drugs (NSAIDs), and/or analgesics may be continued during treatment with CYLTEZO. In the treatment of RA, some patients not taking concomitant MTX may derive additional benefit from increasing the dosing frequency of CYLTEZO to 40 mg every week.

Juvenile Idiopathic Arthritis

The recommended dose of CYLTEZO for patients 4 years of age and older with polyarticular juvenile idiopathic arthritis (JIA) is based on weight as shown below. MTX, glucocorticoids, NSAIDs, and/or analgesics may be continued during treatment with CYLTEZO.

There is no dosage form for CYLTEZO that allows weight based dosing for pediatric patients below 30 kg.

Adalimumab products have not been studied in patients with polyarticular JIA less than 2 years of age or in patients with a weight below 10 kg.

Adult Crohn’s Disease

The recommended CYLTEZO dose regimen for adult patients with Crohn"s disease (CD) is 160 mg initially on Day 1 (four 40 mg injections in one day or two 40 mg injections per day for two consecutive days), followed by 80 mg two weeks later (Day 15). Two weeks later (Day 29) begin a maintenance dose of 40 mg every other week. Aminosalicylates and/or corticosteroids may be continued during treatment with CYLTEZO. Azathioprine, 6-mercaptopurine (6-MP) or MTX may be continued during treatment with CYLTEZO if necessary. The use of adalimumab products in CD beyond one year has not been evaluated in controlled clinical studies.

Ulcerative Colitis

The recommended CYLTEZO dose regimen for adult patients with ulcerative colitis (UC) is 160 mg initially on Day 1 (four 40 mg injections in one day or two 40 mg injections per day for two consecutive days), followed by 80 mg two weeks later (Day 15). Two weeks later (Day 29) continue with a dose of 40 mg every other week.

Only continue CYLTEZO in patients who have shown evidence of clinical remission by eight weeks (Day 57) of therapy. -MP) may be continued during treatment with CYLTEZO if necessary.

Plaque Psoriasis

The recommended dose of CYLTEZO for adult patients with plaque psoriasis (Ps) is an initial dose of 80 mg, followed by 40 mg given every other week starting one week after the initial dose. The use of adalimumab products in moderate to severe chronic Ps beyond one year has not been evaluated in controlled clinical studies.

Monitoring To Assess Safety

Prior to initiating CYLTEZO and periodically during therapy, evaluate patients for active tuberculosis and test for latent infection .

General Considerations For Administration

CYLTEZO is intended for use under the guidance and supervision of a physician. A patient may self-inject CYLTEZO or a caregiver may inject CYLTEZO using the CYLTEZO prefilled syringe if a physician determines that it is appropriate, and with medical follow-up, as necessary, after proper training in subcutaneous injection technique.

You may leave CYLTEZO at room temperature for about 15 to 30 minutes before injecting. Do not remove the cap or cover while allowing it to reach room temperature. Carefully inspect the solution in the CYLTEZO prefilled syringe for particulate matter and discoloration prior to subcutaneous administration. If particulates and discolorations are noted, do not use the product. CYLTEZO does not contain preservatives; therefore, discard unused portions of drug remaining from the syringe. NOTE: Instruct patients sensitive to latex not to handle the gray inner needle cap of the 27 gauge CYLTEZO prefilled syringe because it contains natural rubber latex .

Instruct patients using the CYLTEZO prefilled syringe to inject the full amount in the syringe, according to the directions provided in the Instructions for Use .

Injections should occur at separate sites in the thigh or abdomen. Rotate injection sites and do not give injections into areas where the skin is tender, bruised, red or hard.

None.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Serious Infections

Patients treated with adalimumab products, including CYLTEZO, are at increased risk for developing serious infections involving various organ systems and sites that may lead to hospitalization or death . Opportunistic infections due to bacterial, mycobacterial, invasive fungal, viral, parasitic, or other opportunistic pathogens including aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, legionellosis, listeriosis, pneumocystosis and tuberculosis have been reported with TNF blockers. Patients have frequently presented with disseminated rather than localized disease.

The concomitant use of a TNF blocker and abatacept or anakinra was associated with a higher risk of serious infections in patients with rheumatoid arthritis (RA); therefore, the concomitant use of CYLTEZO and these biologic products is not recommended in the treatment of patients with RA .

Treatment with CYLTEZO should not be initiated in patients with an active infection, including localized infections. Patients greater than 65 years of age, patients with co-morbid conditions and/or patients taking concomitant immunosuppressants (such as corticosteroids or methotrexate), may be at greater risk of infection. Consider the risks and benefits of treatment prior to initiating therapy in patients:

• with chronic or recurrent infection;
• who have been exposed to tuberculosis;
• with a history of an opportunistic infection;
• who have resided or traveled in areas of endemic tuberculosis or endemic mycoses, such as histoplasmosis, coccidioidomycosis, or blastomycosis; or
• with underlying conditions that may predispose them to infection.

Tuberculosis

Cases of reactivation of tuberculosis and new onset tuberculosis infections have been reported in patients receiving adalimumab products, including patients who have previously received treatment for latent or active tuberculosis. Reports included cases of pulmonary and extrapulmonary (i.e., disseminated) tuberculosis. Evaluate patients for tuberculosis risk factors and test for latent infection prior to initiating CYLTEZO and periodically during therapy.

Treatment of latent tuberculosis infection prior to therapy with TNF blocking agents has been shown to reduce the risk of tuberculosis reactivation during therapy. Prior to initiating CYLTEZO, assess if treatment for latent tuberculosis is needed; and consider an induration of ≥ 5 mm a positive tuberculin skin test result, even for patients previously vaccinated with Bacille Calmette-Guerin (BCG).

Consider anti-tuberculosis therapy prior to initiation of CYLTEZO in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but having risk factors for tuberculosis infection. Despite prophylactic treatment for tuberculosis, cases of reactivated tuberculosis have occurred in patients treated with adalimumab products. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision whether initiating anti-tuberculosis therapy is appropriate for an individual patient.

Strongly consider tuberculosis in the differential diagnosis in patients who develop a new infection during CYLTEZO treatment, especially in patients who have previously or recently traveled to countries with a high prevalence of tuberculosis, or who have had close contact with a person with active tuberculosis.

Monitoring

Closely monitor patients for the development of signs and symptoms of infection during and after treatment with CYLTEZO, including the development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy. Tests for latent tuberculosis infection may also be falsely negative while on therapy with CYLTEZO.

Discontinue CYLTEZO if a patient develops a serious infection or sepsis. For a patient who develops a new infection during treatment with CYLTEZO, closely monitor them, perform a prompt and complete diagnostic workup appropriate for an immunocompromised patient, and initiate appropriate antimicrobial therapy.

Invasive Fungal Infections

If patients develop a serious systemic illness and they reside or travel in regions where mycoses are endemic, consider invasive fungal infection in the differential diagnosis. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Consider appropriate empiric antifungal therapy, taking into account both the risk for severe fungal infection and the risks of antifungal therapy, while a diagnostic workup is being performed. To aid in the management of such patients, consider consultation with a physician with expertise in the diagnosis and treatment of invasive fungal infections.

Malignancies

Consider the risks and benefits of TNF-blocker treatment including CYLTEZO prior to initiating therapy in patients with a known malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing a TNF blocker in patients who develop a malignancy.

Malignancies In Adults

In the controlled portions of clinical trials of some TNF-blockers, including adalimumab products, more cases of malignancies have been observed among TNF-blocker-treated adult patients compared to control-treated adult patients. During the controlled portions of 34 global adalimumab clinical trials in adult patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), Crohn"s disease (CD), ulcerative colitis (UC) and plaque psoriasis (Ps), malignancies, other than non melanoma (basal cell and squamous cell) skin cancer, were observed at a rate (95% confidence interval) of 0.6 (0.38, 0.91) per 100 patient years among 7304 adalimumab-treated patients versus a rate of 0.6 (0.30, 1.03) per 100 patient years among 4232 control-treated patients (median duration of treatment of 4 months for adalimumab-treated patients and 4 months for control treated patients). In 47 global controlled and uncontrolled clinical trials of adalimumab in adult patients with RA, PsA, AS, CD, UC, and Ps, the most frequently observed malignancies, other than lymphoma and NMSC, were breast, colon, prostate, lung, and melanoma. The malignancies in adalimumab­treated patients in the controlled and uncontrolled portions of the studies were similar in type and number to what would be expected in the general U.S. population according to the SEER database (adjusted for age, gender, and race).¹

In controlled trials of other TNF blockers in adult patients at higher risk for malignancies (i.e., patients with COPD with a significant smoking history and cyclophosphamide-treated patients with Wegener"s granulomatosis), a greater portion of malignancies occurred in the TNF blocker group compared to the control group.

Non-Melanoma Skin Cancer

During the controlled portions of 34 global adalimumab clinical trials in adult patients with RA, PsA, AS, CD, UC, and Ps, the rate (95% confidence interval) of NMSC was 0.7 (0.49, 1.08) per 100 patient-years among adalimumab-treated patients and 0.2 (0.08, 0.59) per 100 patient-years among control-treated patients. Examine all patients, and in particular patients with a medical history of prior prolonged immunosuppressant therapy or psoriasis patients with a history of PUVA treatment for the presence of NMSC prior to and during treatment with CYLTEZO.

Lymphoma And Leukemia

In the controlled portions of clinical trials of all the TNF-blockers in adults, more cases of lymphoma have been observed among TNF-blocker-treated patients compared to control-treated patients. In the controlled portions of 34 global adalimumab clinical trials in adult patients with RA, PsA, AS, CD, UC and Ps, 3 lymphomas occurred among 7304 adalimumab-treated patients versus 1 among 4232 control-treated patients. In 47 global controlled and uncontrolled clinical trials of adalimumab in adult patients with RA, PsA, AS, CD, UC and Ps with a median duration of approximately 0.6 years, including 23,036 patients and over 34,000 patient-years of adalimumab, the observed rate of lymphomas was approximately 0.11 per 100 patient-years. This is approximately 3-fold higher than expected in the general U.S. population according to the SEER database (adjusted for age, gender, and race).¹ Rates of lymphoma in clinical trials of adalimumab cannot be compared to rates of lymphoma in clinical trials of other TNF blockers and may not predict the rates observed in a broader patient population. Patients with RA and other chronic inflammatory diseases, particularly those with highly active disease and/or chronic exposure to immunosuppressant therapies, may be at a higher risk (up to several fold) than the general population for the development of lymphoma, even in the absence of TNF blockers. Post-marketing cases of acute and chronic leukemia have been reported in association with TNF-blocker use in RA and other indications. Even in the absence of TNF-blocker therapy, patients with RA may be at a higher risk (approximately 2-fold) than the general population for the development of leukemia.

Malignancies In Pediatric Patients And Young Adults

Malignancies, some fatal, have been reported among children, adolescents, and young adults who received treatment with TNF-blockers (initiation of therapy ≤ 18 years of age), of which CYLTEZO is a member . Approximately half the cases were lymphomas, including Hodgkin"s and non-Hodgkin"s lymphoma. The other cases represented a variety of different malignancies and included rare malignancies usually associated with immunosuppression and malignancies that are not usually observed in children and adolescents. The malignancies occurred after a median of 30 months of therapy (range 1 to 84 months). Most of the patients were receiving concomitant immunosuppressants. These cases were reported post-marketing and are derived from a variety of sources including registries and spontaneous postmarketing reports.

Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers including adalimumab products . 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 were in adolescent and young adult males. Almost all of these patients had received treatment with the immunosuppressants azathioprine or 6-mercaptopurine (6-MP) concomitantly with a TNF blocker at or prior to diagnosis. It is uncertain whether the occurrence of HSTCL is related to use of a TNF blocker or a TNF blocker in combination with these other immunosuppressants. The potential risk with the combination of azathioprine or 6-mercaptopurine and adalimumab products should be carefully considered.

Hypersensitivity Reactions

Anaphylaxis and angioneurotic edema have been reported following administration of adalimumab products. If an anaphylactic or other serious allergic reaction occurs, immediately discontinue administration of CYLTEZO and institute appropriate therapy. In clinical trials of adalimumab products in adults, allergic reactions (e.g., allergic rash, anaphylactoid reaction, fixed drug reaction, non-specified drug reaction, urticaria) have been observed.

Hepatitis B Virus Reactivation

Use of TNF blockers, including CYLTEZO, may increase the risk of reactivation of hepatitis B virus (HBV) in patients who are chronic carriers of this virus. In some instances, HBV reactivation occurring in conjunction with TNF blocker therapy has been fatal. The majority of these reports have occurred in patients concomitantly receiving other medications that suppress the immune system, which may also contribute to HBV reactivation. Evaluate patients at risk for HBV infection for prior evidence of HBV infection before initiating TNF blocker therapy. Exercise caution in prescribing TNF blockers for patients identified as carriers of HBV. Adequate data are not available on the safety or efficacy of treating patients who are carriers of HBV with anti-viral therapy in conjunction with TNF blocker therapy to prevent HBV reactivation. For patients who are carriers of HBV and require treatment with TNF blockers, closely monitor such patients for clinical and laboratory signs of active HBV infection throughout therapy and for several months following termination of therapy. In patients who develop HBV reactivation, stop CYLTEZO and initiate effective anti-viral therapy with appropriate supportive treatment. The safety of resuming TNF blocker therapy after HBV reactivation is controlled is not known. Therefore, exercise caution when considering resumption of CYLTEZO therapy in this situation and monitor patients closely.

Neurologic Reactions

Use of TNF blocking agents, including adalimumab products, have been associated with rare cases of new onset or exacerbation of clinical symptoms and/or radiographic evidence of central nervous system demyelinating disease, including multiple sclerosis (MS) and optic neuritis, and peripheral demyelinating disease, including Guillain-Barré syndrome. Exercise caution in considering the use of CYLTEZO in patients with preexisting or recent-onset central or peripheral nervous system demyelinating disorders; discontinuation of CYLTEZO should be considered if any of these disorders develop.

Hematological Reactions

Rare reports of pancytopenia including aplastic anemia have been reported with TNF blocking agents. Adverse reactions of the hematologic system, including medically significant cytopenia (e.g., thrombocytopenia, leukopenia) have been infrequently reported with adalimumab products. The causal relationship of these reports to adalimumab products remains unclear. Advise all patients to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias or infection (e.g., persistent fever, bruising, bleeding, pallor) while on CYLTEZO. Consider discontinuation of CYLTEZO therapy in patients with confirmed significant hematologic abnormalities.

Use With Anakinra

Concurrent use of anakinra (an interleukin-1 antagonist) and another TNF-blocker, was associated with a greater proportion of serious infections and neutropenia and no added benefit compared with the TNF-blocker alone in patients with RA. Therefore, the combination of CYLTEZO and anakinra is not recommended .

Heart Failure

Cases of worsening congestive heart failure (CHF) and new onset CHF have been reported with TNF blockers. Cases of worsening CHF have also been observed with adalimumab. Adalimumab products have not been formally studied in patients with CHF; however, in clinical trials of another TNF blocker, a higher rate of serious CHF-related adverse reactions was observed. Exercise caution when using CYLTEZO in patients who have heart failure and monitor them carefully.

Autoimmunity

Treatment with adalimumab products may result in the formation of autoantibodies and, rarely, in the development of a lupus-like syndrome. If a patient develops symptoms suggestive of a lupus-like syndrome following treatment with CYLTEZO, discontinue treatment .

Immunizations

In a placebo-controlled clinical trial of patients with RA, no difference was detected in anti-pneumococcal antibody response between adalimumab and placebo treatment groups when the pneumococcal polysaccharide vaccine and influenza vaccine were administered concurrently with adalimumab. Similar proportions of patients developed protective levels of anti-influenza antibodies between adalimumab and placebo treatment groups; however, titers in aggregate to influenza antigens were moderately lower in patients receiving adalimumab. The clinical significance of this is unknown. Patients on CYLTEZO may receive concurrent vaccinations, except for live vaccines. No data are available on the secondary transmission of infection by live vaccines in patients receiving adalimumab products.

It is recommended that pediatric patients, if possible, be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating CYLTEZO therapy. Patients on CYLTEZO may receive concurrent vaccinations, except for live vaccines.

The safety of administering live or live-attenuated vaccines in infants exposed to adalimumab products in utero is unknown. Risks and benefits should be considered prior to vaccinating (live or live-attenuated) exposed infants .

Use With Abatacept

In controlled trials, the concurrent administration of TNF-blockers and abatacept was associated with a greater proportion of serious infections than the use of a TNF-blocker alone; the combination therapy, compared to the use of a TNF-blocker alone, has not demonstrated improved clinical benefit in the treatment of RA. Therefore, the combination of abatacept with TNF-blockers including CYLTEZO is not recommended .

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).

Patient Counseling

Provide the CYLTEZO “Medication Guide” to patients or their caregivers, and provide them an opportunity to read it and ask questions prior to initiation of therapy and prior to each time the prescription is renewed. If patients develop signs and symptoms of infection, instruct them to seek medical evaluation immediately.

Advise patients of the potential benefits and risks of CYLTEZO.

• Infections
  Inform patients that CYLTEZO may lower the ability of their immune system to fight infections. Instruct patients of the importance of contacting their doctor if they develop any symptoms of infection, including tuberculosis, invasive fungal infections, and reactivation of hepatitis B virus infections.
• Malignancies
  Counsel patients about the risk of malignancies while receiving CYLTEZO.
• Allergic Reactions
  Advise patients to seek immediate medical attention if they experience any symptoms of severe allergic reactions. Advise latex-sensitive patients that the gray inner needle cap of the 27 gauge CYLTEZO prefilled syringe contains natural rubber latex .
• Other Medical Conditions
  Advise patients to report any signs of new or worsening medical conditions such as congestive heart failure, neurological disease, autoimmune disorders, or cytopenias. Advise patients to report any symptoms suggestive of a cytopenia such as bruising, bleeding, or persistent fever.

Instructions On Injection Technique

Inform patients that the first injection is to be performed under the supervision of a qualified health care professional. If a patient or caregiver is to administer CYLTEZO, instruct them in injection techniques and assess their ability to inject subcutaneously to ensure the proper administration of CYLTEZO .

Instruct patients to dispose of their used needles and syringes in a FDA-cleared sharps disposal container immediately after use. Instruct patients not to dispose of loose needles and syringes in their household trash. Instruct patients that if they do not have a FDA-cleared sharps disposal container, they may use a household container that is made of a heavy-duty plastic, can be closed with a tight-fitting and puncture-resistant lid without sharps being able to come out, upright and stable during use, leak-resistant, and properly labeled to warn of hazardous waste inside the container.

Instruct patients that when their sharps disposal container is almost full, they will need to follow their community guidelines for the correct way to dispose of their sharps disposal container. Instruct patients that there may be state or local laws regarding disposal of used needles and syringes. Refer patients to the FDA"s website at http://www.fda.gov/safesharpsdisposal for more information about safe sharps disposal, and for specific information about sharps disposal in the state that they live in.

Instruct patients not to dispose of their used sharps disposal container in their household trash unless their community guidelines permit this. Instruct patients not to recycle their used sharps disposal container.

Address medical inquiries to: (800) 542-6257 or (800) 459-9906 TTY.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Long-term animal studies of adalimumab products have not been conducted to evaluate the carcinogenic potential or its effect on fertility.

Use In Specific Populations

Pregnancy

Risk Summary

Limited clinical data are available from the adalimumab Pregnancy Registry. Excluding lost-to-follow-up, data from the registry reports a rate of 5.6% for major birth defects with first trimester use of adalimumab in pregnant women with rheumatoid arthritis (RA), and a rate of 7.8% and 5.5% for major birth defects in the disease-matched and non-diseased comparison groups . Adalimumab products are actively transferred across the placenta during the third trimester of pregnancy and may affect immune response in the in-utero exposed infant . In an embryo-fetal perinatal development study conducted in cynomolgus monkeys, no fetal harm or malformations were observed with intravenous administration of adalimumab during organogenesis and later in gestation, at doses that produced exposures up to approximately 373 times the maximum recommended human dose (MRHD) of 40 mg subcutaneous without methotrexate .

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15­20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Monoclonal antibodies are increasingly transported across the placenta as pregnancy progresses, with the largest amount transferred during the third trimester . Risks and benefits should be considered prior to administering live or live-attenuated vaccines to infants exposed to adalimumab products in utero .

Data

Human Data

In a prospective cohort pregnancy exposure registry conducted in the U.S. and Canada between 2004 and 2013, 74 women with RA treated with adalimumab at least during the first trimester, 80 women with RA not treated with adalimumab and 218 women without RA (non-diseased) were enrolled. Excluding lost-to-follow-up, the rate of major defects in the adalimumab-exposed pregnancies (N=72), disease-matched (N=77), and non-diseased comparison groups (N=201) was 5.6%, 7.8% and 5.5%, respectively. However, this study cannot definitely establish the absence of any risk because of methodological limitations, including small sample size and non-randomized study design. Data from the Crohn"s disease portion of the study is in the follow-up phase and the analysis is ongoing.

In an independent clinical study conducted in ten pregnant women with inflammatory bowel disease treated with adalimumab, adalimumab concentrations were measured in maternal serum as well as in cord blood (n=10) and infant serum (n=8) on the day of birth. The last dose of adalimumab was given between 1 and 56 days prior to delivery. Adalimumab concentrations were 0.16-19.7 μg/mL in cord blood, 4.28-17.7 μg/mL in infant serum, and 0-16.1 μg/mL in maternal serum. In all but one case, the cord blood level of adalimumab was higher than the maternal serum level, suggesting adalimumab actively crosses the placenta. In addition, one infant had serum levels at each of the following: 6 weeks (1.94 μg/mL), 7 weeks (1.31 μg/mL), 8 weeks (0.93 μg/mL), and 11 weeks (0.53 μg/mL), suggesting adalimumab can be detected in the serum of infants exposed in utero for at least 3 months from birth.

Animal Data

In an embryo-fetal perinatal development study, pregnant cynomolgus monkeys received adalimumab from gestation days 20 to 97 at doses that produced exposures up to 373 times that achieved with the MRHD without methotrexate (on an AUC basis with maternal IV doses up to 100 mg/kg/week). Adalimumab did not elicit harm to the fetuses or malformations.

Lactation

Risk Summary

Limited data from case reports in the published literature describe the presence of adalimumab in human milk at infant doses of 0.1% to 1% of the maternal serum level. There are no reports of adverse effects of adalimumab products on the breastfed infant and no effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother"s clinical need for CYLTEZO and any potential adverse effects on the breastfed child from CYLTEZO or from the underlying maternal condition.

Pediatric Use

Safety and efficacy of CYLTEZO in pediatric patients for uses other than polyarticular juvenile idiopathic arthritis (JIA) have not been established. Due to its inhibition of TNFα, adalimumab products administered during pregnancy could affect immune response in the in utero-exposed newborn and infant. Data from eight infants exposed to adalimumab in utero suggest adalimumab crosses the placenta . The clinical significance of elevated adalimumab levels in infants is unknown. The safety of administering live or live-attenuated vaccines in exposed infants is unknown. Risks and benefits should be considered prior to vaccinating (live or live-attenuated) exposed infants.

Post-marketing cases of lymphoma, including hepatosplenic T-cell lymphoma and other malignancies, some fatal, have been reported among children, adolescents, and young adults who received treatment with TNF-blockers including adalimumab products .

Juvenile Idiopathic Arthritis

In Study JIA-I, adalimumab was shown to reduce signs and symptoms of active polyarticular JIA in patients 4 to 17 years of age . Adalimumab products have not been studied in patients with polyarticular JIA less than 2 years of age or in patients with a weight below 10 kg.

The safety of adalimumab in patients in the polyarticular JIA trials was generally similar to that observed in adults with certain exceptions .

Geriatric Use

A total of 519 RA patients 65 years of age and older, including 107 patients 75 years of age and older, received adalimumab in clinical studies RA-I through IV. No overall difference in effectiveness was observed between these patients and younger patients. The frequency of serious infection and malignancy among adalimumab treated patients over 65 years of age was higher than for those under 65 years of age. Because there is a higher incidence of infections and malignancies in the elderly population, use caution when treating the elderly.

REFERENCES

1. National Cancer Institute. Surveillance, Epidemiology, and End Results Database (SEER) Program. SEER Incidence Crude Rates, 17 Registries, 2000-2007.

Methotrexate

Adalimumab products have been studied in rheumatoid arthritis (RA) patients taking concomitant methotrexate (MTX). Although MTX reduced the apparent clearance of adalimumab products, the data do not suggest the need for dose adjustment of either adalimumab products or MTX .

Biological Products

In clinical studies in patients with RA, an increased risk of serious infections has been seen with the combination of TNF blockers with anakinra or abatacept, with no added benefit; therefore, use of CYLTEZO with abatacept or anakinra is not recommended in patients with RA . A higher rate of serious infections has also been observed in patients with RA treated with rituximab who received subsequent treatment with a TNF blocker. There is insufficient information regarding the concomitant use of CYLTEZO and other biologic products for the treatment of RA, PsA, AS, CD, UC, and Ps. Concomitant administration of CYLTEZO with other biologic DMARDS (e.g., anakinra and abatacept) or other TNF blockers is not recommended based upon the possible increased risk for infections and other potential pharmacological interactions.

Live Vaccines

Avoid the use of live vaccines with CYLTEZO .

Cytochrome P450 Substrates

The formation of CYP450 enzymes may be suppressed by increased levels of cytokines (e.g., TNFα, IL-6) during chronic inflammation. It is possible for products that antagonize cytokine activity, such as with adalimumab products, to influence the formation of CYP450 enzymes. Upon initiation or discontinuation of CYLTEZO in patients being treated with CYP450 substrates with a narrow therapeutic index, monitoring of the effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) is recommended and the individual dose of the drug product may be adjusted as needed.

The most serious adverse reactions described elsewhere in the labeling include the following:

• Serious Infections
• Malignancies

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The most common adverse reaction with adalimumab was injection site reactions. In placebo-controlled trials, 20% of patients treated with adalimumab developed injection site reactions (erythema and/or itching, hemorrhage, pain or swelling), compared to 14% of patients receiving placebo. Most injection site reactions were described as mild and generally did not necessitate drug discontinuation.

The proportion of patients who discontinued treatment due to adverse reactions during the double-blind, placebo-controlled portion of studies in patients with RA (i.e., Studies RA-I, RA-II, RA-III and RA-IV) was 7% for patients taking adalimumab and 4% for placebo-treated patients. The most common adverse reactions leading to discontinuation of adalimumab in these RA studies were clinical flare reaction (0.7%), rash (0.3%) and pneumonia (0.3%).

Infections

In the controlled portions of the 34 global adalimumab clinical trials in adult patients with RA, PsA, AS, CD, UC and Ps, the rate of serious infections was 4.6 per 100 patient years in 7304 adalimumab treated patients versus a rate of 3.1 per 100 patient years in 4232 control treated patients. Serious infections observed included pneumonia, septic arthritis, prosthetic and post-surgical infections, erysipelas, cellulitis, diverticulitis, and pyelonephritis .

Tuberculosis And Opportunistic Infections

In 47 global controlled and uncontrolled clinical trials in RA, PsA, AS, CD, UC and Ps that included 23,036 adalimumab treated patients, the rate of reported active tuberculosis was 0.22 per 100 patient years and the rate of positive PPD conversion was 0.08 per 100 patient years. In a subgroup of 9396 U.S. and Canadian adalimumab treated patients, the rate of reported active TB was 0.07 per 100 patient years and the rate of positive PPD conversion was 0.08 per 100 patient years. These trials included reports of miliary, lymphatic, peritoneal, and pulmonary TB. Most of the TB cases occurred within the first eight months after initiation of therapy and may reflect recrudescence of latent disease. In these global clinical trials, cases of serious opportunistic infections have been reported at an overall rate of 0.05 per 100 patient-years. Some cases of serious opportunistic infections and TB have been fatal .

Autoantibodies

In the rheumatoid arthritis controlled trials, 12% of patients treated with adalimumab and 7% of placebo-treated patients that had negative baseline ANA titers developed positive titers at week 24. Two patients out of 3046 treated with adalimumab developed clinical signs suggestive of new-onset lupus-like syndrome. The patients improved following discontinuation of therapy. No patients developed lupus nephritis or central nervous system symptoms. The impact of long-term treatment with adalimumab products on the development of autoimmune diseases is unknown.

Liver Enzyme Elevations

There have been reports of severe hepatic reactions including acute liver failure in patients receiving TNF-blockers. In controlled Phase 3 trials of adalimumab (40 mg SC every other week) in patients with RA, PsA, and AS with control period duration ranging from 4 to 104 weeks, ALT elevations ≥ 3 x ULN occurred in 3.5% of adalimumab-treated patients and 1.5% of control-treated patients. Since many of these patients in these trials were also taking medications that cause liver enzyme elevations (e.g., NSAIDS, MTX), the relationship between adalimumab and the liver enzyme elevations is not clear. In a controlled Phase 3 trial of adalimumab in patients with polyarticular JIA who were 4 to 17 years, ALT elevations ≥ 3 x ULN occurred in 4.4% of adalimumab-treated patients and 1.5% of control-treated patients (ALT more common than AST); liver enzyme test elevations were more frequent among those treated with the combination of adalimumab and MTX than those treated with adalimumab alone. In general, these elevations did not lead to discontinuation of adalimumab treatment.

In controlled Phase 3 trials of adalimumab (initial doses of 160 mg and 80 mg, or 80 mg and 40 mg on Days 1 and 15, respectively, followed by 40 mg every other week) in adult patients with CD with a control period duration ranging from 4 to 52 weeks, ALT elevations ≥ 3 x ULN occurred in 0.9% of adalimumab-treated patients and 0.9% of control-treated patients. In controlled Phase 3 trials of adalimumab (initial doses of 160 mg and 80 mg on Days 1 and 15 respectively, followed by 40 mg every other week) in patients with UC with control period duration ranging from 1 to 52 weeks, ALT elevations ≥3 x ULN occurred in 1.5% of adalimumab-treated patients and 1.0% of control-treated patients. In controlled Phase 3 trials of adalimumab (initial dose of 80 mg  then 40 mg every other week) in patients with Ps with control period duration ranging from 12 to 24 weeks, ALT elevations ≥ 3 x ULN occurred in 1.8% of adalimumab-treated patients and 1.8% of control-treated patients.

Immunogenicity

Patients in Studies RA-I, RA-II, and RA-III were tested at multiple time points for antibodies to adalimumab during the 6-to 12 - month period. Approximately 5% (58 of 1062) of adult RA patients receiving adalimumab developed low-titer antibodies to adalimumab at least once during treatment, which were neutralizing in vitro. Patients treated with concomitant methotrexate (MTX) had a lower rate of antibody development than patients on adalimumab monotherapy (1% versus 12%). No apparent correlation of antibody development to adverse reactions was observed. With monotherapy, patients receiving every other week dosing may develop antibodies more frequently than those receiving weekly dosing. In patients receiving the recommended dosage of 40 mg every other week as monotherapy, the ACR 20 response was lower among antibody-positive patients than among antibody-negative patients. The long-term immunogenicity of adalimumab is unknown.

In patients with polyarticular JIA who were 4 to 17 years of age, adalimumab antibodies were identified in 16% of adalimumab - treated patients. In patients receiving concomitant MTX, the incidence was 6% compared to 26% with adalimumab monotherapy.

In patients with AS, the rate of development of antibodies to adalimumab in adalimumab-treated patients was comparable to patients with RA.

In patients with PsA, the rate of antibody development in patients receiving adalimumab monotherapy was comparable to patients with RA; however, in patients receiving concomitant MTX the rate was 7% compared to 1% in RA.

In adult patients with CD, the rate of antibody development was 3%.

In patients with moderately to severely active UC, the rate of antibody development in patients receiving adalimumab was 5%. However, due to the limitation of the assay conditions, antibodies to adalimumab could be detected only when serum adalimumab levels were < 2 mcg/mL. Among the patients whose serum adalimumab levels were < 2 mcg/mL (approximately 25% of total patients studied), the immunogenicity rate was 20.7%.

In patients with Ps, the rate of antibody development with adalimumab monotherapy was 8%. However, due to the limitation of the assay conditions, antibodies to adalimumab could be detected only when serum adalimumab levels were < 2 mcg/mL. Among the patients whose serum adalimumab levels were < 2 mcg/mL (approximately 40% of total patients studied), the immunogenicity rate was 20.7%. In Ps patients who were on adalimumab monotherapy and subsequently withdrawn from the treatment, the rate of antibodies to adalimumab after retreatment was similar to the rate observed prior to withdrawal.

The data reflect the percentage of patients whose test results were considered positive for antibodies to adalimumab or titers, and are highly dependent on the assay. The observed incidence of antibody (including neutralizing antibody) positivity in an assay is highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to adalimumab reported in this section with the incidence of antibodies in other studies or to other products may be misleading.

Other Adverse Reactions

Rheumatoid Arthritis Clinical Studies

The data described below reflect exposure to adalimumab in 2468 patients, including 2073 exposed for 6 months, 1497 exposed for greater than one year and 1380 in adequate and well-controlled studies (Studies RA-I, RA-II, RA-III, and RA-IV). Adalimumab was studied primarily in placebo-controlled trials and in long-term follow up studies for up to 36 months duration. The population had a mean age of 54 years, 77% were female, 91% were Caucasian and had moderately to severely active rheumatoid arthritis. Most patients received 40 mg adalimumab every other week.

Table 1 summarizes reactions reported at a rate of at least 5% in patients treated with adalimumab 40 mg every other week compared to placebo and with an incidence higher than placebo. In Study RA-III, the types and frequencies of adverse reactions in the second year open-label extension were similar to those observed in the one-year double-blind portion.

Table 1: Adverse Reactions Reported by ≥5% of Patients Treated with Adalimumab During Placebo-Controlled Period of Pooled RA Studies (Studies RA-I, RA-II, RA-III, and RA-IV)

Less Common Adverse Reactions In Rheumatoid Arthritis Clinical Studies

Other infrequent serious adverse reactions that do not appear in the Warnings and Precautions or Adverse Reaction sections that occurred at an incidence of less than 5% in adalimumab-treated patients in RA studies were:

Body As A Whole: Pain in extremity, pelvic pain, surgery, thorax pain

Cardiovascular System: Arrhythmia, atrial fibrillation, chest pain, coronary artery disorder, heart arrest, hypertensive encephalopathy, myocardial infarct, palpitation, pericardial effusion, pericarditis, syncope, tachycardia

Digestive System: Cholecystitis, cholelithiasis, esophagitis, gastroenteritis, gastrointestinal hemorrhage, hepatic necrosis, vomiting

Endocrine System: Parathyroid disorder

Hemic And Lymphatic System: Agranulocytosis, polycythemia

Metabolic And Nutritional Disorders: Dehydration, healing abnormal, ketosis, paraproteinemia, peripheral edema

Musculo-Skeletal System: Arthritis, bone disorder, bone fracture (not spontaneous), bone necrosis, joint disorder, muscle cramps, myasthenia, pyogenic arthritis, synovitis, tendon disorder

Neoplasia: Adenoma

Nervous System: Confusion, paresthesia, subdural hematoma, tremor

Respiratory System: Asthma, bronchospasm, dyspnea, lung function decreased, pleural effusion

Special Senses: Cataract

Thrombosis: Thrombosis leg

Urogenital System: Cystitis, kidney calculus, menstrual disorder

Juvenile Idiopathic Arthritis Clinical Studies

In general, the adverse reactions in the adalimumab-treated patients in the polyarticular juvenile idiopathic arthritis (JIA) trial (Study JIA-I) were similar in frequency and type to those seen in adult patients . Important findings and differences from adults are discussed in the following paragraphs.

In Study JIA-I, adalimumab was studied in 171 patients who were 4 to 17 years of age, with polyarticular JIA. Severe adverse reactions reported in the study included neutropenia, streptococcal pharyngitis, increased aminotransferases, herpes zoster, myositis, metrorrhagia, and appendicitis. Serious infections were observed in 4% of patients within approximately 2 years of initiation of treatment with adalimumab and included cases of herpes simplex, pneumonia, urinary tract infection, pharyngitis, and herpes zoster.

In Study JIA-I, 45% of patients experienced an infection while receiving adalimumab with or without concomitant MTX in the first 16 weeks of treatment. The types of infections reported in adalimumab-treated patients were generally similar to those commonly seen in polyarticular JIA patients who are not treated with TNF blockers. Upon initiation of treatment, the most common adverse reactions occurring in this patient population treated with adalimumab were injection site pain and injection site reaction (19% and 16%, respectively). A less commonly reported adverse event in patients receiving adalimumab was granuloma annulare which did not lead to discontinuation of adalimumab treatment.

In the first 48 weeks of treatment in Study JIA-I, non-serious hypersensitivity reactions were seen in approximately 6% of patients and included primarily localized allergic hypersensitivity reactions and allergic rash.

In Study JIA-I, 10% of patients treated with adalimumab who had negative baseline anti-dsDNA antibodies developed positive titers after 48 weeks of treatment. No patient developed clinical signs of autoimmunity during the clinical trial.

Approximately 15% of patients treated with adalimumab developed mild-to-moderate elevations of creatine phosphokinase (CPK) in Study JIA-I. Elevations exceeding 5 times the upper limit of normal were observed in several patients. CPK levels decreased or returned to normal in all patients. Most patients were able to continue adalimumab without interruption.

Psoriatic Arthritis And Ankylosing Spondylitis Clinical Studies

Adalimumab has been studied in 395 patients with psoriatic arthritis (PsA) in two placebo-controlled trials and in an open label study and in 393 patients with ankylosing spondylitis (AS) in two placebo-controlled studies. The safety profile for patients with PsA and AS treated with adalimumab 40 mg every other week was similar to the safety profile seen in patients with RA, adalimumab Studies RA-I through IV.

Adult Crohn"s Disease Clinical Studies

Adalimumab has been studied in 1478 adult patients with Crohn"s disease (CD) in four placebo-controlled and two open-label extension studies. The safety profile for adult patients with CD treated with adalimumab was similar to the safety profile seen in patients with RA.

Ulcerative Colitis Clinical Studies

Adalimumab has been studied in 1010 patients with ulcerative colitis (UC) in two placebo-controlled studies and one open-label extension study. The safety profile for patients with UC treated with adalimumab was similar to the safety profile seen in patients with RA.

Plaque Psoriasis Clinical Studies

Adalimumab has been studied in 1696 subjects with plaque psoriasis (Ps) in placebo-controlled and open-label extension studies. The safety profile for subjects with Ps treated with adalimumab was similar to the safety profile seen in subjects with RA with the following exceptions. In the placebo-controlled portions of the clinical trials in Ps subjects, adalimumab-treated subjects had a higher incidence of arthralgia when compared to controls (3% vs. 1%).

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of adalimumab products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to adalimumab products exposure.

Gastrointestinal disorders: Diverticulitis, large bowel perforations including perforations associated with diverticulitis and appendiceal perforations associated with appendicitis, pancreatitis

General disorders and administration site conditions: Pyrexia

Hepato-biliary disorders: Liver failure, hepatitis

Immune system disorders: Sarcoidosis

Neoplasms benign, malignant and unspecified (including cysts and polyps): Merkel Cell Carcinoma (neuroendocrine carcinoma of the skin)

Nervous system disorders: Demyelinating disorders (e.g., optic neuritis, Guillain-Barré syndrome), cerebrovascular accident

Respiratory disorders: Interstitial lung disease, including pulmonary fibrosis, pulmonary embolism

Skin reactions: Stevens Johnson Syndrome, cutaneous vasculitis, erythema multiforme, new or worsening psoriasis (all sub-types including pustular and palmoplantar), alopecia

Vascular disorders: Systemic vasculitis, deep vein thrombosis

Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately.

Mechanism Of Action

Adalimumab products bind specifically to TNF-alpha and block its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab products also lyse surface TNF expressing cells in vitro in the presence of complement. Adalimumab products do not bind or inactivate lymphotoxin (TNF-beta). TNF is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. Elevated levels of TNF are found in the synovial fluid of patients with RA, JIA, PsA, and AS and play an important role in both the pathologic inflammation and the joint destruction that are hallmarks of these diseases. Increased levels of TNF are also found in psoriasis plaques. In Ps, treatment with CYLETZO may reduce the epidermal thickness and infiltration of inflammatory cells. The relationship between these pharmacodynamic activities and the mechanism(s) by which adalimumab products exert their clinical effects is unknown.

Adalimumab products also modulate biological responses that are induced or regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10^-10M).

Pharmacodynamics

After treatment with adalimumab, a decrease in levels of acute phase reactants of inflammation (C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)) and serum cytokines (IL-6) was observed compared to baseline in patients with rheumatoid arthritis. A decrease in CRP levels was also observed in patients with Crohn"s disease and ulcerative colitis. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that produce tissue remodeling responsible for cartilage destruction were also decreased after adalimumab administration.

Pharmacokinetics

The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three studies following a single 40 mg subcutaneous dose was 64%. The pharmacokinetics of adalimumab were linear over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose.

The single dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The distribution volume (Vss) ranged from 4.7 to 6.0 L. The systemic clearance of adalimumab is approximately 12 mL/hr. The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. Adalimumab concentrations in the synovial fluid from five rheumatoid arthritis patients ranged from 31 to 96% of those in serum.

In RA patients receiving 40 mg adalimumab every other week, adalimumab mean steady-state trough concentrations of approximately 5 μg/mL and 8 to 9 μg/mL, were observed without and with methotrexate (MTX), respectively. MTX reduced adalimumab apparent clearance after single and multiple dosing by 29% and 44% respectively, in patients with RA. Mean serum adalimumab trough levels at steady state increased approximately proportionally with dose following 20, 40, and 80 mg every other week and every week subcutaneous dosing. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time.

Adalimumab mean steady-state trough concentrations were slightly higher in psoriatic arthritis patients treated with 40 mg adalimumab every other week (6 to 10 μg/mL and 8.5 to 12 μg/mL, without and with MTX, respectively) compared to the concentrations in RA patients treated with the same dose.

The pharmacokinetics of adalimumab in patients with AS were similar to those in patients with RA.

In patients with CD, the loading dose of 160 mg adalimumab on Week 0 followed by 80 mg adalimumab on Week 2 achieves mean serum adalimumab trough levels of approximately 12 μg/mL at Week 2 and Week 4. Mean steady-state trough levels of approximately 7 μg/mL were observed at Week 24 and Week 56 in CD patients after receiving a maintenance dose of 40 mg adalimumab every other week.

In patients with UC, the loading dose of 160 mg adalimumab on Week 0 followed by 80 mg adalimumab on Week 2 achieves mean serum adalimumab trough levels of approximately 12 μg/mL at Week 2 and Week 4. Mean steady-state trough level of approximately 8 μg/mL was observed at Week 52 in UC patients after receiving a dose of 40 mg adalimumab every other week, and approximately 15 μg/mL at Week 52 in UC patients who increased to a dose of 40 mg adalimumab every week.

In patients with Ps, the mean steady-state trough concentration was approximately 5 to 6 μg/mL during adalimumab 40 mg every other week monotherapy treatment.

Population pharmacokinetic analyses in patients with RA revealed that there was a trend toward higher apparent clearance of adalimumab in the presence of anti-adalimumab antibodies, and lower clearance with increasing age in patients aged 40 to >75 years.

Minor increases in apparent clearance were also predicted in RA patients receiving doses lower than the recommended dose and in RA patients with high rheumatoid factor or CRP concentrations. These increases are not likely to be clinically important.

No gender-related pharmacokinetic differences were observed after correction for a patient"s body weight. Healthy volunteers and patients with rheumatoid arthritis displayed similar adalimumab pharmacokinetics.

No pharmacokinetic data are available in patients with hepatic or renal impairment.

In Study JIA-I for patients with polyarticular JIA the mean steady-state trough serum adalimumab concentrations for patients weighing ≥30 kg receiving 40 mg adalimumab subcutaneously every other week as monotherapy or with concomitant MTX were 6.6 μg/mL and 8.1 μg/mL, respectively.

Clinical Studies

Rheumatoid Arthritis

The efficacy and safety of adalimumab were assessed in five randomized, double-blind studies in patients ≥18 years of age with active rheumatoid arthritis (RA) diagnosed according to American College of Rheumatology (ACR) criteria. Patients had at least 6 swollen and 9 tender joints. Adalimumab was administered subcutaneously in combination with methotrexate (MTX) (12.5 to 25 mg, Studies RA-I, RA-III and RA-V) or as monotherapy (Studies RA-II and RA-V) or with other disease-modifying anti-rheumatic drugs (DMARDs) (Study RA-IV).

Study RA-I evaluated 271 patients who had failed therapy with at least one but no more than four DMARDs and had inadequate response to MTX. Doses of 20, 40 or 80 mg of adalimumab or placebo were given every other week for 24 weeks.

Study RA-II evaluated 544 patients who had failed therapy with at least one DMARD. Doses of placebo, 20 or 40 mg of adalimumab were given as monotherapy every other week or weekly for 26 weeks.

Study RA-III evaluated 619 patients who had an inadequate response to MTX. Patients received placebo, 40 mg of adalimumab every other week with placebo injections on alternate weeks, or 20 mg of adalimumab weekly for up to 52 weeks. Study RA-III had an additional primary endpoint at 52 weeks of inhibition of disease progression (as detected by X-ray results). Upon completion of the first 52 weeks, 457 patients enrolled in an open-label extension phase in which 40 mg of adalimumab was administered every other week for up to 5 years.

Study RA-IV assessed safety in 636 patients who were either DMARD-naive or were permitted to remain on their pre-existing rheumatologic therapy provided that therapy was stable for a minimum of 28 days. Patients were randomized to 40 mg of adalimumab or placebo every other week for 24 weeks.

Study RA-V evaluated 799 patients with moderately to severely active RA of less than 3 years duration who were ≥18 years old and MTX naïve. Patients were randomized to receive either MTX (optimized to 20 mg/week by week 8), adalimumab 40 mg every other week or adalimumab/MTX combination therapy for 104 weeks. Patients were evaluated for signs and symptoms, and for radiographic progression of joint damage. The median disease duration among patients enrolled in the study was 5 months. The median MTX dose achieved was 20 mg.

Clinical Response

The percent of adalimumab treated patients achieving ACR 20, 50 and 70 responses in Studies RA-II and III are shown in Table 2.

Table 2: ACR Responses in Studies RA-II and RA-III (Percent of Patients)

The results of Study RA-I were similar to Study RA-III; patients receiving adalimumab 40 mg every other week in Study RA-I also achieved ACR 20, 50 and 70 response rates of 65%, 52% and 24%, respectively, compared to placebo responses of 13%, 7% and 3% respectively, at 6 months (p<0.01).

The results of the components of the ACR response criteria for Studies RA-II and RA-III are shown in Table 3. ACR response rates and improvement in all components of ACR response were maintained to week 104. Over the 2 years in Study RA-III, 20% of adalimumab patients receiving 40 mg every other week (EOW) achieved a major clinical response, defined as maintenance of an ACR 70 response over a 6-month period. ACR responses were maintained in similar proportions of patients for up to 5 years with continuous adalimumab treatment in the open-label portion of Study RA-III.

Table 3: Components of ACR Response in Studies RA-II and RA-III

The time course of ACR 20 response for Study RA-III is shown in Figure 1.

In Study RA-III, 85% of patients with ACR 20 responses at week 24 maintained the response at 52 weeks. The time course of ACR 20 response for Study RA-I and Study RA-II were similar.

Figure 1: Study RA-III ACR 20 Responses over 52 Weeks

In Study RA-IV, 53% of patients treated with adalimumab 40 mg every other week plus standard of care had an ACR 20 response at week 24 compared to 35% on placebo plus standard of care (p<0.001). No unique adverse reactions related to the combination of adalimumab and other DMARDs were observed.

In Study RA-V with MTX naïve patients with recent onset RA, the combination treatment with adalimumab plus MTX led to greater percentages of patients achieving ACR responses than either MTX monotherapy or adalimumab monotherapy at Week 52 and responses were sustained at Week 104 .

Table 4: ACR Response in Study RA-V (Percent of Patients)

At Week 52, all individual components of the ACR response criteria for Study RA-V improved in the adalimumab/MTX group and improvements were maintained to Week 104.

Radiographic Response

In Study RA-III, structural joint damage was assessed radiographically and expressed as change in Total Sharp Score (TSS) and its components, the erosion score and Joint Space Narrowing (JSN) score, at month 12 compared to baseline. At baseline, the median TSS was approximately 55 in the placebo and 40 mg every other week groups. The results are shown in Table 5. Adalimumab/MTX treated patients demonstrated less radiographic progression than patients receiving MTX alone at 52 weeks.

Table 5: Radiographic Mean Changes Over 12 Months in Study RA-III

In the open-label extension of Study RA-III, 77% of the original patients treated with any dose of adalimumab were evaluated radiographically at 2 years. Patients maintained inhibition of structural damage, as measured by the TSS. Fifty-four percent had no progression of structural damage as defined by a change in the TSS of zero or less. Fifty-five percent (55%) of patients originally treated with 40 mg adalimumab every other week have been evaluated radiographically at 5 years. Patients had continued inhibition of structural damage with 50% showing no progression of structural damage defined by a change in the TSS of zero or less.

In Study RA-V, structural joint damage was assessed as in Study RA-III. Greater inhibition of radiographic progression, as assessed by changes in TSS, erosion score and JSN was observed in the adalimumab/MTX combination group as compared to either the MTX or adalimumab monotherapy group at Week 52 as well as at Week 104 .

Table 6: Radiographic Mean Change* in Study RA-V

Physical Function Response

In studies RA-I through IV, adalimumab showed significantly greater improvement than placebo in the disability index of Health Assessment Questionnaire (HAQ-DI) from baseline to the end of study, and significantly greater improvement than placebo in the health-outcomes as assessed by The Short Form Health Survey (SF 36). Improvement was seen in both the Physical Component Summary (PCS) and the Mental Component Summary (MCS).

In Study RA-III, the mean (95% CI) improvement in HAQ-DI from baseline at week 52 was 0.60 (0.55, 0.65) for the adalimumab patients and 0.25 (0.17, 0.33) for placebo/MTX (p<0.001) patients. Sixty-three percent of adalimumab-treated patients achieved a 0.5 or greater improvement in HAQ-DI at week 52 in the double-blind portion of the study. Eighty-two percent of these patients maintained that improvement through week 104 and a similar proportion of patients maintained this response through week 260 (5 years) of open-label treatment. Mean improvement in the SF-36 was maintained through the end of measurement at week 156 (3 years).

In Study RA-V, the HAQ-DI and the physical component of the SF-36 showed greater improvement (p<0.001) for the adalimumab/MTX combination therapy group versus either the MTX monotherapy or the adalimumab monotherapy group at Week 52, which was maintained through Week 104.

Juvenile Idiopathic Arthritis

The safety and efficacy of adalimumab was assessed in two studies (Studies JIA-I and JIA-II) in patients with active polyarticular juvenile idiopathic arthritis (JIA).

Study JIA-I

The safety and efficacy of adalimumab were assessed in a multicenter, randomized, withdrawal, double-blind, parallel-group study in 171 patients who were 4 to 17 years of age with polyarticular JIA. In the study, the patients were stratified into two groups: MTX-treated or non-MTX-treated. All patients had to show signs of active moderate or severe disease despite previous treatment with NSAIDs, analgesics, corticosteroids, or DMARDS. Patients who received prior treatment with any biologic DMARDS were excluded from the study.

The study included four phases: an open-label lead in phase (OL-LI; 16 weeks), a double-blind randomized withdrawal phase (DB; 32 weeks), an open-label extension phase (OLE-BSA; up to 136 weeks), and an open-label fixed dose phase (OLE-FD; 16 weeks). In the first three phases of the study, adalimumab was administered based on body surface area at a dose of 24 mg/m² up to a maximum total body dose of 40 mg subcutaneously (SC) every other week. In the OLE-FD phase, the patients were treated with 20 mg of adalimumab SC every other week if their weight was less than 30 kg and with 40 mg of adalimumab SC every other week if their weight was 30 kg or greater. Patients remained on stable doses of NSAIDs and or prednisone (≤0.2 mg/kg/day or 10 mg/day maximum).

Patients demonstrating a Pediatric ACR 30 response at the end of OL-LI phase were randomized into the double blind (DB) phase of the study and received either adalimumab or placebo every other week for 32 weeks or until disease flare. Disease flare was defined as a worsening of ≥30% from baseline in ≥3 of 6 Pediatric ACR core criteria, ≥2 active joints, and improvement of >30% in no more than 1 of the 6 criteria. After 32 weeks or at the time of disease flare during the DB phase, patients were treated in the open-label extension phase based on the BSA regimen (OLE-BSA), before converting to a fixed dose regimen based on body weight (OLE-FD phase).

Study JIA-I Clinical Response

At the end of the 16-week OL-LI phase, 94% of the patients in the MTX stratum and 74% of the patients in the non-MTX stratum were Pediatric ACR 30 responders. In the DB phase significantly fewer patients who received adalimumab experienced disease flare compared to placebo, both without MTX (43% vs. 71%) and with MTX (37% vs. 65%). More patients treated with adalimumab continued to show pediatric ACR 30/50/70 responses at Week 48 compared to patients treated with placebo. Pediatric ACR responses were maintained for up to two years in the OLE phase in patients who received adalimumab throughout the study.

Psoriatic Arthritis

The safety and efficacy of adalimumab was assessed in two randomized, double-blind, placebo controlled studies in 413 patients with psoriatic arthritis (PsA). Upon completion of both studies, 383 patients enrolled in an open-label extension study, in which 40 mg adalimumab was administered every other week.

Study PsA-I enrolled 313 adult patients with moderately to severely active PsA (>3 swollen and >3 tender joints) who had an inadequate response to NSAID therapy in one of the following forms: (1) distal interphalangeal (DIP) involvement (N=23); (2) polyarticular arthritis (absence of rheumatoid nodules and presence of plaque psoriasis) (N=210); (3) arthritis mutilans (N=1); (4) asymmetric PsA (N=77); or (5) AS-like (N=2). Patients on MTX therapy (158 of 313 patients) at enrollment (stable dose of ≤30 mg/week for >1 month) could continue MTX at the same dose. Doses of adalimumab 40 mg or placebo every other week were administered during the 24-week double-blind period of the study.

Compared to placebo, treatment with adalimumab resulted in improvements in the measures of disease activity . Among patients with PsA who received adalimumab, the clinical responses were apparent in some patients at the time of the first visit (two weeks) and were maintained up to 88 weeks in the ongoing open-label study. Similar responses were seen in patients with each of the subtypes of psoriatic arthritis, although few patients were enrolled with the arthritis mutilans and ankylosing spondylitis-like subtypes. Responses were similar in patients who were or were not receiving concomitant MTX therapy at baseline.

Patients with psoriatic involvement of at least three percent body surface area (BSA) were evaluated for Psoriatic Area and Severity Index (PASI) responses. At 24 weeks, the proportions of patients achieving a 75% or 90% improvement in the PASI were 59% and 42% respectively, in the adalimumab group (N=69), compared to 1% and 0% respectively, in the placebo group (N=69) (p<0.001). PASI responses were apparent in some patients at the time of the first visit (two weeks). Responses were similar in patients who were or were not receiving concomitant MTX therapy at baseline.

Table 7: ACR Response in Study PsA-I (Percent of Patients)

Table 8: Components of Disease Activity in Study PsA-I

Similar results were seen in an additional, 12-week study in 100 patients with moderate to severe psoriatic arthritis who had suboptimal response to DMARD therapy as manifested by ≥3 tender joints and ≥3 swollen joints at enrollment.

Radiographic Response

Radiographic changes were assessed in the PsA studies. Radiographs of hands, wrists, and feet were obtained at baseline and Week 24 during the double-blind period when patients were on adalimumab or placebo and at Week 48 when all patients were on open-label adalimumab. A modified Total Sharp Score (mTSS), which included distal interphalangeal joints (i.e., not identical to the TSS used for rheumatoid arthritis), was used by readers blinded to treatment group to assess the radiographs.

Adalimumab-treated patients demonstrated greater inhibition of radiographic progression compared to placebo-treated patients and this effect was maintained at 48 we

Dosage Forms And Strengths

Prefilled Syringe

Injection: 40 mg/0.8 mL of CYLTEZO is a clear to slightly opalescent and colorless to slightly yellow solution provided by a single-use, 1 mL prefilled glass syringe with a fixed 27 gauge, ½ inch needle and a gray inner needle cap.

Storage And Handling

CYLTEZO™(adalimumab-adbm) injection is supplied as a preservative-free, sterile, clear to slightly opalescent and colorless to slightly yellow solution for subcutaneous administration. The following packaging configurations are available.

Prefilled Syringe Carton -40 mg/0.8 mL

CYLTEZO is supplied in a carton containing two alcohol preps and two dose trays. Each dose tray consists of a single-use, 1 mL prefilled glass syringe with a fixed 27 gauge, ½ inch needle, providing 40 mg/0.8 mL of CYLTEZO. The gray inner needle cap contains natural rubber latex. The NDC number is 0597-0370-82.

Storage And Stability

Do not use beyond the expiration date on the container. CYLTEZO must be refrigerated at 36°F to 46°F (2°C to 8°C). DO NOT FREEZE. Do not use if frozen even if it has been thawed.

Store in original carton until time of administration to protect from light.

If needed, for example when traveling, CYLTEZO may be stored at room temperature up to a maximum of 77°F (25°C) for a period of up to 14 days, with protection from light. CYLTEZO should be discarded if not used within the 14-day period. Record the date when CYLTEZO is first removed from the refrigerator in the spaces provided on the carton.

Do not store CYLTEZO in extreme heat or cold.

Manufactured by: Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877 USA. Revised: Aug 2017