Disease modifying agents  (Anti-rheumatic agents)

adalimumab (Humira ®): anakinra (Kineret ®) auranofin (Ridaura ®) azathioprine (Imuran ®) etanercept (Enbrel ® ) hydroxychloroquine (Plaquenil ®) infliximab (Remicade ® ) leflunomide (Arava ®) methotrexate (Rheumatrex ®) sulfasalazine (Azulfidine ®)

adalimumab  (Humira ®):

Mechanism of Action Adalimumab binds specifically to TNF-alpha and blocks its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface TNF expressing cells in vitro in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (TNF-beta). TNF is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. Elevated levels of TNF are found in the synovial fluid of rheumatoid arthritis, including juvenile idiopathic arthritis, psoriatic arthritis, and ankylosing spondylitis patients and play an important role in both the pathologic inflammation and the joint destruction that are hallmarks of these diseases. Increased levels of TNF are also found in psoriasis (Ps) plaques. In plaque psoriasis, treatment with HUMIRA may reduce the epidermal thickness and infiltration of inflammatory cells. The relationship between these pharmacodynamic activities and the mechanism(s) by which HUMIRA exerts its clinical effects is unknown. Adalimumab also modulates biological responses that are induced or regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). INDICATIONS AND USAGE 1.1 Rheumatoid Arthritis HUMIRA is indicated for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in adult patients with moderately to severely active rheumatoid arthritis. HUMIRA can be used alone or in combination with methotrexate or other disease-modifying anti-rheumatic drugs (DMARDs). 1.2 Juvenile Idiopathic Arthritis HUMIRA is indicated for reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis in patients 4 years of age and older. HUMIRA can be used alone or in combination with methotrexate. 1.3 Psoriatic Arthritis HUMIRA is indicated for reducing signs and symptoms of active arthritis, inhibiting the progression of structural damage, and improving physical function in patients with psoriatic arthritis. HUMIRA can be used alone or in combination with DMARDs. 1.4 Ankylosing Spondylitis HUMIRA is indicated for reducing signs and symptoms in patients with active ankylosing spondylitis. 1.5 Crohn’s Disease HUMIRA is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in adult patients with moderately to severely active Crohn’s disease who have had an inadequate response to conventional therapy. HUMIRA is indicated for reducing signs and symptoms and inducing clinical remission in these patients if they have also lost response to or are intolerant to infliximab. 1.6 Plaque Psoriasis HUMIRA is indicated for the treatment of adult patients with moderate to severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy, and when other systemic therapies are medically less appropriate. HUMIRA should only be administered to patients who will be closely monitored and have regular follow-up visits with a physician. Dosing (Adults): rheumatoid arthritis: 40 mg SQ every other week. The drug can be given concomitantly with methotrexate. Whether adalimumab will offer a significant advantage over infliximab or etanercept remains to be determined. SUPPLIED: Injection, solution [preservative free]: 40 mg/0.8 mL (1 mL) [prefilled glass syringe; packaged with alcohol preps]

anakinra  (Kineret ®)

CLINICAL PHARMACOLOGY Kineret® blocks the biologic activity of IL-1 by competitively inhibiting IL-1 binding to the interleukin-1 type I receptor (IL-1RI), which is expressed in a wide variety of tissues and organs.1 IL-1 production is induced in response to inflammatory stimuli and mediates various physiologic responses including inflammatory and immunological responses. IL-1 has a broad range of activities including cartilage degradation by its induction of the rapid loss of proteoglycans, as well as stimulation of bone resorption.2 The levels of the naturally occurring IL-1Ra in synovium and synovial fluid from rheumatoid arthritis (RA) patients are not sufficient to compete with the elevated amount of locally produced IL-1. Dosing (Adults): Rheumatoid arthritis: 100 mg/day SQ daily. Higher doses did not result in a higher response. The dose should be administered at approximately the same time every day. SUPPLIED: Injection, solution [preservative free]: 100 mg/0.67 mL (1 mL) [prefilled syringe]

auranofin  (Ridaura ®)

Oral gold compound. Dosing (Adults): Normal dose (rheumatoid arthritis): Adults: 6 mg/day in 1-2 divided doses; after 3 months may be increased to 9 mg/day in 3 divided doses; if still no response after 3 months at 9 mg/day, discontinue drug SUPPLIED: Capsule: 3 mg [29% gold]

azathioprine  (Imuran ®)

An immunosuppressive agent. Dosing (Adults): (Rheumatoid arthritis): Initial dose: 1 mg/kg (50-100mg) orally once daily or divided twice daily. In the absence of serious toxicity and if response is unsatisfactory, the dose can be increased, beginning at 6 to 8 weeks and thereafter at 4 week intervals, in increments of 0.5 milligrams/kilogram/day up to a maximum dose of 2.5 milligrams/kilogram/day. Patients who do not improve after 12 weeks of therapy can be considered refractory. Dosing adjustment in renal impairment: Clcr 10-50 mL/minute: Administer 75% of normal dose daily Clcr<10 mL/minute: Administer 50% of normal dose daily Hemodialysis: Slightly dialyzable (5% to 20%) Administer dose post hemodialysis: CAPD effects: Unknown; CAVH effects: Unknown SUPPLIED: Injection, powder for reconstitution, as sodium: 100 mg Tablet [scored]: 50 mg Azasan®: 25 mg, 50 mg, 75 mg, 100 mg Imuran®: 50 mg

etanercept  (Enbrel ® )

General Etanercept binds specifically to tumor necrosis factor (TNF) and blocks its interaction with cell surface TNF receptors. TNF is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. It plays an important role in the inflammatory processes of rheumatoid arthritis (RA), polyarticular-course juvenile idiopathic arthritis (JIA), and ankylosing spondylitis and the resulting joint pathology. In addition, TNF plays a role in the inflammatory process of plaque psoriasis. Elevated levels of TNF are found in involved tissues and fluids of patients with RA, psoriatic arthritis, ankylosing spondylitis (AS), and plaque psoriasis. Two distinct receptors for TNF (TNFRs), a 55 kilodalton protein (p55) and a 75 kilodalton protein (p75), exist naturally as monomeric molecules on cell surfaces and in soluble forms. Biological activity of TNF is dependent upon binding to either cell surface TNFR. Etanercept is a dimeric soluble form of the p75 TNF receptor that can bind to two TNF molecules. It inhibits the activity of TNF in vitro and has been shown to affect several animal models of inflammation, including murine collagen-induced arthritis. Etanercept inhibits binding of both TNFα and TNFβ (lymphotoxin alpha [LTα]) to cell surface TNFRs, rendering TNF biologically inactive. Cells expressing transmembrane TNF that bind ENBREL® are not lysed in vitro in the presence or absence of complement. Etanercept can also modulate biological responses that are induced or regulated by TNF, including expression of adhesion molecules responsible for leukocyte migration (i.e., E-selectin and to a lesser extent intercellular adhesion molecule-1 [ICAM-1]), serum levels of cytokines (e.g., IL-6), and serum levels of matrix metalloproteinase-3 (MMP-3 or stromelysin INDICATIONS AND USAGE 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. ENBREL® is indicated for reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis in patients ages 2 and older. 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. ENBREL® is indicated for reducing signs and symptoms in patients with active ankylosing spondylitis. 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. CONTRAINDICATIONS ENBREL® should not be administered to patients with sepsis or with known hypersensitivity to ENBREL® or any of its components Dosing (Adults): Rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis: Once-weekly dosing: 50 mg once weekly Twice weekly dosing: 25 mg given twice weekly (individual doses should be separated by 72-96 hours) Note: If the physician determines that it is appropriate, patients may self-inject after proper training in injection technique. 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. Powder for reconstitution: Follow package instructions carefully for reconstitution. Note: The needle cover of the diluent syringe (multidose vial) may contain dry natural rubber (latex) which should not be handled by persons sensitive to this substance. The maximum amount injected at any single site should not exceed 25 mg. Prefilled syringe: May be allowed to reach room temperature prior to injection. SUPPLIED: Injection, powder for reconstitution: 25 mg [diluent contains benzyl alcohol; packaging may contain dry natural rubber (latex)] Injection, solution: 50 mg/mL (0.98 mL) [prefilled syringe with 27-gauge 1 /2 inch needle]

hydroxychloroquine  (Plaquenil ®)

ACTIONS The drug possesses antimalarial actions and also exerts a beneficial effect in lupus erythematosus (chronic discoid or systemic) and acute or chronic rheumatoid arthritis. The precise mechanism of action is not known. Dosing (Adults): (Rheumatoid arthritis) Initial dose: 400 to 600 mg orally once daily with food or milk. qd--then taper dose (usually after 4 to 12 weeks) to 200-400mg orally once daily. If there is no improvement after 6 months, discontinue drug. SUPPLIED: Tablet, as sulfate: 200 mg

infliximab  (Remicade ® )

Dosing (Adults): Rheumatoid Arthritis. The recommended dose of Remicade is 3 mg/kg given as an intravenous infusion followed with additional similar doses at 2 and 6 weeks after the first infusion then every 8 weeks thereafter. Should be given in combination with methotrexate. For patients who have an incomplete response, consideration may be given to adjusting the dose up to 10 mg/kg or treating as often as every 4 weeks. SUPPLIED: Injection, powder for reconstitution [preservative free]: 100 mg

leflunomide  (Arava ®)

Mechanism of Action Leflunomide is an isoxazole immunomodulatory agent which inhibits dihydroorotate dehydrogenase (an enzyme involved in de novo pyrimidine synthesis) and has antiproliferative activity. Several in vivo and in vitro experimental models have demonstrated an anti-inflammatory effect. INDICATIONS AND USAGE Leflunomide tablets are indicated in adults for the treatment of active rheumatoid arthritis (RA): 1. to reduce signs and symptoms 2. to inhibit structural damage as evidenced by X-ray erosions and joint space narrowing. Aspirin, nonsteroidal anti-inflammatory agents and/or low dose corticosteroids may be continued during treatment with leflunomide tablets. The combined use of leflunomide tablets with antimalarials, intramuscular or oral gold, D penicillamine, azathioprine, or methotrexate has not been adequately studied. Dosing (Adults): (active rheumatoid arthritis): Oral: Initial: 100 mg/day for 3 days, followed by 20 mg/day; dosage may be decreased to 10 mg/day in patients who have difficulty tolerating the 20 mg dose. Due to the long half-life of the active metabolite, plasma levels may require a prolonged period to decline after dosage reduction. Elderly: Although hepatic function may decline with age, no specific dosage adjustment is recommended. Patients should be monitored closely for adverse effects which may require dosage adjustment. Dosing adjustment in hepatic toxicity: Guidelines for dosage adjustment or discontinuation based on the severity and persistence of ALT elevation secondary to leflunomide have been developed. If ALT elevations >2 times but </= 3 times ULN are noted, reduce dose to 10 mg/day, and monitor closely. If elevations persist or if elevations >3 times ULN are observed, discontinue leflunomide and initiate protocol to accelerate elimination. Cholestyramine (8 g 3 times/day for 1-3 days) or activated charcoal (50 g every 6 hours for 24 hours) may be administered to decrease leflunomide concentrations rapidly. If elevations >3 times ULN persist additional cholestyramine and/or activated charcoal may be required. SUPPLIED: Tablet: 10 mg, 20 mg

methotrexate  (Rheumatrex ®)

CLINICAL PHARMACOLOGY: Methotrexate inhibits dihydrofolic acid reductase. Dihydrofolates must be reduced to tetrahydrofolates by this enzyme before they can be utilized as carriers of one-carbon groups in the synthesis of purine nucleotides and thymidylate. Therefore, methotrexate interferes with DNA synthesis, repair, and cellular replication. Actively proliferating tissues such as malignant cells, bone marrow, fetal cells, buccal and intestinal mucosa, and cells of the urinary bladder are in general more sensitive to this effect of methotrexate. When cellular proliferation in malignant tissues is greater than in most normal tissues, methotrexate may impair malignant growth without irreversible damage to normal tissues. The mechanism of action in rheumatoid arthritis is unknown; it may affect immune function. Two reports describe in vitro methotrexate inhibition of DNA precursor uptake by stimulated mononuclear cells, and another describes, in animal polyarthritis partial correction by methotrexate of spleen cell hyporesponsiveness and suppressed IL 2 production. Other laboratories, however, have been unable to demonstrate similar effects. Clarification of methotrexate’s effect on immune activity and its relation to rheumatoid immunopathogenesis await further studies. In patients with rheumatoid arthritis, effects of methotrexate on articular swelling and tenderness can be seen as early as 3 to 6 weeks. Although methotrexate clearly ameliorates symptoms of inflammation (pain, swelling, stiffness), there is no evidence that it induces remission of rheumatoid arthritis nor has a beneficial effect been demonstrated on bone erosions and other radiologic changes which result in impaired joint use, functional disability, and deformity. Most studies of methotrexate in patients with rheumatoid arthritis are relatively short term (3 to 6 months). Limited data from long-term studies indicate that an initial clinical improvement is maintained for at least two years with continued therapy. In psoriasis, the rate of production of epithelial cells in the skin is greatly increased over normal skin. This differential in proliferation rates is the basis for the use of methotrexate to control the psoriatic process. In a 6-month, double-blind, placebo-controlled trial of 127 pediatric patients with juvenile rheumatoid arthritis (JRA) (mean age, 10.1 years; age range, 2.5 to 18 years; mean duration of disease, 5.1 years) on background nonsteroidal anti-inflammatory drugs (NSAIDs) and/or prednisone, methotrexate given weekly at an oral dose of 10 mg/m2 provided significant clinical improvement compared to placebo as measured by either the physician’s global assessment, or by a patient composite (25% reduction in the articular-severity score plus improvement in parent and physician global assessments of disease activity.) Over two-thirds of the patients in this trial had polyarticular-course JRA, and the numerically greatest response was seen in this subgroup treated with 10 mg/m2/wk methotrexate. The overwhelming majority of the remaining patients had systemic-course JRA. All patients were unresponsive to NSAIDs; approximately one-third were using low dose corticosteroids. Weekly methotrexate at a dose of 5 mg/m2 was not significantly more effective than placebo in this trial. INDICATIONS AND USAGE: Neoplastic Diseases: Methotrexate tablets are indicated in the treatment of gestational choriocarcinoma, chorioadenoma destruens and hydatidiform mole. Methotrexate is used alone or in combination with other anticancer agents in the treatment of breast cancer, epidermoid cancers of the head and neck, advanced mycosis fungoides, (cutaneous T cell lymphoma), and lung cancer, particularly squamous cell and small cell types. Methotrexate is also used in combination with other chemotherapeutic agents in the treatment of advanced stage non-Hodgkin’s lymphomas. Psoriasis: Methotrexate tablets are indicated in the symptomatic control of severe, recalcitrant, disabling psoriasis that is not adequately responsive to other forms of therapy, but only when the diagnosis has been established, as by biopsy and/or after dermatologic consultation. It is important to ensure that a psoriasis “flare” is not due to an undiagnosed concomitant disease affecting immune responses. Rheumatoid Arthritis including Polyarticular-Course Juvenile Rheumatoid Arthritis: Methotrexate tablets are indicated in the management of selected adults with severe, active, rheumatoid arthritis (ARC criteria), or children with active polyarticular-course juvenile rheumatoid arthritis, who have had an insufficient therapeutic response to, or are intolerant of, an adequate trial of first-line therapy including full dose non-steroidal anti-inflammatory agents (NSAIDs). Aspirin, NSAIDs, and/or low dose steroids may be continued, although the possibility of increased toxicity with concomitant use of NSAIDs including salicylates has not been fully explored (see PRECAUTIONS, Drug Interactions). Steroids may be reduced gradually in patients who respond to methotrexate. Combined use of methotrexate with gold, penicillamine, hydroxychloroquine, sulfasalazine, or cytotoxic agents, has not been studied and may increase the incidence of adverse effects. Rest and physiotherapy as indicated should be continued Dosing (Adults): Rheumatoid arthritis: Starting dose: 7.5 milligrams orally once a week. This dosage may be administered as a single dose or as a divided dose of 2.5 mg every 12 hours for 3 doses once a week. Once a response has been achieved, reduce the dosage if possible to the lowest effective dose. Maximum recommended dose: 20 mg/week. Consider folate supplementation. SUPPLIED: Injection, powder for reconstitution [preservative free]: 20 mg, 1 g Injection, solution, as sodium: 25 mg/mL (2 mL, 10 mL) Injection, solution, as sodium [preservative free]: 25 mg/mL (2 mL, 4 mL, 8 mL, 10 mL) Tablet, as sodium: 2.5 mg Rheumatrex®: 2.5 mg Trexall™: 5 mg, 7.5 mg, 10 mg, 15 mg Tablet, as sodium [dose pack] (Rheumatrex® Dose Pack): 2.5 mg (4 cards with 2, 3, 4, 5, or 6 tablets each)

sulfasalazine  (Azulfidine ®)

Indicated in the treatment of rheumatoid arthritis in patients who have responded inadequately to salicylates or other non-steroidal anti-inflammatory drugs. Dosing (Adults): Rheumatoid arthritis: Enteric coated tablet: Initial: 0.5-1 g/day; increase weekly to maintenance dose of 2 g/day in 2 divided doses; maximum: 3 g/day (if response to 2 g/day is inadequate after 12 weeks of treatment) Dosing interval in renal impairment: Clcr 10-30 mL/minute: Administer twice daily Clcr<10 mL/minute: Administer once daily Dosing adjustment in hepatic impairment: Avoid use SUPPLIED: Tablet (Azulfidine®): 500 mg Tablet, delayed release, enteric coated (Azulfidine® EN-tabs®): 500 mg

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