CinnoRA®


(Adalimumab)


INDICATIONS AND USAGE

Rheumatoid Arthritis

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

Juvenile Idiopathic Arthritis

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

Psoriatic Arthritis

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

Ankylosing Spondylitis

CinnoRA® is indicated for reducing signs and symptoms in adult patients with active ankylosing Spondylitis.

Adult Crohn’s Disease

CinnoRA® 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. CinnoRA® 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.

Pediatric Crohn’s Disease

CinnoRA® 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 who have had an inadequate response to corticosteroids or immunomodulators such as azathioprine, 6-mercaptopurine, or methotrexate.

Ulcerative Colitis

CinnoRA® 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 CinnoRA® has not been established in patients who have lost response to or were intolerant to TNF blockers.

Plaque Psoriasis

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

Hidradenitis Suppurativa

CinnoRA® is indicated for the treatment of moderate to severe hidradenitis suppurativa.

Uveitis

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

DOSAGE AND ADMINISTRATION

CinnoRA® is administered by subcutaneous injection.

Rheumatoid Arthritis, Psoriatic Arthritis, and Ankylosing Spondylitis

The recommended dose of CinnoRA® 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 CinnoRA®. In the treatment of RA, some patients not taking concomitant MTX may derive additional benefit from increasing the dosing frequency of CinnoRA® to 40 mg every week.

Juvenile Idiopathic Arthritis

The recommended dose of CinnoRA® for patients 2 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 adalimumab.

Patients

(2 years of age and older)
Dose
10 kg (22 lbs) to <15 kg (33 lbs) 10 mg every other week
15 kg (33 lbs) to <30 kg (66 lbs) 20 mg every other week
≥30 kg (66 lbs) 40 mg every other week

Adalimumab has 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 CinnoRA® dose regimen for adult patients with Crohn’s disease (CD) is 160 mg initially on Day 1 (given as four 40 mg injections in one day or as two 40 mg injections per day for two consecutive days), followed by 80 mg two weeks later (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 CinnoRA®. Azathioprine, 6-mercaptopurine (6-MP) or MTX may be continued during treatment with CinnoRA® if necessary. The use of Adalimumab in CD beyond one year has not been evaluated in controlled clinical studies.

Pediatric Crohn’s Disease

The recommended CinnoRA® dose regimen for pediatric patients 6 years of age and older with Crohn’s disease (CD) is based on body weight as shown below:

Pediatric Patients Induction Dose Maintenance Dose Starting at Week 4 (Day 29)

17 kg (37 lbs) to

< 40 kg (88 lbs)
  • 80 mg on Day 1 (administered as two 40 mg injections in one day); and
  • 40 mg two weeks later (on Day 15)
20 mg every other week
≥ 40 kg (88 lbs)
  • 160 mg on Day 1 (administered as four injections in one day or as two 40 mg injections per day for two consecutive days); and
  • 80 mg two weeks later (on Day 15) (administered as two 40 mg injections in one day)
40 mg every other week

Ulcerative Colitis

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

Only continue CinnoRA® in patients who have shown evidence of clinical remission by eight weeks (Day 57) of therapy. Aminosalicylates and/or corticosteroids may be continued during treatment with CinnoRA®. Azathioprine and 6-mercaptopurine (6-MP) may be continued during treatment with CinnoRA® if necessary.

Plaque Psoriasis or Uveitis

The recommended dose of CinnoRA® for adult patients with plaque psoriasis (Ps) or Uveitis (UV) 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 in moderate to severe chronic Ps beyond one year has not been evaluated in controlled clinical studies.

Hidradenitis Suppurativa

The recommended dose of CinnoRA® for adult patients with hidradenitis suppurativa (HS) is 160 mg (given as four 40 mg injections on Day 1 or as two 40 mg injections per day on Days 1 and 2), followed by 80 mg two weeks later (Day 15). Begin 40 mg weekly dosing two weeks later (Day 29).

Monitoring to Assess Safety

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

General Considerations for Administration

CinnoRA® is intended for use under the guidance and supervision of a physician. A patient may self-inject CinnoRA® or a caregiver may inject CinnoRA® using prefilled syringe in Auto Injector Device 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 CinnoRA® 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 prefilled syringe for particulate matter and discoloration prior to subcutaneous administration. If particulates and discolorations are noted, do not use the product. CinnoRA® does not contain preservatives; therefore, discard unused portions of drug remaining from the syringe.

Instruct patients using the CinnoRA® 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.

 

 

DOSAGE FORMS AND STRENGTHS

Prefilled Syringe:

Injection: 40 mg/0.8 mL of CinnoRA® is provided by a single-use, sterile Pre-filled syringe in Auto Injector Device

0.8 mL prefilled glass syringe with a fixed 29 gauge, ½ inch needle and a gray needle cover.

WARNINGS AND PRECAUTIONS

Serious Infections

Patients treated with adalimumab are at increased risk for developing serious infections involving various organ systems and sites that may lead to hospitalization or death [see Boxed Warning]. 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

adalimumab and these biologic products is not recommended in the treatment of patients with RA.

Treatment with adalimumab 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, 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 adalimumab 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 adalimumab, 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 adalimumab 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. 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 adalimumab 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 adalimumab, 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 adalimumab.

Discontinue adalimumab if a patient develops a serious infection or sepsis. For a patient who develops a new infection during treatment with adalimumab, 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 adalimumab 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, more cases of malignancies have been observed among TNF-blocker-treated adult patients compared to control treated adult patients. During the controlled portions of 39 global adalimumab clinical trials in adult patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), Crohn’s disease (CD), ulcerative colitis (UC), plaque psoriasis (Ps), hidradenitis suppurativa (HS) and uveitis (UV), malignancies, other than non-melanoma (basal cell and squamous cell) skin cancer, were observed at a rate (95% confidence interval) of 0.7 (0.48, 1.03) per 100 patient-years among 7973 adalimumab treated patients versus a rate of 0.7 (0.41, 1.17) per 100 patient-years among 4848 control-treated patients (median duration of treatment of 4 months for adalimumab -treated patients and 4 months for control-treated patients). In 52 global controlled and uncontrolled clinical trials of adalimumab in adult patients with RA, PsA, AS, CD, UC, Ps, HS and UV the most frequently observed malignancies, other than lymphoma and NMSC, were breast, colon, prostate, lung, and melanoma. The malignancies in adalimumab-treated 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).

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 39 global adalimumab clinical trials in adult patients with RA, PsA, AS, CD, UC, Ps, HS and UV, the rate (95% confidence interval) of NMSC was 0.8 (0.52, 1.09) per 100 patient-years among adalimumab-treated patients and 0.2 (0.10, 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 adalimumab.

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 39 global adalimumab clinical trials in adult patients with RA, PsA, AS, CD, UC, Ps, HS and UV, 2 lymphomas occurred among 7973 adalimumab -treated patients versus 1 among 4848 control-treated patients. In 52 global controlled and uncontrolled clinical trials of adalimumab in adult patients with RA, PsA, AS, CD, UC, Ps, HS and UV with a median duration of approximately 0.7 years, including 24,605 patients and over 40,215 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). 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 adalimumab 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 post marketing reports.

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 adalimumab. 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 should be carefully considered.

Hypersensitivity Reactions

Anaphylaxis and angioneurotic edema have been reported following adalimumab administration. If an anaphylactic or other serious allergic reaction occurs, immediately discontinue administration of adalimumab and institute appropriate therapy. In clinical trials of adalimumab 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 adalimumab, 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 adalimumab 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 adalimumab therapy in this situation and monitor patients closely.

Neurologic Reactions

Use of TNF blocking agents, including adalimumab, has 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 adalimumab in patients with preexisting or recent-onset central or peripheral nervous system demyelinating disorders; discontinuation of adalimumab should be considered if any of these disorders develop. There is a known association between intermediate uveitis and central demyelinating disorders.

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. The causal relationship of these reports to adalimumab 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 adalimumab. Consider discontinuation of adalimumab 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 adalimumab 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 has 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 adalimumab in patients who have heart failure and monitor them carefully.

Autoimmunity

Treatment with adalimumab 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 adalimumab, 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 adalimumab 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.

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 adalimumab therapy. Patients on adalimumab may receive concurrent vaccinations, except for live vaccines.

The safety of administering live or live-attenuated vaccines in infants exposed to adalimumab 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 adalimumab is not recommended.

ADVERSE REACTIONS

Adverse Reactions Significant

 

>10%:

Central nervous system: Headache (12%)

Dermatologic: Rash (6% to 12%)

Local: Injection site reaction (12% to 20%; includes erythema, itching, hemorrhage, pain, swelling)

Neuromuscular & skeletal: CPK increased (15%)

Respiratory: Upper respiratory tract infection (17%), sinusitis (11%)

Miscellaneous: Serious infection (adults 1.4-6.7 events/100 person years, children 2 events/100 person years [Burmester, 2012]), antibodies to adalimumab (3% to 26%; significance unknown), positive ANA (12%)

 

5% to 10%:

Cardiovascular: Hypertension (5%)

Endocrine & metabolic: Hyperlipidemia (7%), hypercholesterolemia (6%)

Gastrointestinal: Nausea (9%), abdominal pain (7%)

Genitourinary: Urinary tract infection (8%)

Hepatic: Alkaline phosphatase increased (5%)

Local: Injection site reaction (8%; other than erythema, itching, hemorrhage, pain, swelling)

Neuromuscular & skeletal: Back pain (6%)

Renal: Hematuria (5%)

Miscellaneous: Accidental injury (10%), flu-like syndrome (7%), hypersensitivity reactions (children 6%; adults <1%)

 

1% to 5%:

Cardiovascular: Arrhythmia, atrial fibrillation, chest pain, CHF, coronary artery disorder, deep vein thrombosis, heart arrest, MI, palpitation, pericardial effusion, pericarditis, peripheral edema, syncope, tachycardia, vascular disorder

Central nervous system: Confusion, fever, hypertensive encephalopathy, multiple sclerosis, subdural hematoma

Dermatologic: Alopecia, cellulitis, erysipelas

Endocrine & metabolic: Dehydration, menstrual disorder, parathyroid disorder

Gastrointestinal: Diverticulitis, esophagitis, gastroenteritis, gastrointestinal hemorrhage, vomiting

Genitourinary: Cystitis, pelvic pain

Hematologic: Agranulocytosis, granulocytopenia, leukopenia, pancytopenia, paraproteinemia, polycythemia

Hepatic: Cholecystitis, cholelithiasis, hepatic necrosis

Neuromuscular & skeletal: Arthralgia, arthritis, bone fracture, bone necrosis, joint disorder, muscle cramps, myasthenia, pain in extremity, paresthesia, pyogenic arthritis, synovitis, tendon disorder, tremor

Ocular: Cataract

Renal: Kidney calculus, pyelonephritis

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

Miscellaneous: Adenoma, allergic reactions (1%), carcinoma (including breast, gastrointestinal, skin, urogenital), healing abnormality, herpes zoster, ketosis, lupus erythematosus syndrome, lymphoma, melanoma, postsurgical infection, sepsis, tuberculosis (reactivation of latent infection; miliary, lymphatic, peritoneal and pulmonary)

 

<1% (Limited to important or life-threatening):

Abscess (limb, perianal), anal fistula, anaphylactoid reaction, anaphylaxis, angioedema, aplastic anemia, appendicitis, basal cell carcinoma, cerebrovascular accident, cervical dysplasia, circulatory collapse, cutaneous vasculitis, cytopenia, endometrial hyperplasia, erythema multiforme, fixed drug eruption, granuloma annulare (children and adolescents), Guillain-Barré syndrome, HBV reactivation, hepatic failure, herpes virus infection, histoplasmosis, infections (bacterial, viral, fungal and protozoal), interstitial lung disease (eg, pulmonary fibrosis), intestinal obstruction, intestinal perforation, leukemias, liver metastases, lupus-like syndrome, lymphadenopathy, lymphocytosis, mycobacterium avium complex infection, myositis (children and adolescents), necrotizing fasciitis, neutropenia, optic neuritis, ovarian cancer, pancreatitis, pharyngitis (children and adolescents), psoriasis (including new onset, palmoplantar, pustular, or exacerbation), pulmonary embolism, respiratory failure, sarcoidosis, septic arthritis, septic shock, skin ulceration, Stevens-Johnson syndrome, streptococcal pharyngitis (children and adolescents), systemic vasculitis, testicular cancer, thrombocytopenia, transaminases increased, viral meningitis.

DRUG INTERACTIONS

Methotrexate

Adalimumab has been studied in rheumatoid arthritis (RA) patients taking concomitant methotrexate (MTX).

Although MTX reduced the apparent adalimumab clearance, the data do not suggest the need for dose adjustment of either adalimumab 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 adalimumab 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 adalimumab and other biologic products for the treatment of RA, PsA, AS, CD, UC, Ps, HS and UV. Concomitant administration of CinnoRA® 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 CinnoRA®.

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 a molecule that antagonizes cytokine activity, such as adalimumab, to influence the formation of CYP450 enzymes. Upon initiation or discontinuation of adalimumab 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.

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 is 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 miscarriage is 15-20%, 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 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 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 adalimumab and any potential adverse effects on the breastfed child from adalimumab or from the underlying maternal condition.

pediatric use

Safety and efficacy of Adalimumab in pediatric patients for uses other than polyarticular juvenile idiopathic arthritis (JIA) and pediatric Crohn’s disease have not been established. Due to its inhibition of TNFα, adalimumab 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.

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. In Study JIA-II, the safety profile for patients 2 to <4 years of age was similar to the safety profile for patients 4 to 17 years of age with polyarticular JIA. Adalimumab has 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.

Pediatric Crohn’s Disease

The safety and effectiveness of adalimumab for reducing signs and symptoms and inducing and maintaining clinical remission have been established in pediatric patients 6 years of age and older with moderately to severely active Crohn’s disease who have had an inadequate response to corticosteroids or immunomodulators such as azathioprine, 6-mercaptopurine, or methotrexate. Use of adalimumab in this age group is supported by evidence from adequate and well-controlled studies of adalimumab in adults with additional data from a randomized, double-blind, 52-week clinical study of two dose levels of adalimumab in 192 pediatric patients (6 to 17 years of age) with moderately to severely active Crohn’s disease. The safety and effectiveness of adalimumab has not been established in pediatric patients with Crohn’s disease less than 6 years of age.

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.

OVERDOSAGE

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.

DESCRIPTION

CinnoRA® (adalimumab) is a recombinant human IgG1 monoclonal antibody specific for human tumor necrosis factor (TNF). Adalimumab was created using phage display technology resulting in an antibody with human derived heavy and light chain variable regions and human IgG1:k constant regions.

CinnoRA® is produced by recombinant DNA technology in a mammalian cell expression system and is purified by a process that includes specific viral inactivation and removal steps. It consists of 1330 amino acids and has a molecular weight of approximately 148 kilodaltons.

CinnoRA® is supplied as a sterile, preservative-free solution of adalimumab for subcutaneous administration.

The drug product is supplied as a 0.8 mL single-use pre-filled syringe in Auto Injector Device. The solution of CinnoRA® is clear and colorless, with a pH of about 5-5.5.

Each 40 mg/0.8 mL prefilled syringe, delivers 0.8 mL (40 mg) of drug product. Each 0.8 mL of CinnoRA® contains adalimumab 40 mg, citric acid monohydrate 1.04 mg, dibasic sodium phosphate dihydrate 1.22 mg, mannitol 9.6 mg, monobasic sodium phosphate dihydrate 0.69 mg, polysorbate 80 0.8 mg, sodium chloride 4.93 mg, sodium citrate 0.24 mg and Water for Injection, EP.

CLINICAL PHARMACOLOGY

Mechanism of action

Adalimumab binds specifically to TNF-alpha and blocks its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface TNF expressing cells in vitro in the presence of complement. Adalimumab does 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 CinnoRA® may reduce the epidermal thickness and infiltration of inflammatory cells. The relationship between these pharmacodynamic activities and the mechanism(s) by which CinnoRA® exerts its clinical effects is unknown.

Adalimumab also modulates biological responses that are induced or regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 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, ulcerative colitis and hidradenitis suppurativa. 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. In subjects with HS, a dose of 160 mg adalimumab on Week 0 followed by 80 mg on Week 2 achieved serum adalimumab trough concentrations of approximately 7 to 8 µg/mL at Week 2 and Week 4. The mean steady-state trough concentrations at Week 12 through Week 36 were approximately 7 to 11 µg/mL during adalimumab 40 mg every week treatment.

In patients with UV, the mean steady concentration was approximately 8 to 10 µg/mL during adalimumab 40 mg every other week 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 who were 4 to 17 years of age, the mean steady-state trough serum adalimumab concentrations for patients weighing <30 kg receiving 20 mg adalimumab subcutaneously every other week as monotherapy or with concomitant MTX were 6.8 µg/mL and 10.9 µg/mL, respectively. 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. In Study JIA-II for patients with polyarticular JIA who were 2 to <4 years of age or 4 years of age and older weighing <15 kg, the mean steady-state trough serum adalimumab concentrations for patients receiving adalimumab subcutaneously every other week as monotherapy or with concomitant MTX were 6.0 µg/mL and 7.9 µg/mL, respectively. In pediatric subjects with CD weighing ≥ 40 kg, the mean ±SD serum adalimumab concentrations were 15.7±6.5 mcg/mL at Week 4 following subcutaneous doses of 160 mg at Week 0 and 80 mg at Week 2 and the mean ±SD steady-state trough serum adalimumab concentrations were 10.5±6.0 mcg/mL at Week 52 following subcutaneous doses of 40 mg every other week. In pediatric subjects with CD weighing < 40 kg, the mean ±SD serum adalimumab concentrations were 10.6±6.1 mcg/mL at Week 4 following subcutaneous doses of 80 mg at Week 0 and 40 mg at Week 2 and the mean ±SD steady-state trough serum adalimumab concentrations were 6.9±3.6 mcg/mL at Week 52 following subcutaneous doses of 20 mg every other week.

 

 

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

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

CLINICAL STUDIES

The safety and efficacy of CinnoRA® were assessed in a randomized, double-blind, active-controlled study. This Study have finished in August 2016.

In this study, the efficacy and safety of a locally developed Adalimumab, CinnoRA®, and Humira® were compared on the patients with active Rheumatoid Arthritis.

This was a non-inferiority randomized double-blind parallel clinical trial. In this study, the efficacy and safety of CinnoRA® and Humira® were evaluated in 136 patients with active Rheumatoid Arthritis who met the inclusion/exclusion criteria.

The percentage of the patients, who have met DAS based EULAR good and moderate response, was measured after 3 and 6 months of treatment and was compared between two groups.

The primary endpoint of the study was to compare the percentage of patients who have met DAS based EULAR good and moderate response. After signing the written informed consents, a total of 136 patients have been randomized and assigned to receive CinnoRA® or Humira® over a six-month period (group A=68, group B=68). Every 2 weeks, 40 mg of either of the drugs was administered to each patient subcutaneously. The percentage of patients who met ACR 20/50/70 criteria were reported as well as the frequency of adverse events. The data was analyzed through STATA ver.11, using both parametric and non-parametric tests. P≤0.05 was considered as a statistically significant value.

According to the results, there is no statistically significant difference in the percentage of subjects meeting DAS based EULAR good and moderate response in the 3rd and 6th months of the trial between CinnoRA® and Humira® groups.

Evaluating each of the seven parts of ACR criteria in the 3rd and 6th months of the trial showed no significant differences between two groups. There is no statistically significant difference in the percentage of patients who have improved according to criteria of ACR 20 in the 3rd and 6th months of the trial. Furthermore, ACR 50 and ACR 70 of the American College of Rheumatology criteria proved that drug effectiveness for both treatment groups were comparable to each other after 3 and 6 months.

According to the study findings, there is no statistically significant difference in the efficacy and safety between CinnoRA® and Humira® groups.

Finally it is concluded that these two drugs are similar in safety and efficacy for treatment of patients with active rheumatoid arthritis.

HOW SUPPLIED/STORAGE AND HANDLING

CinnoRA® (adalimumab) is supplied as a preservative-free, sterile solution for subcutaneous administration.

  • Prefilled Syringe in Auto Injector Device - 40 mg/0.8 mL (Physioject™)

CinnoRA® is dispensed in a carton containing two alcohol preps and two dose trays. Each dose tray consists of a single-use, 0.8 mL prefilled glass syringe in Auto Injector Device with a fixed 29 gauge, ½ inch needle, providing 40 mg/0.8 mL of CinnoRA®.

  • Storage and Stability
  • Do not use beyond the expiration date on the container. CinnoRA® 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, CinnoRA® 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. CinnoRA® should be discarded if not used within the 14-day period. Record the date when CinnoRA® is first removed from the refrigerator in the spaces provided on the carton and dose tray.

PATIENT COUNSELING INFORMATION

The healthcare provider should ask the patient questions to determine any risk factors for treatment. Patients developing signs and symptoms of infection should seek medical evaluation immediately.

Advise patients of the potential benefits and risks of CinnoRA®. Physicians should instruct their patients to read the medication guide before starting CinnoRA® therapy and to reread each time the prescription is renewed.

Infections

Inform patients that CinnoRA® 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 CinnoRA®.

Allergic Reactions

Advise patients to seek immediate medical attention if they experience any symptoms of

severe allergic reactions.

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.

 

 

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