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What should be considered when prescribing ENBREL?
Important Safety Information
Risk of Serious Infections
Infections, including serious infections leading to hospitalization or death, have been observed in patients treated with ENBREL. Infections have included bacterial sepsis and tuberculosis. Patients should be educated about the symptoms of infection and closely monitored for signs and symptoms of infection during and after treatment with ENBREL. Patients who develop an infection should be evaluated for appropriate antimicrobial treatment and, in patients who develop a serious infection, ENBREL should be discontinued.
Tuberculosis (frequently disseminated or extrapulmonary at clinical presentation) has been observed in patients receiving TNF-blocking agents, including ENBREL. Tuberculosis may be due to reactivation of latent tuberculosis infection or to new infection. Data from clinical trials and preclinical studies suggest that the risk of reactivation of latent tuberculosis infection is lower with ENBREL than with TNF-blocking monoclonal antibodies. Nonetheless, postmarketing cases of tuberculosis reactivation have been reported for TNF blockers, including ENBREL. Patients should be evaluated for tuberculosis risk factors and be tested for latent tuberculosis infection prior to initiating ENBREL and during treatment. Treatment of latent tuberculosis infection should be initiated prior to therapy with ENBREL. Treatment of latent tuberculosis in patients with a reactive tuberculin test reduces the risk of tuberculosis reactivation in patients receiving TNF blockers. Some patients who tested negative for latent tuberculosis prior to receiving ENBREL have developed active tuberculosis. Physicians should monitor patients receiving ENBREL for signs and symptoms of active tuberculosis, including patients who tested negative for latent tuberculosis infection.
Many of these serious infections occurred in patients predisposed to infection because of concomitant immunosuppressive therapy and/or their underlying disease. Do not start ENBREL in the presence of sepsis, active infections (including chronic or localized), or allergy to ENBREL or its components. Use caution in patients predisposed to infection, such as those with advanced or poorly controlled diabetes.
Neurologic Events
TNF inhibitors, including ENBREL, have been associated with rare cases of new onset or exacerbation of CNS demyelinating disorders (some presenting with mental status changes and some associated with permanent disability). Transverse myelitis, optic neuritis, multiple sclerosis, and cases of new onset or exacerbation of seizure disorders have been observed in association with ENBREL therapy. The causal relationship to ENBREL therapy remains unclear. Exercise caution when considering ENBREL for patients with these disorders.
Hematologic Events
Rare cases of pancytopenia, including aplastic anemia, some fatal, have been reported. The causal relationship to ENBREL therapy is unclear. Exercise caution in patients who have a previous history of significant hematologic abnormalities. Advise patients to seek immediate medical attention if they develop signs or symptoms of blood dyscrasias or infection. Consider discontinuing ENBREL if significant hematologic abnormalities are confirmed.
Malignancies
In clinical trials of all TNF inhibitors, more cases of lymphoma were seen compared to control patients. The risk of lymphoma may be up to several-fold higher in RA and psoriasis patients; the role of TNF inhibitors in the development of malignancies is unknown. In clinical trials, the incidence of malignancies other than lymphoma has not increased with exposure to ENBREL and is similar to what would be expected in the general population.
Hepatitis B Reactivation
TNF inhibitors, including ENBREL, have been associated reactivation of hepatitis B virus (HBV) in chronic carriers of this virus. The majority of these reports occurred in patients on concomitant immunosuppressive agents, which may also contribute to HBV reactivation. Prescribers should exercise caution in prescribing TNF blockers for patients identified as carriers of HBV.
Adverse Events
The most commonly reported adverse events in RA clinical trials were injection site reaction, infection, and headache. In clinical trials of all other adult indications, adverse events were similar to those reported in RA clinical trials. In a JIA study, infection, headache, abdominal pain, vomiting, and nausea occurred more frequently than in adult RA patients in placebo controlled trials. The types of infections reported in JIA patients were generally mild and consistent with those commonly seen in outpatient pediatric populations.
Please see Prescribing Information.
INDICATIONS
Moderate to Severe Rheumatoid Arthritis (RA)
ENBREL is indicated for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in patients with moderately to severely active rheumatoid arthritis. ENBREL can be initiated in combination with methotrexate (MTX) or used alone.
- In medical studies, ENBREL was shown to be effective in about 2 out of 3 adults with RA who used it, and has been shown to begin working in as few as 2 weeks, with most patients receiving benefit within 3 months. In an RA medical study, 55% of patients had no progression of joint damage.
Moderate to Severe Polyarticular Juvenile Idiopathic Arthritis (JIA)
ENBREL is indicated for reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis in patients ages 2 and older.
- In a medical study, ENBREL was shown to be effective in about 3 out of 4 children with JIA who used it. For these JIA patients, ENBREL has been shown to begin working in approximately 2 to 4 weeks.
Psoriatic Arthritis
ENBREL is indicated for reducing signs and symptoms, inhibiting the progression of structural damage of active arthritis, and improving physical function in patients with psoriatic arthritis. ENBREL can be used in combination with methotrexate in patients who do not respond adequately to methotrexate alone.
- In a medical study, ENBREL was shown to be effective in about 50% of psoriatic arthritis patients who used it. Clinical responses were apparent at the time of the first visit (4 weeks) and were maintained through 6 months of therapy.
Ankylosing Spondylitis (AS)
ENBREL is indicated for reducing signs and symptoms in patients with active ankylosing spondylitis.
- In a medical study, ENBREL was shown to be effective in about 3 out of 5 adults with AS who used it. Clinical responses were seen at 2 weeks in 46% of patients, with 59% of patients receiving benefit within 8 weeks.
Moderate to Severe Plaque Psoriasis
ENBREL is indicated for the treatment of adult patients (18 years or older) with chronic moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy.
- In medical studies, nearly half of patients saw a significant improvement in their plaque psoriasis within 3 months of using ENBREL. Overall, 3 out of 4 patients saw improvement. ENBREL can work fast; many patients saw improvement within 2 months. ENBREL has been shown to be effective through 12 months of therapy.
ENBREL has been studied in 1442 patients with RA, followed for up to 80 months, in 169 patients with psoriatic arthritis for up to 24 months, in 222 patients with ankylosing spondylitis for up to 10 months, and 1261 patients with plaque psoriasis for up to 15 months. In controlled trials, the proportion of ENBREL-treated patients who discontinued treatment due to adverse events was approximately 4% of the indications studied. The vast majority of these patients were treated with 25 mg SC twice weekly. In plaque psoriasis studies, ENBREL doses studied were 25 mg SC once a week, 25 mg SC twice a week, and 50 mg SC twice a week.
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| Does ENBREL affect immunity? |
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Anti-TNF therapies, including ENBREL, affect host defenses against infections and malignancies since TNF mediates inflammation and modulates cellular immune responses. In a study of 49 RA patients treated with ENBREL, there was no evidence of depression of delayed-type hypersensitivity, depression of immunoglobulin levels, or change in enumeration of effector cell populations. The impact of treatment with ENBREL on the development and course of malignancies, as well as active and/or chronic infections, is not fully understood. The safety and efficacy of ENBREL in patients with immunosuppression of chronic infections have not been evaluated.1
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| What about vaccinations and ENBREL? |
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Most psoriatic arthritis patients receiving ENBREL were able to mount effective B-cell immune responses to pneumococcal polysaccharide vaccines, but titers in aggregate were moderately lower and fewer patients had twofold rises in titers compared with patients not receiving ENBREL. The clinical significance of this is unknown. Patients receiving ENBREL may receive concurrent vaccinations, except for live vaccines. No data are available on the secondary transmission of infection by live vaccines in patients receiving ENBREL.1
It is recommended that JIA patients, if possible, be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating therapy with ENBREL. Patients with a significant exposure to varicella virus should temporarily discontinue therapy with ENBREL and be considered for prophylactic treatment with varicella-zoster immune globulin.1
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| How was ENBREL tolerated by geriatric patients? |
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A total of 480 RA patients and 89 plaque psoriasis patients ages 65 years or older have been studied in clinical trials. No overall differences in safety or effectiveness were observed between these patients and younger patients. Because there is a higher incidence of infections in the elderly population in general, caution should be used in treating the elderly.
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| How was ENBREL tolerated by pediatric patients with JIA? |
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In general, the adverse events in pediatric patients were similar in frequency and type as those seen in adult patients (see WARNINGS and other sections under ADVERSE REACTIONS in the ENBREL Prescribing Information).
Severe adverse reactions reported in 69 JIA patients ages 4 to 17 years included varicella (see also PRECAUTIONS, Immunizations in the ENBREL Prescribing Information), gastroenteritis, depression/personality disorder, cutaneous ulcer, esophagitis/gastritis, group A streptococcal septic shock, type I diabetes mellitus, and soft-tissue and postoperative wound infection.1
Forty-three of 69 (62%) children with JIA experienced an infection while receiving ENBREL during 3 months of study (part 1, open-label), and the frequency and severity of infections were similar in 58 patients completing 12 months of open-label extension therapy. The types of infections reported in JIA patients were generally mild and consistent with those commonly seen in outpatient pediatric populations. Two JIA patients developed varicella infection and signs and symptoms of aseptic meningitis, which resolved without sequelae.1
- In a JIA study, infection, headache, abdominal pain, vomiting, and nausea occurred more frequently than in adult RA patients in placebo-controlled trials. The types of infections reported in JIA patients were generally mild and consistent with those commonly seen in outpatient pediatric populations.
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- Serious adverse reactions reported rarely in a JIA study were varicella, gastroenteritis, depression/personality disorder, cutaneous ulcer, esophagitis/gastritis, group A streptococcal septic shock, type I diabetes mellitus, and soft tissue and postoperative wound infection.
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Please see Important Safety Information.
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| Have patients developed antibodies to ENBREL? |
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Patients with moderate to severe RA, psoriatic arthritis, ankylosing spondylitis, or plaque psoriasis were tested at multiple time points for antibodies to ENBREL. Antibodies to the TNF receptor portion or other protein components of the ENBREL drug product were detected at least once in sera of approximately 6% of adult patients with moderate to severe RA, psoriatic arthritis, ankylosing spondylitis, or plaque psoriasis. These antibodies were all non-neutralizing. No apparent correlation of antibody development to clinical response or adverse events was observed. Results from JIA patients were similar to those seen in adult RA patients treated with ENBREL. The long-term immunogenicity of ENBREL is unknown.
The data reflect the percentage of patients whose test results were considered positive for antibodies to ENBREL in an ELISA (Enzyme-Linked Immunosorbant Assay), and are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of any antibody positivity in an assay is highly dependant on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to ENBREL with the incidence of antibodies to other products may be misleading.
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| Is there a need to monitor patients treated with ENBREL? |
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Patients should be evaluated for tuberculosis risk factors and be tested for latent tuberculosis infection prior to initiating ENBREL and during treatment.
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| Does ENBREL have an effect on fertility or mutagenesis? |
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Long-term animal studies have not been conducted to evaluate the carcinogenic potential of ENBREL or its effect on fertility. Mutagenesis studies were conducted in vitro and in vivo, and no evidence of mutagenic activity was observed.1
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| In RA, AS, and psoriatic arthritis, what is the dosage of ENBREL and how is it administered? |
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The recommended dose of ENBREL for adult patients with moderate to severe RA, AS, or psoriatic arthritis is 50 mg per week, which can be given as one subcutaneous (SC) injection using an ENBREL® SureClick™ autoinjector or a 50 mg/mL single-use prefilled syringe. A 50 mg dose can also be given as two 25 mg SC injections using 25 mg/0.5 mL single-use prefilled syringes or multiple use vials.*
*25 mg vials for reconstitution are still available
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| In JIA, what is the dosage of ENBREL and how is it administered? |
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The recommended dose for pediatric patients ages 2 to 17 years with active polyarticular JIA is 0.8 mg/kg per week (up to a maximum of 50 mg per week). For pediatric patients weighing 63 kg (138 pounds) or more, the weekly dose of 50 mg may be administered using ENBREL® SureClick™ autoinjectors or prefilled syringes. For pediatric patients weighing 31 to 62 kg (68 to 136 pounds), the total weekly dose should be administered as two subcutaneous (SC) injections, either on the same day or 3 or 4 days apart, using the 25 mg/0.5 mL pre-filled syringe or multiple-use vial. The dose for pediatric patients weighing less than 31 kg (68 pounds) should be administered as a single SC injection once weekly using the correct volume from the multiple-use vial.1
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| In psoriasis, what is the dosage of ENBREL and how is it administered? |
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For moderate to severe plaque psoriasis, the recommended starting dose of ENBREL for adult patients is 50 mg, twice a week (3 or 4 days apart), given for 3 months. After 3 months, the recommended dose is to step down to 50 mg once weekly after 3 months.
Step-down dosing that is easy to learn:
- Step 1: ENBREL 50 mg twice weekly for the first 3 months
- Step 2: ENBREL 50 mg once weekly for maintenance after 3 months
A 50 mg dose can be given as one subcutaneous (SC) injection using the ENBREL® SureClick™ autoinjector or the 50 mg/mL single-use prefilled syringe. 25 mg/0.5 mL prefilled syringes and 25 mg vials of ENBREL are also available.
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| Is there any latex content in the ENBREL® SureClick™ autoinjector or the prefilled syringes and their components? |
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Yes, the needle cover on the ENBREL® SureClick™ autoinjector and the single-use prefilled syringes contain dry natural rubber (derivative of latex), which should not be handled by persons sensitive to the substance.
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| Are there any contraindications to ENBREL use? |
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ENBREL should not be administered to patients with sepsis or known hypersensitivity to ENBREL or any of its components.1
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| Can ENBREL be used in pregnant women and nursing mothers? |
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ENBREL is classified as Pregnancy Category B. Developmental toxicity studies have been performed in rats and rabbits at doses ranging from 60- to 100-fold higher than the human dose, and have revealed no evidence of harm to fetuses due to ENBREL. There are, however, no studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.1
It is not known whether ENBREL is excreted in human milk or absorbed systemically after ingestion. Because many drugs and immunoglobulins are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ENBREL, a decision should be made whether to discontinue nursing or to discontinue the drug.1
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| Is there more information about the tolerability profile of ENBREL? |
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For a complete description of the tolerability profile for ENBREL, including warnings and precautions, please click here to see full ENBREL Prescribing Information and Important Safety Information.
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| How is ENBREL supplied? |
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ENBREL prefilled syringes are supplied in cartons containing 4 syringes.1
ENBREL 50 mg/mL prefilled SureClick™ autoinjectors are supplied in cartons containing 4 ENBREL® SureClick™ autoinjectors.
ENBREL multiple-use vials are supplied in a carton containing 4 dose trays. Each dose tray contains:
- One prefilled diluent syringe containing 1 mL of diluent
- One plunger
- One ENBREL vial
- One 27-gauge, ½-inch" needle in hard plastic cover
- One vial adapter
- Two alcohol swabs
If the 7 items are not included in the dose tray, patients can call 1-888-4ENBREL (1-888-436-2735) for assistance.
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| How is ENBREL stored? |
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ENBREL must be refrigerated at 2° to 8°C (36° to 46°F). DO NOT FREEZE. Administer reconstituted solutions of ENBREL as soon as possible after reconstitution. If not administered immediately after reconstitution, ENBREL may be stored at 2° to 8°C (36° to 46°F) for not more than 14 days. Do not use an ENBREL dose tray beyond the date stamped on the carton or vial label.1
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