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Special Alerts
Tumor Necrosis Factor (TNF) Blockers: Surveillance of Malignancies in Pediatric, Adolescent, and Young Adult Patients
November 2011
The U.S. Food and Drug Administration (FDA) is updating the public about an ongoing surveillance program of reported cases of malignancy in patients ≤30 years of age treated with TNF blockers, including adalimumab, certolizumab pegol, etanercept, golimumab, and infliximab. The FDA is requiring enhanced safety surveillance by the manufacturers of TNF blockers to include:
- In-depth follow-up on all reported malignancy cases
- Expedited reporting of all malignancy cases to the FDA
- Yearly summary and assessment of malignancies and TNF blocker usage data
Collected data will be re-evaluated periodically by the FDA over the next 10 years. Healthcare professionals should continue to be alert for possible malignancies in patients being treated with TNF blockers and report positive findings to the FDA's MedWatch program (1-800-332-1088 or https://www.accessdata.fda.gov/scripts/medwatch/medwatch-online.htm) or to the manufacturer.
For additional information, please refer to http://www.fda.gov/Drugs/DrugSafety/ucm278267.htm
Tumor Necrosis Factor-alpha (TNFα) Blockers: Risk of Infection from Legionella and Listeria
September 2011
The U.S. Food and Drug Administration (FDA) is notifying healthcare professionals of an update to the Boxed Warning for the entire class of tumor necrosis factor-alpha (TNFα) blockers including Remicade® (infliximab), Enbrel® (etanercept), Humira® (adalimumab), Cimzia® (certolizumab pegol), and Simponi® (golimumab). The Boxed Warning will include the risk of infection from two bacterial pathogens, Legionella and Listeria.
For additional information, please refer to http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm270977.htm
ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Pronunciation
(a da LIM yoo mab)
Generic Available (U.S.)
No
Index Terms
Medication Guide
An FDA-approved patient medication guide, which is available with the product information and at http://www.fda.gov/downloads/Drugs/DrugSafety/ucm088611.pdf, must be dispensed with this medication.
REMS Components
Humira®: Released from REMS 12/13/2011
Brand Names: U.S.
Brand Names: Canada
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Treatment of active rheumatoid arthritis (moderate-to-severe) and active psoriatic arthritis; may be used alone or in combination with disease-modifying antirheumatic drugs (DMARDs); treatment of ankylosing spondylitis
Treatment of moderately- to severely-active Crohn's disease in patients with inadequate response to conventional treatment, or patients who have lost response to or are intolerant of infliximab
Treatment of moderate-to-severe plaque psoriasis
Treatment of moderately- to severely-active juvenile idiopathic arthritis
Pregnancy Risk Factor
B
Pregnancy Considerations
Teratogenic effects were not observed in animal studies, however, there are no adequate and well-controlled studies in pregnant women. Use during pregnancy only if clearly needed. A pregnancy registry has been established to monitor outcomes of women exposed to adalimumab during pregnancy (877-311-8972).
Lactation
Excretion in breast milk unknown/not recommended
Breast-Feeding Considerations
It is not known whether adalimumab is secreted in human milk. Because many immunoglobulins are secreted in milk and the potential for serious adverse reactions exists, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
Contraindications
There are no contraindications listed within the FDA-approved labeling.
Canadian labeling: Additional contraindications (not in U.S. labeling): Hypersensitivity to adalimumab or any component of the formulation; severe infection (eg, sepsis, tuberculosis, opportunistic infection)
Warnings/Precautions
Boxed warnings:
• Fatal infections: See “Concerns related to adverse effects” below.
• Malignancy: See “Concerns related to adverse effects” below.
• Tuberculosis: See “Concerns related to adverse effects” below.
Concerns related to adverse effects:
• Anaphylaxis/hypersensitivity reactions: May rarely cause hypersensitivity, anaphylaxis, anaphylactoid reactions, or angioedema; medications for the treatment of hypersensitivity reactions should be available for immediate use.
• Autoimmune disorder: Positive antinuclear antibody titers have been detected in patients (with negative baselines). Rare cases of autoimmune disorder, including lupus-like syndrome, have been reported; monitor and discontinue if symptoms develop.
• Hepatitis B: Rare reactivation of hepatitis B (HBV) has occurred in chronic carriers of the virus, usually in patients receiving concomitant immunosuppressants; evaluate for HBV prior to initiation in all patients. Monitor during and for several months following discontinuation of treatment in HBV carriers; interrupt therapy if reactivation occurs and treat appropriately with antiviral therapy; if resumption of therapy is deemed necessary, exercise caution and monitor patient closely.
• Infections: [U.S. Boxed Warning]: Patients receiving adalimumab are at increased risk for serious infections which may result in hospitalization and/or fatality; infections usually developed in patients receiving concomitant immunosuppressive agents (eg, methotrexate or corticosteroids) and may present as disseminated (rather than local) disease. Active tuberculosis (or reactivation of latent tuberculosis), invasive fungal (including aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, and pneumocystosis) and bacterial, viral or other opportunistic infections (including legionellosis and listeriosis) have been reported in patients receiving TNF-blocking agents, including adalimumab. Monitor closely for signs/symptoms of infection. Discontinue for serious infection or sepsis. Consider risks versus benefits prior to use in patients with a history of chronic or recurrent infection. Consider empiric antifungal therapy in patients who are at risk for invasive fungal infection and develop severe systemic illness. Caution should be exercised when considering use in the elderly or in patients with conditions that predispose them to infections (eg, diabetes) or residence/travel from areas of endemic mycoses (blastomycosis, coccidioidomycosis, histoplasmosis), or with latent or localized infections. Do not initiate adalimumab therapy with clinically important active infection. Patients who develop a new infection while undergoing treatment should be monitored closely.
• Malignancy: [U.S. Boxed Warning]: Lymphoma and other malignancies have been reported in children and adolescent patients receiving other TNF-blocking agents. Half the cases are lymphomas (Hodgkin's and non-Hodgkin's) and the other cases are varied, but include malignancies not typically observed in this population. Most patients were receiving concomitant immunosuppressants. [U.S. Boxed Warning]: Hepatosplenic T-cell lymphoma (HSTCL), a rare T-cell lymphoma, has also been reported primarily in patients with Crohn's disease or ulcerative colitis treated with adalimumab and who received concomitant azathioprine or mercaptopurine; reports occurred predominantly in adolescent and young adult males. 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. A higher incidence of nonmelanoma skin cancers was noted in adalimumab-treated patients (0.7/100 patient years), when compared to the control group (0.2/100 patient years). Hepatosplenic T-cell lymphoma (HSTCL), a rare T-cell lymphoma, has also been associated with TNF-blocking agents, primarily reported in adolescent and young adult males with Crohn's disease or ulcerative colitis.
• Pancytopenia: Rare cases of pancytopenia (including aplastic anemia) have been reported with TNF-blocking agents; with significant hematologic abnormalities, consider discontinuing therapy.
• Tuberculosis: Tuberculosis (disseminated or extrapulmonary) has been reactivated while on adalimumab; most cases have been reported within the first 8 months of treatment. Doses higher than recommended are associated with an increased risk for tuberculosis reactivation. [U.S. Boxed Warnings]: Patients should be evaluated for latent tuberculosis infection with a tuberculin skin test prior to therapy. Treatment of latent tuberculosis should be initiated before use. Patients with initial negative tuberculin skin tests should receive continued monitoring for tuberculosis throughout treatment; active tuberculosis has developed in this population during treatment. Use with caution in patients who have resided in regions where tuberculosis is endemic
Disease-related concerns:
• Demyelinating disease: Use with caution in patients with pre-existing or recent onset central or peripheral nervous system demyelinating disorders; rare cases of new-onset or exacerbation of demyelinating disorders (eg, multiple sclerosis, Guillain-Barré syndrome) have been reported. Consider discontinuing use in patients who develop peripheral or central nervous system demyelinating disorders during treatment.
• Heart failure (HF): Use with caution in patients with HF or decreased left ventricular function; worsening and new-onset HF has been reported.
Concurrent drug therapy issues:
• Abatacept: Serious infections were reported when abatacept was used with TNF-blocking agents; therefore, concurrent use of adalimumab and abatacept is not recommended.
• Anakinra: Serious infections were reported when anakinra was used with TNF-blocking agents; therefore, concurrent use of adalimumab and anakinra is not recommended.
Special populations:
• Elderly: Infection and malignancy has been reported at a higher incidence in elderly patients compared to younger adults; use caution in elderly patients.
• Pediatrics: Malignancies have been reported among children and adolescents receiving TNF-blocking agents.
Dosage form specific issues:
• Latex: The packaging (needle cover of prefilled syringe) may contain latex.
• Polysorbate 80: Product may contain polysorbate 80.
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 the effects of therapy on vaccination or secondary transmission of live vaccines in patients receiving therapy.
Adverse Reactions
>10%:
Central nervous system: Headache (12%)
Dermatologic: Rash (6% to 12%)
Local: Injection site reaction (12% to 20%; includes erythema, itching, hemorrhage, pain, swelling)
Neuromuscular & skeletal: CPK increased (15%)
Respiratory: Upper respiratory tract infection (17%), sinusitis (11%)
Miscellaneous: Antibodies to adalimumab (3% to 26%; significance unknown), positive ANA (12%)
5% to 10%:
Cardiovascular: Hypertension (5%)
Endocrine & metabolic: Hyperlipidemia (7%), hypercholesterolemia (6%)
Gastrointestinal: Nausea (9%), abdominal pain (7%)
Genitourinary: Urinary tract infection (8%)
Hepatic: Alkaline phosphatase increased (5%)
Local: Injection site reaction (8%; other than erythema, itching, hemorrhage, pain, swelling)
Neuromuscular & skeletal: Back pain (6%)
Renal: Hematuria (5%)
Miscellaneous: Accidental injury (10%), flu-like syndrome (7%)
1% to 5%:
Cardiovascular: Arrhythmia, atrial fibrillation, chest pain, CHF, coronary artery disorder, heart arrest, MI, palpitation, pericardial effusion, pericarditis, peripheral edema, syncope, tachycardia, thrombosis (leg), vascular disorder
Central nervous system: Confusion, fever, hypertensive encephalopathy, multiple sclerosis, subdural hematoma
Dermatologic: Alopecia, cellulitis, erysipelas
Endocrine & metabolic: Dehydration, menstrual disorder, parathyroid disorder
Gastrointestinal: Diverticulitis, esophagitis, gastroenteritis, gastrointestinal hemorrhage, vomiting
Genitourinary: Cystitis, pelvic pain
Hematologic: Agranulocytosis, granulocytopenia, leukopenia, pancytopenia, paraproteinemia, polycythemia
Hepatic: Cholecystitis, cholelithiasis, hepatic necrosis
Neuromuscular & skeletal: Arthralgia, arthritis, bone fracture, bone necrosis, joint disorder, muscle cramps, myasthenia, pain in extremity, paresthesia, pyogenic arthritis, synovitis, tendon disorder, tremor
Ocular: Cataract
Renal: Kidney calculus, pyelonephritis
Respiratory: Asthma, bronchospasm, dyspnea, lung function decreased, pleural effusion, pneumonia
Miscellaneous: Adenoma, allergic reactions (1%), carcinoma (including breast, gastrointestinal, skin, urogenital), healing abnormality, herpes zoster, ketosis, lupus erythematosus syndrome, lymphoma, melanoma, postsurgical infection, sepsis, tuberculosis (reactivation of latent infection; miliary, lymphatic, peritoneal and pulmonary)
<1%, postmarketing, and/or case reports: Abscess (limb, perianal), anal fistula, anaphylactoid reaction, anaphylaxis, anemia, angioedema, aplastic anemia, appendicitis, basal cell carcinoma, blepharitis, bronchitis, cerebrovascular accident, cervical dysplasia, chest pain (noncardiac), circulatory collapse, clonus, cutaneous vasculitis, cytopenia, diarrhea, diplopia, endometrial hyperplasia, eosinophilia, erythema multiforme, eye swelling, fixed drug eruption, Guillain-Barré syndrome, HBV reactivation, herpes virus infection, histoplasmosis, hyperreflexia, hypersensitivity, infections (bacterial, viral, fungal and protozoal), interstitial lung disease (eg, pulmonary fibrosis), intestinal obstruction, intestinal perforation, leukemias, liver metastases, lupus-like syndrome, lymphadenopathy, lymphocytosis, mycobacterium avium complex infection, necrotizing fasciitis, neutropenia, nocturia, optic neuritis, ovarian cancer, pancreatitis, psoriasis (including new onset, palmoplantar, pustular, or exacerbation), pulmonary embolism, respiratory failure, sarcoidosis, septic arthritis, septic shock, skin ulceration, Stevens-Johnson syndrome, supraventricular arrhythmia, systemic vasculitis, testicular cancer, thrombocytopenia, transaminases increased, urticaria, viral meningitis, weakness
Metabolism/Transport Effects
None known.
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 X: Avoid combination
Abciximab: May enhance the potential for allergic or hypersensitivity reactions to Monoclonal Antibodies. Also may cause thrombocytopenia or diminished therapeutic effects. Risk C: Monitor therapy
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
BCG: Immunosuppressants may diminish the therapeutic effect of BCG. Risk X: Avoid combination
Belimumab: Monoclonal Antibodies may enhance the adverse/toxic effect of Belimumab. Risk X: Avoid combination
Canakinumab: Anti-TNF Agents may enhance the adverse/toxic effect of Canakinumab. Specifically, the risk for serious infections and/or neutropenia may be increased. Risk X: Avoid combination
Certolizumab Pegol: Anti-TNF Agents may enhance the immunosuppressive effect of Certolizumab Pegol. Risk X: Avoid combination
Coccidioidin Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioidin Skin Test. Risk C: Monitor therapy
Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Risk C: Monitor therapy
Echinacea: May diminish the therapeutic effect of Immunosuppressants. Risk D: Consider therapy modification
Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. 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
Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Risk X: Avoid combination
Rilonacept: Anti-TNF Agents may enhance the adverse/toxic effect of Rilonacept. Risk X: Avoid combination
Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Risk D: Consider therapy modification
Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Risk C: Monitor therapy
Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. 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). Vaccinial infections may develop. Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Risk X: Avoid combination
Ethanol/Nutrition/Herb Interactions
Herb/nutraceutical: Echinacea may decrease the therapeutic effects of adalimumab; avoid concurrent use.
Storage
Store under refrigeration at 2°C to 8°C (36°F to 46°F); do not freeze. Protect from light.
Mechanism of Action
Adalimumab is a recombinant monoclonal antibody that binds to human tumor necrosis factor alpha (TNF-alpha), thereby interfering with binding to TNFα receptor sites and subsequent cytokine-driven inflammatory processes. Elevated TNF levels in the synovial fluid are involved in the pathologic pain and joint destruction in immune-mediated arthritis. Adalimumab decreases signs and symptoms of psoriatic arthritis, rheumatoid arthritis, and ankylosing spondylitis. It inhibits progression of structural damage of rheumatoid and psoriatic arthritis. Reduces signs and symptoms and maintains clinical remission in Crohn's disease; reduces epidermal thickness and inflammatory cell infiltration in plaque psoriasis.
Pharmacodynamics/Kinetics
Distribution: Vd: 4.7-6 L; Synovial fluid concentrations: 31% to 96% of serum
Bioavailability: Absolute: 64%
Half-life elimination: Terminal: ~2 weeks (range: 10-20 days)
Time to peak, serum: SubQ: 131 ± 56 hours
Excretion: Clearance increased in the presence of anti-adalimumab antibodies; decreased in patients ≥40 years of age
Dosage
SubQ:
Children ≥4 years: Juvenile idiopathic arthritis (JIA):
15 kg to <30 kg: 20 mg every other week
≥30 kg: 40 mg every other week
Adults:
Rheumatoid arthritis: 40 mg every other week; may be administered with other DMARDs; patients not taking methotrexate may increase dose to 40 mg every week
Ankylosing spondylitis, psoriatic arthritis: 40 mg every other week
Crohn's disease: Initial: 160 mg (given as 4 injections on day 1 or as 2 injections/day over 2 consecutive days), then 80 mg 2 weeks later (day 15); Maintenance: 40 mg every other week beginning day 29. Note: Some patients may require 40 mg every week as maintenance therapy (Lichtenstein, 2009).
Plaque psoriasis: Initial: 80 mg as a single dose; maintenance: 40 mg every other week beginning 1 week after initial dose
Administration: Other
For SubQ injection; rotate injection sites. Do not use if solution is discolored. Do not administer to skin which is red, tender, bruised, or hard. Needle cap of the prefilled syringe may contain latex.
Monitoring Parameters
Monitor improvement of symptoms and physical function assessments. Latent TB screening prior to initiating and during therapy; signs/symptoms of infection (prior to, during, and following therapy); CBC with differential; signs/symptoms/worsening of heart failure; HBV screening prior to initiating (all patients), HBV carriers (during and for several months following therapy); signs and symptoms of hypersensitivity reaction; symptoms of lupus-like syndrome; signs/symptoms of malignancy (eg, splenomegaly, hepatomegaly, abdominal pain, persistent fever, night sweats, weight loss)
Patient Education
Inform prescriber of any allergies, history of tuberculosis, or any kind of infection you have. If self-administered, follow directions for injection and needle/syringe disposal exactly. You may be more susceptible to infection. May cause headache or dizziness; if persistent, consult prescriber. Report persistent fever, increased bruising or bleeding, respiratory tract infection, unhealed or infected wounds, urinary tract infection, flu-like symptoms, unexplained weight loss, persistent cough, enlarged lymph nodes, new skin lesions or eruptions, or unusual bump or sore that does not heal. Stop drug and report immediately persistent nausea or abdominal pain; numbness or tingling; problems with vision; weakness in legs; chest pains, respiratory difficulty; weight gain; swelling of extremities; joint pain; skin rash; or redness, swelling, or pain at injection site.
Geriatric Considerations
In studies, the elderly have an increased incidence of infection and malignancy compared to younger adults <65 years of age. Given the higher incidence of infections and malignancies in the elderly population, caution and close monitoring are recommended when using adalimumab in this population. Additionally, elderly patients with a history of HF may be at risk for HF exacerbation.
Dental Health: Effects on Dental Treatment
No significant effects or complications reported
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
May cause confusion; may exacerbate pre-existing or recent-onset demyelinating CNS disorder
Mental Health: Effects on Psychiatric Treatment
Rare reports of pancytopenia, including aplastic anemia, have been reported with TNF-α-blocking agents. Medically-significant thrombocytopenia and leukopenia have been infrequently reported; use with caution in patients receiving clozapine, carbamazepine, valproic acid, and mirtazapine.
Nursing: Physical Assessment/Monitoring
Perform tuberculin skin test prior to initiating therapy. Monitor for signs of tuberculosis throughout therapy. Do not initiate therapy if active infection is present. Monitor for signs and symptoms of infection, enlarged lymph nodes, or skin lesions/eruptions. Assess for liver dysfunction. Assess results of PDD at regular intervals during treatment. Teach patient proper injection technique and syringe/needle disposal. Latex-sensitive patients: Needle cap of prefilled syringe contains latex.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, solution [preservative free]:
Humira®: 40 mg/0.8 mL (0.8 mL) [contains natural rubber/natural latex in packaging, polysorbate 80; prefilled syringe]
Humira® Pen: 40 mg/0.8 mL (0.8 mL) [contains natural rubber/natural latex in packaging, polysorbate 80]
Injection, solution [pediatric, preservative free]:
Humira®: 20 mg/0.4 mL (0.4 mL) [contains natural rubber/natural latex in packaging, polysorbate 80; prefilled syringe]
Pricing: U.S. (www.drugstore.com)
Kit (Humira)
20 mg/0.4 mL (2): $2144.99
40 mg/0.8 mL (2): $2040.01
Kit (Humira Pen)
40 mg/0.8 mL (2): $2046.90
References
Dommasch E and Gelfand JM, “Is There Truly a Risk of Lymphoma From Biologic Therapies?” Dermatol Ther, 2009, 22 (5):418-30.
Gordon KB, Langley RG, Leonardi C, et al, “Clinical Response to Adalimumab Treatment in Patients With Moderate to Severe Psoriasis: Double-Blind, Randomized Controlled Trial and Open-Label Extension Study,” J Am Acad Dermatol, 2006, 55(4):598-606.
Keystone EC, Kavanaugh AF, Sharp JYT, et al, “Radiographic, Clinical, and Functional Outcomes of Treatment With Adalimumab (A Human Anti-Tumor Necrosis Factor Monoclonal Antibody) in Patients With Active Rheumatoid Arthritis Receiving Concomitant Methotrexate Therapy: A Randomized, Placebo-Controlled, 52-Week Trial,” Arthritis Rheum, 2004, 50(5):1400-11.
Lichtenstein GR, Hanauer SB, and Sandborn WJ, “Management of Crohn's Disease in Adults,” Am J Gastroenterol, 2009, 104(2):465-83.
Parakkal D, Sifuentes H, Semer R, et al, “Hepatosplenic T-Cell Lymphoma in Patients Receiving TNF-α Inhibitor Therapy: Expanding the Groups at Risk,” Eur J Gastroenterol Hepatol, 2011, 23(12):1150-6.
Sandborn WJ, Rutgeerts P, Enns R, et al, "Adalimumab Induction Therapy for Crohn Disease Previously Treated With Infliximab: A Randomized Trial.," Ann Intern Med, 2007, 146(12):829-38.
van der Heijde D, Kivitz A, Schiff MH, et al, “Efficacy and Safety of Adalimumab in Patients With Ankylosing Spondylitis: Results of a Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial,” Arthritis Rheum, 2006, 54(7):2136-46.
International Brand Names
Lexi-Comp.com
Last full review/revision March 2012
Content last modified March 2012
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