PRINCIPAL DISPLAY PANEL - 80 mg Autoinjector Carton

AMJEVITA™
(adalimumab-atto)
Injection

NDC 55513-481-01

80 mg/
0.8 mL

80 mg/0.8 mL

For Subcutaneous Use Only

Sterile Solution – No Preservative

Store refrigerated at 2°C to 8°C (36°F to 46°F).
Do not Freeze. Do not re-use.
Do not Shake. Protect from light.
(see side panel for additional storage information)
Keep out of the sight and reach of children.

ATTENTION: Enclosed Medication Guide is
required for each patient.

Rx Only

Not made with
natural rubber latex

1
Single-dose Prefilled
SureClick® Autoinjector

Refrigerate
until ready
to use

CAUTION, Consult
Accompanying Documents

AMGEN®

WARNING: SERIOUS INFECTIONS and MALIGNANCY

4 CONTRAINDICATIONS

None.

6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Serious Infections [see Warnings and Precautions (5.1)]
• Malignancies [see Warnings and Precautions (5.2)]
• Hypersensitivity Reactions [see Warnings and Precautions (5.3)]
• Hepatitis B Virus Reactivation [see Warnings and Precautions (5.4)]
• Neurologic Reactions [see Warnings and Precautions (5.5)]
• Hematological Reactions [see Warnings and Precautions (5.6)]
• Heart Failure [see Warnings and Precautions (5.8)]
• Autoimmunity [see Warnings and Precautions (5.9)]

6.1 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 39 global adalimumab clinical trials in adult patients with RA, PsA, AS, CD, UC, Ps, HS and UV, the rate of serious infections was 4.3 per 100 patient-years in 7973 adalimumab-treated patients versus a rate of 2.9 per 100 patient-years in 4848 control-treated patients. Serious infections observed included pneumonia, septic arthritis, prosthetic and post-surgical infections, erysipelas, cellulitis, diverticulitis, and pyelonephritis [see Warnings and Precautions (5.1)].

Tuberculosis and Opportunistic Infections

In 52 global controlled and uncontrolled clinical trials in RA, PsA, AS, CD, UC, Ps, HS and UV that included 24,605 adalimumab-treated patients, the rate of reported active tuberculosis was 0.20 per 100 patient-years and the rate of positive PPD conversion was 0.09 per 100 patient-years. In a subgroup of 10,113 U.S. and Canadian adalimumab-treated patients, the rate of reported active TB was 0.05 per 100 patient-years and the rate of positive PPD conversion was 0.07 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 [see Warnings and Precautions (5.1)].

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 × 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 × 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. No ALT elevations ≥ 3 × ULN occurred in the open- label study of adalimumab in patients with polyarticular JIA who were 2 to < 4 years.

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 × ULN occurred in 0.9% of adalimumab- treated patients and 0.9% of control-treated patients. In the Phase 3 trial of adalimumab in pediatric patients with Crohn's disease which evaluated efficacy and safety of two body weight based maintenance dose regimens following body weight based induction therapy up to 52 weeks of treatment, ALT elevations ≥ 3 × ULN occurred in 2.6% (5/192) of patients, of whom 4 were receiving concomitant immunosuppressants at baseline; none of these patients discontinued due to abnormalities in ALT tests. 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 adult patients with UC with control period duration ranging from 1 to 52 weeks, ALT elevations ≥ 3 × 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 × ULN occurred in 1.8% of adalimumab-treated patients and 1.8% of control-treated patients. In controlled trials of adalimumab (initial doses of 160 mg at Week 0 and 80 mg at Week 2, followed by 40 mg every week starting at Week 4), in subjects with HS with a control period duration ranging from 12 to 16 weeks, ALT elevations ≥ 3 × ULN occurred in 0.3% of adalimumab-treated subjects and 0.6% of control- treated subjects. In controlled trials of adalimumab (initial doses of 80 mg at Week 0, followed by 40 mg every other week starting at Week 1) in adult patients with uveitis with an exposure of 165.4 PYs and 119.8 PYs in adalimumab-treated and control-treated patients, respectively, ALT elevations ≥ 3 × ULN occurred in 2.4% of adalimumab-treated patients and 2.4% of control- treated patients.

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 [see Clinical Studies (14.1)].

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.

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) trials (Studies JIA-I and JIA-II) [see Clinical Studies (14.2)] were similar in frequency and type to those seen in adult patients [see Warnings and Precautions (5), Adverse Reactions (6)]. 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 concentrations decreased or returned to normal in all patients. Most patients were able to continue adalimumab without interruption.

In Study JIA-II, adalimumab was studied in 32 patients who were 2 to < 4 years of age or 4 years of age and older weighing < 15 kg with polyarticular JIA. The safety profile for this patient population was similar to the safety profile seen in patients 4 to 17 years of age with polyarticular JIA.

In Study JIA-II, 78% of patients experienced an infection while receiving adalimumab. These included nasopharyngitis, bronchitis, upper respiratory tract infection, otitis media, and were mostly mild to moderate in severity. Serious infections were observed in 9% of patients receiving adalimumab in the study and included dental caries, rotavirus gastroenteritis, and varicella.

In Study JIA-II, non-serious allergic reactions were observed in 6% of patients and included intermittent urticaria and rash, which were all mild in severity.

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 [see Clinical Studies (14.3, 14.4)]. 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.

Crohn's Disease Clinical Studies

Adults: The safety profile of adalimumab in 1478 adult patients with Crohn's disease (CD) from four placebo-controlled and two open-label extension studies [see Clinical Studies (14.5)] was similar to the safety profile seen in patients with RA.

Pediatric Patients 6 Years to 17 Years: The safety profile of adalimumab in 192 pediatric patients from one double-blind study (Study PCD-I) and one open- label extension study [see Clinical Studies (14.6)] was similar to the safety profile seen in adult patients with CD.

During the 4-week open-label induction phase of Study PCD-I, the most common adverse reactions occurring in the pediatric population treated with adalimumab were injection site pain and injection site reaction (6% and 5%, respectively).

A total of 67% of children experienced an infection while receiving adalimumab in Study PCD-I. These included upper respiratory tract infection and nasopharyngitis.

A total of 5% of children experienced a serious infection while receiving adalimumab in Study PCD-I. These included viral infection, device related sepsis (catheter), gastroenteritis, H1N1 influenza, and disseminated histoplasmosis.

In Study PCD-I, allergic reactions were observed in 5% of children which were all non-serious and were primarily localized reactions.

Ulcerative Colitis Clinical Studies

Adults: The safety profile of adalimumab in 1010 adult patients with ulcerative colitis (UC) from two placebo-controlled studies and one open-label extension study [see Clinical Studies (14.7)] 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 [see Clinical Studies (14.8)]. 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%).

Hidradenitis Suppurativa Clinical Studies

Adalimumab has been studied in 727 subjects with hidradenitis suppurativa (HS) in three placebo-controlled studies and one open-label extension study [see Clinical Studies (14.9)]. The safety profile for subjects with HS treated with adalimumab weekly was consistent with the known safety profile of adalimumab.

Flare of HS, defined as ≥25% increase from baseline in abscesses and inflammatory nodule counts and with a minimum of 2 additional lesions, was documented in 22 (22%) of the 100 subjects who were withdrawn from adalimumab treatment following the primary efficacy timepoint in two studies.

Uveitis Clinical Studies

Adalimumab has been studied in 464 adult patients with uveitis (UV) in placebo-controlled and open-label extension studies [see Clinical Studies (14.10)]. The safety profile for patients with UV treated with adalimumab was similar to the safety profile seen in patients with RA.

6.2 Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other adalimumab products may be misleading. There are two assays that have been used to measure anti-adalimumab antibodies. With the ELISA, antibodies to adalimumab could be detected only when serum adalimumab concentrations were < 2 mcg/mL. The ECL assay can detect anti-adalimumab antibody titers independent of adalimumab concentrations in the serum samples. The incidence of anti- adalimumab antibody (AAA) development in patients treated with adalimumab are presented in Table 2.

In plaque psoriasis 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

One 12-week Phase 2 study and one 52-week Phase 3 study

Among subjects in the two Phase 3 studies who stopped adalimumab treatment for up to 24 weeks and in whom adalimumab serum levels subsequently declined to < 2 mcg/mL (approximately 22% of total subjects studied)

No apparent association between antibody development and safety was observed

No correlation of antibody development to safety or efficacy outcomes was observed

Rheumatoid Arthritis and Psoriatic Arthritis: Patients in Studies RA-I, RA-II, and RA-III were tested at multiple time points for antibodies to adalimumab using the ELISA during the 6- to 12-month period. 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 products is unknown.

6.3 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, lichenoid skin reaction

Vascular disorders: Systemic vasculitis, deep vein thrombosis

7 DRUG INTERACTIONS

7.1 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 AMJEVITA or MTX [see Clinical Pharmacology (12.3)].

7.2 Biological Products

In clinical studies in patients with RA, an increased risk of serious infections has been observed with the combination of TNF‑blockers with anakinra or abatacept, with no added benefit; therefore, use of AMJEVITA with abatacept or anakinra is not recommended in patients with RA [see Warnings and Precautions (5.7, 5.11)]. 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 AMJEVITA and other biologic products for the treatment of RA, PsA, AS, CD, UC, Ps, HS and UV. Concomitant administration of AMJEVITA 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.

7.3 Live Vaccines

Avoid the use of live vaccines with AMJEVITA [see Warnings and Precautions (5.10)].

7.4 Cytochrome P450 Substrates

The formation of CYP450 enzymes may be suppressed by increased concentrations of cytokines (e.g., TNFα, IL-6) during chronic inflammation. It is possible for products that antagonize cytokine activity, such as adalimumab products, to influence the formation of CYP450 enzymes. Upon initiation or discontinuation of AMJEVITA 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.

RECENT MAJOR CHANGES

3 DOSAGE FORMS AND STRENGTHS

AMJEVITA is a clear, colorless to slightly yellow solution available as:

*Prefilled SureClick Autoinjector

Injection: 80mg/0.8 mL in a single-dose prefilled SureClick autoinjector.
Injection: 40 mg/0.8 mL in a single-dose prefilled SureClick autoinjector.
Injection: 40mg/0.4 mL in a single-dose prefilled SureClick autoinjector.

*Prefilled Syringe

Injection: 80 mg/0.8 mL in a single-dose prefilled glass syringe.
Injection: 40 mg/0.8 mL in a single-dose prefilled glass syringe. 
Injection: 40 mg/0.4 mL in a single-dose prefilled glass syringe.
Injection: 20 mg/0.4 mL in a single-dose prefilled glass syringe.
Injection: 20 mg/0.2 mL in a single-dose prefilled glass syringe.
Injection: 10 mg/0.2 mL in a single-dose prefilled glass syringe.

12 CLINICAL PHARMACOLOGY

12.1 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 concentrations 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 concentrations of TNF are also found in psoriasis plaques. In Ps, treatment with AMJEVITA 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 concentrations of adhesion molecules responsible for leukocyte migration (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 × 10-10M).

12.2 Pharmacodynamics

After treatment with adalimumab, a decrease in concentrations 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 concentrations was also observed in patients with Crohn's disease, ulcerative colitis, and hidradenitis suppurativa. Serum concentrations of matrix metalloproteinases (MMP-1 and MMP-3) that produce tissue remodeling responsible for cartilage destruction were also decreased after adalimumab administration.

12.3 Pharmacokinetics

The pharmacokinetics of adalimumab were linear over the dose range of 0.5 to 10 mg/kg following administration of a single intravenous dose (adalimumab products are not approved for intravenous use). Following 20, 40, and 80 mg every other week and every week subcutaneous administration, adalimumab mean serum trough concentrations at steady state increased approximately proportionally with dose in RA patients. The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. Healthy subjects and patients with RA displayed similar adalimumab pharmacokinetics.

Adalimumab exposure in patients treated with 80 mg every other week is estimated to be comparable with that in patients treated with 40 mg every week.

Absorption

The average absolute bioavailability of adalimumab following a single 40 mg subcutaneous dose was 64%. The mean time to reach the maximum concentration was 5.5 days (131 ± 56 hours) and the maximum serum concentration was 4.7 ± 1.6 mcg/mL in healthy subjects following a single 40 mg subcutaneous administration of adalimumab.

Distribution

The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients.

Elimination

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 systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients.

Patient Population

Rheumatoid Arthritis and Ankylosing Spondylitis: In patients receiving 40 mg adalimumab every other week, adalimumab mean steady-state trough concentrations were approximately 5 mcg/mL and 8 to 9 mcg/mL, without and with MTX concomitant treatment, respectively. Adalimumab concentrations in the synovial fluid from five rheumatoid arthritis patients ranged from 31 to 96% of those in serum. The pharmacokinetics of adalimumab in patients with AS were similar to those in patients with RA.

Psoriatic Arthritis: In patients receiving 40 mg every other week, adalimumab mean steady-state trough concentrations were 6 to 10 mcg/mL and 8.5 to 12 mcg/mL, without and with MTX concomitant treatment, respectively.

Plaque Psoriasis: Adalimumab mean steady-state trough concentration was approximately 5 to 6 mcg/mL during adalimumab 40 mg every other week treatment.

Adult Uveitis: Adalimumab mean steady concentration was approximately 8 to 10 mcg/mL during adalimumab 40 mg every other week treatment.

Adult Hidradenitis Suppurativa: Adalimumab trough concentrations were approximately 7 to 8 mcg/mL at Week 2 and Week 4, respectively, after receiving 160 mg on Week 0 followed by 80 mg on Week 2. Mean steady-state trough concentrations at Week 12 through Week 36 were approximately 7 to 11 mcg/mL during adalimumab 40 mg every week treatment.

Adult Crohn's Disease: Adalimumab mean trough concentrations were approximately 12 mcg/mL at Week 2 and Week 4 after receiving 160 mg on Week 0 followed by 80 mg on Week 2. Mean steady-state trough concentrations were 7 mcg/mL at Week 24 and Week 56 during adalimumab 40 mg every other week treatment.

Adult Ulcerative Colitis: Adalimumab mean trough concentrations were approximately 12 mcg/mL at Week 2 and Week 4 after receiving 160 mg on Week 0 followed by 80 mg on Week 2. Mean steady-state trough concentrations were approximately 8 mcg/mL and 15 mcg/mL at Week 52 after receiving a dose of adalimumab 40 mg every other week and 40 mg every week, respectively.

Anti-Drug Antibody Effects on Pharmacokinetics

Rheumatoid Arthritis: A trend toward higher apparent clearance of adalimumab in the presence of anti-adalimumab antibodies was identified.

Hidradenitis Suppurativa: In subjects with moderate to severe HS, antibodies to adalimumab were associated with reduced serum adalimumab concentrations. In general, the extent of reduction in serum adalimumab concentrations is greater with increasing titers of antibodies to adalimumab.

Specific Populations

Geriatric Patients: A lower clearance with increasing age was observed in patients with RA aged 40 to > 75 years.

Pediatric Patients:

Juvenile Idiopathic Arthritis:

• 4 years to 17 years of age: The adalimumab mean steady-state trough concentrations were 6.8 mcg/mL and 10.9 mcg/mL in patients weighing < 30 kg receiving 20 mg adalimumab subcutaneously every other week as monotherapy or with concomitant MTX, respectively. The adalimumab mean steady-state trough concentrations were 6.6 mcg/mL and 8.1 mcg/mL in patients weighing ≥ 30 kg receiving 40 mg adalimumab subcutaneously every other week as monotherapy or with MTX concomitant treatment, respectively.
• 2 years to < 4 years of age or 4 years of age and older weighing < 15 kg: The adalimumab mean steady-state trough adalimumab concentrations were 6.0 mcg/mL and 7.9 mcg/mL in patients receiving adalimumab subcutaneously every other week as monotherapy or with MTX concomitant treatment, respectively.

Pediatric Crohn's Disease: Adalimumab mean ± SD concentrations were 15.7±6.5 mcg/mL at Week 4 following 160 mg at Week 0 and 80 mg at Week 2, and 10.5±6.0 mcg/mL at Week 52 following 40 mg every other week dosing in patients weighing ≥ 40 kg. Adalimumab mean ± SD concentrations were 10.6±6.1 mcg/mL at Week 4 following dosing 80 mg at Week 0 and 40 mg at Week 2, and 6.9±3.6 mcg/mL at Week 52 following 20 mg every other week dosing in patients weighing < 40 kg.

Male and Female Patients: No gender-related pharmacokinetic differences were observed after correction for a patient's body weight. Healthy subjects and patients with rheumatoid arthritis displayed similar adalimumab pharmacokinetics.

Patients with Renal or Hepatic Impairment: No pharmacokinetic data are available in patients with hepatic or renal impairment.

Rheumatoid factor or CRP concentrations: Minor increases in apparent clearance were 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.

Drug Interaction Studies:

Methotrexate: MTX reduced adalimumab apparent clearance after single and multiple dosing by 29% and 44%, respectively, in patients with RA [see Drug Interactions (7.1)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Available studies with use of adalimumab during pregnancy do not reliably establish an association between adalimumab and major birth defects. Clinical data are available from the Organization of Teratology Information Specialists (OTIS)/MotherToBaby Pregnancy Registry in pregnant women with rheumatoid arthritis (RA) or Crohn's disease (CD) treated with adalimumab. Registry results showed a rate of 10% for major birth defects with first trimester use of adalimumab in pregnant women with RA or CD and a rate of 7.5% for major birth defects in the disease-matched comparison cohort. The lack of pattern of major birth defects is reassuring and differences between exposure groups may have impacted the occurrence of birth defects (see Data).

Adalimumab is actively transferred across the placenta during the third trimester of pregnancy and may affect immune response in the in utero exposed infant (see Clinical Considerations). 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 (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

Disease-associated maternal and embryo/fetal risk

Published data suggest that the risk of adverse pregnancy outcomes in women with RA or inflammatory bowel disease (IBD) is associated with increased disease activity. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) infants, and small for gestational age at birth.

Fetal/Neonatal Adverse Reactions

Monoclonal antibodies are increasingly transported across the placenta as pregnancy progresses, with the largest amount transferred during the third trimester [see Data]. Risks and benefits should be considered prior to administering live or live-attenuated vaccines to infants exposed to adalimumab products in utero [see Use in Specific Populations (8.4)].

Data

Human Data

A prospective cohort pregnancy exposure registry conducted by OTIS/MotherToBaby in the U.S. and Canada between 2004 and 2016 compared the risk of major birth defects in live-born infants of 221 women (69 RA, 152 CD) treated with adalimumab during the first trimester and 106 women (74 RA, 32 CD) not treated with adalimumab.

The proportion of major birth defects among live-born infants in the adalimumab-treated and untreated cohorts was 10% (8.7% RA, 10.5% CD) and 7.5% (6.8% RA, 9.4% CD), respectively. The lack of pattern of major birth defects is reassuring and differences between exposure groups may have impacted the occurrence of birth defects. This study cannot reliably establish whether there is an association between adalimumab and major birth defects because of methodological limitations of the registry, including small sample size, the voluntary nature of the study, and the non-randomized design.

In an independent clinical study conducted in ten pregnant women with IBD 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 mcg/mL in cord blood, 4.28-17.7 mcg/mL in infant serum, and 0-16.1 mcg/mL in maternal serum. In all but one case, the cord blood concentration of adalimumab was higher than the maternal serum concentration, suggesting adalimumab actively crosses the placenta. In addition, one infant had serum concentrations at each of the following: 6 weeks (1.94 mcg/mL), 7 weeks (1.31 mcg/mL), 8 weeks (0.93 mcg/mL), and 11 weeks (0.53 mcg/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.

8.2 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 concentration. Published data suggest that the systemic exposure to a breastfed infant is expected to be low because adalimumab is a large molecule and is degraded in the gastrointestinal tract. However, the effects of local exposure in the gastrointestinal tract are unknown. 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 AMJEVITA and any potential adverse effects on the breastfed child from AMJEVITA or from the underlying maternal condition.

8.4 Pediatric Use

The safety and effectiveness of AMJEVITA have been established for:

• reducing signs and symptoms of moderately to severely active polyarticular JIA in pediatric patients 2 years of age and older.
• the treatment of moderately to severely active Crohn's disease in pediatric patients 6 years of age and older.

Pediatric assessments for AMJEVITA demonstrate that AMJEVITA is safe and effective for pediatric patients in indications for which HUMIRA (adalimumab) is approved. However, AMJEVITA is not approved for such indications due to marketing exclusivity for HUMIRA (adalimumab).

Due to their 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 [see Use in Specific Populations (8.1)]. The clinical significance of elevated adalimumab concentrations 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 [see Warnings and Precautions (5.2)].

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 [see Clinical Studies (14.2)]. 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 [see Adverse Reactions (6.1)]. 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 [see Adverse Reactions (6.1)].

The safety and effectiveness of adalimumab products have not been established in pediatric patients with JIA less than 2 years of age.

Pediatric Crohn's Disease

The safety and effectiveness of adalimumab products for the treatment of moderately to severely active Crohn's disease have been established in pediatric patients 6 years of age and older. Use of adalimumab products for this indication is supported by evidence from adequate and well-controlled studies in adults with additional data from a randomized, double-blind, 52-week clinical study of two dose concentrations of adalimumab in 192 pediatric patients (6 years to 17 years of age) [see Adverse Reactions (6.1), Clinical Pharmacology (12.2, 12.3), Clinical Studies (14.6)]. The adverse reaction profile in patients 6 years to 17 years of age was similar to adults.

The safety and effectiveness of adalimumab products have not been established in pediatric patients with Crohn's disease less than 6 years of age.

8.5 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 65 years of age and older was higher than for those less than 65 years of age. Consider the benefits and risks of AMJEVITA in patients 65 years of age and older. In patients treated with AMJEVITA, closely monitor for the development of infection or malignancy [see Warnings and Precautions (5.1, 5.2)].

10 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.

15 REFERENCES

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

11 DESCRIPTION

Adalimumab-atto is a tumor necrosis factor blocker. Adalimumab-atto is a recombinant human IgG1 monoclonal antibody with human derived heavy and light chain variable regions and human IgG1:k constant regions. Adalimumab-atto is produced by recombinant DNA technology in a mammalian cell (Chinese Hamster Ovary (CHO)) 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.

AMJEVITA™ (adalimumab-atto) injection is supplied as a sterile, preservative- free solution for subcutaneous administration. The drug product is supplied as either a single-dose, prefilled SureClick autoinjector, or as a single-dose, 1 mL prefilled glass syringe. Enclosed within the autoinjector is a single-dose, 1 mL prefilled glass syringe. The solution of AMJEVITA is clear, colorless to slightly yellow, with a pH of about 5.2.

Each 80 mg/0.8 mL prefilled syringe or prefilled autoinjector delivers 0.8 mL (80 mg) of drug product. Each 0.8 mL of AMJEVITA is formulated with L-lactic acid (1.7 mg), polysorbate 80 (0.8 mg), sodium hydroxide for pH adjustment, sucrose (67 mg), and Water for Injection, USP, pH 5.2.

Each 40 mg/0.8 mL prefilled syringe or prefilled autoinjector delivers 0.8 mL (40 mg) of drug product. Each 0.8 mL of AMJEVITA is formulated with glacial acetic acid (0.48 mg), polysorbate 80 (0.8 mg), sodium hydroxide for pH adjustment, sucrose (72 mg), and Water for Injection, USP, pH 5.2.

Each 40 mg/0.4 mL prefilled syringe or prefilled autoinjector delivers 0.4 mL (40 mg) of drug product. Each 0.4 mL of AMJEVITA is formulated with L-lactic acid (0.9 mg), polysorbate 80 (0.4 mg), sodium hydroxide for pH adjustment, sucrose (34 mg), and Water for Injection, USP, pH 5.2.

Each 20 mg/0.4 mL prefilled syringe delivers 0.4 mL (20 mg) of drug product. Each 0.4 mL of AMJEVITA is formulated with glacial acetic acid (0.24 mg), polysorbate 80 (0.4 mg), sodium hydroxide for pH adjustment, sucrose (36 mg), and Water for Injection, USP, pH 5.2.

Each 20 mg/0.2 mL prefilled syringe delivers 0.2 mL (20 mg) of drug product. Each 0.2 mL of AMJEVITA is formulated with L-lactic acid (0.4 mg), polysorbate 80 (0.2 mg), sodium hydroxide for pH adjustment, sucrose (17 mg), and Water for Injection, USP, pH 5.2.

Each 10 mg/0.2 mL prefilled syringe delivers 0.2 mL (10 mg) of drug product. Each 0.2 mL of AMJEVITA is formulated with glacial acetic acid (0.12 mg), polysorbate 80 (0.2 mg), sodium hydroxide for pH adjustment, sucrose (18 mg), and Water for Injection, USP, pH 5.2.

AMJEVITA™ (adalimumab-atto)

Manufactured by:
Amgen Inc.
One Amgen Center Drive
Thousand Oaks, CA 91320-1799

U.S. License Number 1080

AMGEN® and AMJEVITA™ (adalimumab-atto) are trademarks owned or licensed by Amgen Inc., its subsidiaries, or affiliates.

© 2022-2023 Amgen Inc. All rights reserved.

1xxxxxx-v9

INSTRUCTIONS FOR USE

AMJEVITA™ (am-jeh-vee'-tah)
(adalimumab-atto)
injection, for subcutaneous use
20 mg/0.2 mL
40 mg/0.4 mL
80 mg/0.8 mL
single-dose prefilled syringe

This Instructions for Use contains information on how to inject AMJEVITA with a prefilled syringe.

If your healthcare provider decides that you or a caregiver may be able to give your injections of AMJEVITA at home, you should receive training on the right way to prepare and inject AMJEVITA. Do not try to inject yourself until you have been shown the right way to give the injections by your healthcare provider or nurse.

The medicine in the AMJEVITA prefilled syringe is for injection under the skin (subcutaneous injection). See the AMJEVITA Medication Guide for information about AMJEVITA.

1. Important Information You Need to Know Before Injecting AMJEVITA

Dosing:

• AMJEVITA comes in 3 different doses: 20 mg/0.2 mL, 40 mg/0.4 mL, and 80 mg/0.8 mL. Check your prescription to make sure you have the correct dose.
• The color and look of the prefilled syringe will be different for each dose. The amount of medicine in the syringe will also be different for each dose.
• For example, it is okay for the 20 mg/0.2 mL dose to have a small amount of medicine and the 80 mg/0.8 mL to have a large amount of medicine. Check the illustrations below to see what your dose looks like in the syringe.

• It is important that you do not try to give the injection until you have fully read and understood this Instructions for Use. *Do not use the syringe if the carton is damaged or the seal is broken. *Do not use the syringe after the expiration date on the label. *Do not shake the syringe. *Do not remove the needle cap from the syringe until you are ready to inject. *Do not use the syringe if it has been frozen. *Do not use the syringe if it has been dropped on a hard surface. Part of the syringe may be broken even if you cannot see the break. Use a new syringe, and call 1-800-77-AMGEN (1-800-772-6436).
• The syringe is not made with natural rubber latex.

Frequently asked questions:

For additional information and answers to frequently asked questions, visit www.amjevita.com.

Where to get help:

If you want more information or help using AMJEVITA:

• Contact your healthcare provider,
• Visitwww.amjevita.com, or
• Call 1-800-77-AMGEN (1-800-772-6436)

2. Storing and Preparing to Inject AMJEVITA

2a Refrigerate the syringe carton until you are ready to use it.

• Keep the syringe in the refrigerator between 36°F to 46°F (2°C to 8°C).
• Keep the syringe in the original carton to protect it from light or physical damage. *Do not freeze the syringe. *Do not store the syringe in extreme heat or cold. For example, avoid storing in your vehicle's glove box or trunk.

2b Grasp the syringe by the body and remove it from the carton.

*Do not grab the finger grip, plunger rod, or the needle cap.

• Remove the number of syringes you need for your injection.
• Put any unused syringes back into the refrigerator.

2c Wait 15 to 30 minutes for the syringe to reach room temperature.

• Let the syringe warm up naturally. *Do not heat the syringe with hot water, a microwave, or direct sunlight. *Do not shake the syringe at any time.
• Using the syringe at room temperature allows for a more comfortable injection**.**

2d You may keep AMJEVITA at room temperature for up to 14 days, if needed.

• For example, when you are traveling, you may keep AMJEVITA at room temperature.
  • Keep it at room temperature between 68°F to 77°F (20°C to 25°C). *Do not put it back in the refrigerator.
  • Record the date you removed it from the refrigerator and use it within14 days.

2e Gather and place the following items for your injection on a clean, flat, and well-lit surface:

• AMJEVITA syringe (room temperature)
• Sharps disposal container [see Disposing of AMJEVITA and Checking the Injection Site]
• Alcohol wipe
• Adhesive bandage
• Cotton ball or gauze pad

3. Getting Ready for Your Injection

3a Inspect the medicine. It should be clear and colorless to pale yellow.

• It is okay to see air bubbles in the syringe. *Do not use AMJEVITA if the medicine is cloudy, discolored, or has flakes or particles.

3b Check the expiration date (Exp.) and inspect the syringe for damage.

*Do not use the syringe if the expiration date has passed. *Do not use the syringe if: * the needle cap is missing or loose. * it has cracks or broken parts. * it has been dropped on a hard surface.

• Make sure you have the right medicine and dose.

3c Inject into 1 of these locations.

• Inject into the front of your thigh or stomach (except for 2 inches around your belly button).
• Choose a different site for each injection.

3d Wash hands thoroughly with soap and water.

3e Clean the injection site with an alcohol wipe.

• Let the skin dry on its own. *Do not touch this area again before injecting.

4. Injecting AMJEVITA

4a Pull the needle cap straight off while holding the syringe body.

*Do not twist or bend the needle cap. *Never put the needle cap back on. It may damage the needle. *Do not let anything touch the needle after you remove the needle cap. *Do not place the uncapped syringe on any surface after you remove the needle cap. *Do not try to push air bubbles out of the syringe. It is okay to see air bubbles.

• It is normal to see a drop of medicine come out of the needle.

4b Place the needle cap in the sharps disposal container.

4c Pinch the skin around the injection site before injection.

• Pinch the skin between the thumb and pointer (index) finger to create a bump for the injection.
• If possible, the bump should be about 2 inches wide.

4d Insert the needle into the pinched skin at a 45-degree angle.

*Do not place your finger on the plunger rod while inserting the needle, as this may result in lost medicine.

4e Slowly press the plunger rod all the way down until it reaches the bottom of the syringe to inject the medicine.

*Do not pull back on the plunger rod at any time. *Do not remove the syringe until all of the medicine has been injected.

5. Disposing of AMJEVITA and Checking the Injection Site

5a Place the used syringe in an FDA-cleared sharps disposal container right away after use.

*Do not reuse the syringe.

5b Check the injection site.

*Do not rub the injection site.

• If there is blood, press a cotton ball or gauze pad on your injection site. Apply an adhesive bandage if necessary.

Additional information about your sharps disposal container

If you do not have an FDA-cleared sharps disposal container, you may use a household container that is:

Disposing of sharps disposal containers:

When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container.

There may be state or local laws about how you should throw away used needles and syringes.

For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA's website at:

http://www.fda.gov/safesharpsdisposal

Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this.

Do not recycle your used sharps disposal container.

For more information or help call 1-800-77-AMGEN (1-800-772-6436).

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

AMJEVITA (adalimumab-atto)

Manufactured by:
Amgen Inc.
One Amgen Center Drive
Thousand Oaks, California 91320-1799
US License Number 1080
©2023 Amgen Inc. All rights reserved.
nnnnnnnnnn
Issued: 8/2023

13 NONCLINICAL TOXICOLOGY

13.1 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.

16 HOW SUPPLIED/STORAGE AND HANDLING

AMJEVITA™ (adalimumab-atto) injection is supplied as a preservative-free, sterile, clear, colorless to slightly yellow solution for subcutaneous administration. AMJEVITA is supplied in a single-dose prefilled syringe (PFS) or single-dose prefilled SureClick autoinjector (AI). The AMJEVITA prefilled syringe and prefilled SureClick autoinjector are not made with natural rubber latex. The following packaging configurations are available.

Storage and Stability

Do not use beyond the expiration date on the container. AMJEVITA 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, AMJEVITA 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. AMJEVITA should be discarded if not used within the 14-day period. Record the date when AMJEVITA is first removed from the refrigerator in the spaces provided on the carton.

Do not store AMJEVITA in extreme heat or cold.

17 PATIENT COUNSELING INFORMATION

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

Infections

Inform patients that AMJEVITA 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 [see Warnings and Precautions (5.1, 5.2, 5.4)].

Malignancies

Counsel patients about the risk of malignancies while receiving AMJEVITA [see Warnings and Precautions (5.2)].

Hypersensitivity Reactions

Advise patients to seek immediate medical attention if they experience any symptoms of severe hypersensitivity 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 [see Warnings and Precautions (5.5, 5.6, 5.8, 5.9)].

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 AMJEVITA, instruct them in injection techniques and assess their ability to inject subcutaneously to ensure the proper administration of AMJEVITA [see Instructions for Use].

Instruct patients to dispose of their used needles and syringes or used prefilled autoinjector in a FDA-cleared sharps disposal container immediately after use.Instruct patients not to dispose of loose needles and syringes or prefilled autoinjector 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.