Etanercept- from uptodate

Etanercept: Drug information


SPECIAL ALERTS
Tumor Necrosis Factor (TNF) Blockers and Malignancy Risk - June 5, 2008

The U.S. Food and Drug Administration (FDA) issued an Early Communication to healthcare professionals regarding a possible association between TNF blocker (adalimumab, certolizumb pegol, etanercept, and infliximab) use and the development of malignancies in children and young adults. Over the last 10 years, the FDA has received ~30 reports of cancer in children or young adults who had been treated with TNF blockers prior to the age of 18 years. TNF blockers were given for the treatment of Juvenile Idiopathic Arthritis (JIA [formerly termed Juvenile Rheumatoid Arthritis]), Crohn's disease, or other indications in combination with other immunosuppressive medications (eg, azathioprine, 6-mercaptopurine or methotrexate). Approximately half of the reported cancers were lymphomas (Hodgkin's and non-Hodgkin's), which are cancers involving the cells of the immune system.

TNF blockers work by suppressing the immune system. The prescribing information for each TNF blocker contains warnings regarding the possible association of malignancy development with use. Malignancies may not be detected in short-term studies; long-term studies are necessary to identify the impact of TNF blocker therapy on malignancy development. The manufacturers of the four TNF blockers available in the U.S. are being asked by the FDA to provide information regarding all cases of cancer reported in children taking TNF blockers. The FDA is expected to report its findings in approximately 6 months, after completing a safety review and evaluation.

Additional information is available at http://www.fda.gov/medwatch/safety/2008/safety08.htm#TNF

Etanercept (Enbrel®): Revised Prescribing Information With the Addition of a Boxed Warning Concerning the Risk of Infection, Including Tuberculosis - May 2008

These product labeling changes have previously been incorporated into the etanercept Lexi-Comp monograph.

The FDA MedWatch alert can be found at: http://www.fda.gov/medwatch/safety/2008/safety08.htm#Enbrel

U.S. BRAND NAMES — Enbrel®

PHARMACOLOGIC CATEGORY
Antirheumatic, Disease Modifying
Tumor Necrosis Factor (TNF) Blocking Agent

DOSING: ADULTS
Rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis: SubQ:
Once-weekly dosing: 50 mg once weekly
Twice-weekly dosing: 25 mg given twice weekly (individual doses should be separated by 72-96 hours)

Plaque psoriasis:
Initial: 50 mg twice weekly, 3-4 days apart (starting doses of 25 or 50 mg once weekly have also been used successfully); maintain initial dose for 3 months
Maintenance dose: 50 mg once weekly

DOSING: PEDIATRIC — Juvenile idiopathic arthritis: Children 2-17 years: SubQ:

(For additional information see "Etanercept: Pediatric drug information")

Once-weekly dosing: 0.8 mg/kg (maximum: 50 mg/dose) once weekly

Twice-weekly dosing: 0.4 mg/kg (maximum: 25 mg/dose) twice weekly (individual doses should be separated by 72-96 hours)

DOSING: ELDERLY — SubQ: Refer to adult dosing. Although greater sensitivity of some elderly patients cannot be ruled out, no overall differences in safety or effectiveness were observed.

DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Injection, powder for reconstitution:
Enbrel®: 25 mg [contains sucrose 10 mg; diluent contains benzyl alcohol]

Injection, solution [preservative free]:
Enbrel®: 50 mg/mL (0.51 mL, 0.98 mL) [contains sucrose 1%; natural rubber/natural latex in packaging]

DOSAGE FORMS: CONCISE
Injection, powder for reconstitution:
Enbrel®: 25 mg

Injection, solution [preservative free]:
Enbrel®: 50 mg/mL (0.51 mL, 0.98 mL)

GENERIC EQUIVALENT AVAILABLE — No

ADMINISTRATION — Administer subcutaneously. Rotate injection sites. New injections should be given at least one inch from an old site and never into areas where the skin is tender, bruised, red, or hard. Note: If the physician determines that it is appropriate, patients may self-inject after proper training in injection technique.

Powder for reconstitution: Follow package instructions carefully for reconstitution. The maximum amount injected at any single site should not exceed 25 mg.

Solution for injection: May be allowed to reach room temperature prior to injection.

USE — Treatment of moderately- to severely-active rheumatoid arthritis (RA); moderately- to severely-active polyarticular juvenile idiopathic arthritis (JIA); psoriatic arthritis; active ankylosing spondylitis (AS); moderate-to-severe chronic plaque psoriasis

ADVERSE REACTIONS SIGNIFICANT — Percentages reported for adults except where specified.

>10%:
Central nervous system: Headache (17%; children 19%)
Gastrointestinal: Abdominal pain (5%; children 19%), vomiting (3%; children 13%)
Local: Injection site reaction (14% to 37%; erythema, itching, pain or swelling)
Respiratory: Respiratory tract infection (upper; 12% to 29%), rhinitis (12% to 16%)
Miscellaneous: Infection (35%; children 63%), positive ANA (11%), positive antidouble-stranded DNA antibodies (15% by RIA, 3% by Crithidia luciliae assay)

≥3% to 10%:
Cardiovascular: Edema (2% to 8%)
Central nervous system: Dizziness (7%)
Dermatologic: Rash (5%)
Gastrointestinal: Dyspepsia (4%), nausea (children 9%)
Neuromuscular & skeletal: Weakness (5%)
Respiratory: Pharyngitis (7%), respiratory disorder (5%), sinusitis (3%), cough (6%)

<3%, postmarketing, and/or case reports: Abscess, adenopathy, allergic reactions, alopecia, anemia, angioedema, anorexia, aplastic anemia, appendicitis, aseptic meningitis, bursitis, cerebral ischemia, chest pain, cholecystitis, coagulopathy; demyelinating CNS disorders (suggestive of multiple sclerosis, transverse myelitis, or optic neuritis); deep vein thrombosis, depression, diarrhea, dyspnea, erythema multiforme, fatigue, fever, flushing, flu-like syndrome, gastrointestinal hemorrhage, heart failure, hepatitis (autoimmune), hydrocephalus (with normal pressure), hyper-/hypotension; infections (bacterial, fungal, protozoal, viral); interstitial lung disease, intestinal perforation, joint pain, leukopenia, lupus-like syndrome, lymphadenopathy, malignancies (including lymphoma), membranous glomerulopathy, MI, mouth ulcer, multiple sclerosis, myocardial ischemia, neutropenia, ocular inflammation, optic neuritis, pancytopenia, pancreatitis, paresthesia, polymyositis, pruritus, psoriasis exacerbation, pulmonary disease, pulmonary embolism, renal calculus, sarcoidosis, seizure, stroke, Stevens-Johnson syndrome, subcutaneous nodules, taste disturbances, thrombocytopenia, thrombophlebitis, toxic epidermal necrolysis, transaminases increased, tuberculosis, tuberculous arthritis, urinary tract infection, urticaria, vasculitis (cutaneous), weight gain, xerophthalmia, xerostomia

CONTRAINDICATIONS — Hypersensitivity to etanercept or any component of the formulation; patients with sepsis (mortality may be increased); active infections (including chronic or local infection)

WARNINGS / PRECAUTIONS
Boxed warnings:

* Infections: See "Concerns related to adverse effects" below.

* Tuberculosis: See "Concerns related to adverse effects" below.

Concerns related to adverse effects:

* Anaphylaxis/hypersensitivity reactions: Allergic reactions may occur, but anaphylaxis has not been observed. If an anaphylactic reaction or other serious allergic reaction occurs, administration should be discontinued immediately and appropriate therapy initiated.
* Autoimmune disorder: Positive antinuclear antibody titers have been detected in patients (with negative baselines). Rare cases of autoimmune disorder, including lupus-like syndrome or autoimmune hepatitis, have been reported; monitor and discontinue if symptoms develop.
* Hepatitis B: Rare reactivation of hepatitis B has occurred in chronic carriers of the virus; evaluate prior to initiation and during treatment in patients at risk for hepatitis B infection.
* Infections: [U.S. Boxed Warning]: Serious and potentially fatal infections have been reported including bacterial sepsis and tuberculosis. Discontinue administration if patient develops a serious infection or sepsis. Caution should be exercised when considering the use in patients with chronic infection, history of recurrent infection, or predisposition to infection (such as poorly-controlled diabetes). Do not give to patients with an active chronic or localized infection. Patients should be educated about the symptoms of infection and closely monitored for signs and symptoms while undergoing treatment.
* Malignancy: Use may affect defenses against malignancies; impact on the development and course of malignancies is not fully defined. As compared to the general population, an increased risk of lymphoma has been noted in clinical trials; however, rheumatoid arthritis has been previously associated with an increased rate of lymphoma.
* Tuberculosis: [U.S. Boxed Warning]: Tuberculosis (disseminated or extrapulmonary) has been reported in patients receiving etanercept; both reactivation of latent infection and new infections have been reported. Patients should be evaluated for latent tuberculosis infection with a tuberculin skin test prior to starting therapy. Treatment of latent tuberculosis should be initiated before therapy is used. Some patients who tested negative prior to therapy have developed active infection; monitor for signs and symptoms of tuberculosis in all patients.

Disease-related concerns:

* Demyelinating CNS disease: Use with caution in patients with pre-existing or recent onset CNS demyelinating disorders; rare cases of new onset or exacerbation of CNS demyelinating disorders have occurred; may present with mental status changes and some may be associated with permanent disability. Optic neuritis, transverse myelitis, multiple sclerosis, and new onset or exacerbation of seizures have been reported.
* Heart failure: Use with caution in patients with heart failure or decreased left ventricular function; worsening and new-onset heart failure has been reported.
* Hematologic disorders: Use with caution in patients with a history of significant hematologic abnormalities; has been associated with pancytopenia and aplastic anemia (rare cases in postmarketing experience). Patients must be advised to seek medical attention if they develop signs and symptoms suggestive of blood dyscrasias; discontinue if significant hematologic abnormalities are confirmed.
* Wegener's granulomatosis: Use is not recommended for use in patients with Wegener's granulomatosis who are receiving immunosuppressive therapy due to higher incidence of noncutaneous solid malignancies.

Concurrent drug therapy issues:

* Anakinra: Due to higher incidence of serious infections, should not be used in combination with anakinra unless no satisfactory alternatives exist, and then only with extreme caution.

Special populations:

* Pediatrics: Safety and efficacy have not been established in children <2 years of age.
* Varicella virus exposure: Patients with a significant exposure to varicella virus should temporarily discontinue therapy; treatment with varicella zoster immune globulin should be considered.

Dosage form specific issues:

* Latex: Some dosage forms may contain dry natural rubber (latex).

Other warnings/precautions:

* Immunizations: Patients should be brought up to date with all immunizations before initiating therapy. Live vaccines should not be given concurrently; there is no data available concerning secondary transmission of live vaccines in patients receiving therapy.

RESTRICTIONS
An FDA-approved patient medication guide is available and must be distributed when dispensing an outpatient prescription (new or refill) where this medication is to be used without direct supervision of a healthcare provider. Medication guides are available at http://www.fda.gov/cder/Offices/ODS/medication_guides.htm.

DRUG INTERACTIONS
Abatacept: Anti-TNF Agents may enhance the adverse/toxic effect of Abatacept. An increased risk of serious infection during concomitant use has been reported. Risk D: Consider therapy modification

(For additional information: Launch Lexi-Interact™ Drug Interactions Program )

Anakinra: Anti-TNF Agents may enhance the adverse/toxic effect of Anakinra. An increased risk of serious infection during concomitant use has been reported. Risk X: Avoid combination

Cyclophosphamide: Etanercept may enhance the adverse/toxic effect of Cyclophosphamide. An increased risk of solid cancer development may be present. Risk D: Consider therapy modification

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Risk D: Consider therapy modification

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Risk X: Avoid combination

Rilonacept: Anti-TNF Agents may enhance the adverse/toxic effect of Rilonacept. Risk X: Avoid combination

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Risk C: Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Risk C: Monitor therapy

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Vaccinal infections may develop. Immunosuppressants may also decrease therapeutic response to vaccines. Risk X: Avoid combination

ETHANOL / NUTRITION / HERB INTERACTIONS — Herb/Nutraceutical: Echinacea may decrease the therapeutic effects of etanercept (avoid concurrent use).

PREGNANCY RISK FACTOR — B (show table)

PREGNANCY IMPLICATIONS — Developmental toxicity studies performed in animals have revealed no evidence of harm to the fetus. There are no studies in pregnant women; this drug should be used during pregnancy only if clearly needed. A pregnancy registry has been established to monitor outcomes of women exposed to etanercept during pregnancy (877-311-8972).

LACTATION — Excretion in breast milk unknown/not recommended

BREAST-FEEDING CONSIDERATIONS — It is not known whether etanercept is excreted in human milk. Because many immunoglobulins are excreted in human milk and the potential for serious adverse reactions exists, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

PRICING — (data from drugstore.com)
Kit (Enbrel)
25 mg (4): $748.92

Solution (Enbrel)
50 mg/mL (3.92): $1471.69

Solution (Enbrel SureClick)
50 mg/mL (3.92): $1541.98

MONITORING PARAMETERS
Signs and symptoms of infection (prior to and during therapy); latent TB screening prior to therapy initiation

CANADIAN BRAND NAMES — Enbrel®

INTERNATIONAL BRAND NAMES — Enbrel (AR, AT, AU, BE, BG, BR, CH, CN, CO, CR, CZ, DE, DK, ES, FI, FR, GB, GR, GT, HK, HN, IE, IL, IN, IT, KP, MX, MY, NI, NL, NO, PA, PE, PH, PL, PT, RU, SE, SG, SV, TH, TR, VE)

MECHANISM OF ACTION — Etanercept is a recombinant DNA-derived protein composed of tumor necrosis factor receptor (TNFR) linked to the Fc portion of human IgG1. Etanercept binds tumor necrosis factor (TNF) and blocks its interaction with cell surface receptors. TNF plays an important role in the inflammatory processes and the resulting joint pathology of rheumatoid arthritis (RA), polyarticular-course juvenile idiopathic arthritis (JIA), ankylosing spondylitis (AS), and plaque psoriasis.

PHARMACODYNAMICS / KINETICS
Onset of action: ~2-3 weeks; RA: 1-2 weeks

Half-life elimination: RA: SubQ: 72-132 hours

Time to peak: RA: SubQ: 35-103 hours

Excretion: Clearance: Children: 45.9 mL/hour/m2; Adults: 89 mL/hour (52 mL/hour/m2)

PATIENT INFORMATION — If self-injecting, follow instructions for injection and disposal of needles exactly. If redness, swelling, or irritation appears at the injection site, contact prescriber. Do not have any vaccinations while using this medication without consulting prescriber first. You may experience headache or dizziness (use caution when driving or engaging in tasks requiring alertness until response to drug is known). If stomach pain or cramping, unusual bleeding or bruising, persistent fever, paleness, blood in vomitus, stool, or urine occurs, stop taking medication and contact prescriber immediately. Also immediately report skin rash, unusual muscle or bone weakness, or signs of respiratory flu or other infection (eg, chills, fever, sore throat, easy bruising or bleeding, mouth sores, unhealed sores).