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Disease modifying agents  (Anti-rheumatic agents)

DMARDS - Also Biological response modifiers (BRMs)

abatacept - ORENCIA® --
adalimumab (Humira ®): anakinra (Kineret ®)
auranofin (Ridaura ®) azathioprine (Imuran ®)
etanercept (Enbrel ® ) hydroxychloroquine (Plaquenil ®)
infliximab (Remicade ® ) leflunomide (Arava ®)
methotrexate (Rheumatrex ®, OTREXUP™, RASUVO) sulfasalazine (Azulfidine ®)
tocilizumab -ACTEMRA® tofacitinib - XELJANZ ®

Other TNF inhibitors - Biological response modifiers (BRMs)

certolizumab pegol - Cimzia® golimumab - Simponi®
-- --
Disclaimer - Please see package insert for additional information and possible updates. The authors make no claims of the accuracy of the information contained herein; and these suggested doses are not a substitute for clinical judgment. Neither GlobalRPh Inc. nor any other party involved in the preparation of this program shall be liable for any special, consequential, or exemplary damages resulting in whole or part from any user's use of or reliance upon this material. PLEASE READ THE DISCLAIMER CAREFULLY BEFORE ACCESSING OR USING THIS SITE. BY ACCESSING OR USING THIS SITE, YOU AGREE TO BE BOUND BY THE TERMS AND CONDITIONS SET FORTH IN THE DISCLAIMER.   Read the disclaimer

abatacept - ORENCIA®: top of page

Mechanism of Action
Abatacept, a selective costimulation modulator, inhibits T cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. This interaction provides a costimulatory signal necessary for full activation of T lymphocytes. Activated T lymphocytes are implicated in the pathogenesis of RA and are found in the synovium of patients with RA.


In vitro, abatacept decreases T cell proliferation and inhibits the production of the cytokines TNF alpha (TNFalpha), interferon-gamma, and interleukin-2. In a rat collagen-induced arthritis model, abatacept suppresses inflammation, decreases anti-collagen antibody production, and reduces antigen specific production of interferon-gamma. The relationship of these biological response markers to the mechanisms by which ORENCIA exerts its effects in RA is unknown.


INDICATIONS AND USAGE:
ORENCIA is a selective T cell costimulation modulator indicated for:

Adult Rheumatoid Arthritis (RA) : moderately to severely active RA in adults. ORENCIA may be used as monotherapy or concomitantly with DMARDs other than TNF antagonists.

Juvenile Idiopathic Arthritis: moderately to severely active polyarticular juvenile idiopathic arthritis in pediatric patients 6 years of age and older. ORENCIA may be used as monotherapy or concomitantly with methotrexate.

Important Limitations of Use: should not be given concomitantly with TNF antagonists.

USE IN SPECIFIC POPULATIONS
Pregnancy: Registry available. Based on animal data, may cause fetal harm

DOSAGE AND ADMINISTRATION:
Intravenous Administration for Adult RA:
Body Weight of Patient Dose Number of Vials
Less than 60 kg 500 mg 2
60 to 100 kg 750 mg 3
More than 100 kg 1000 mg 4

Subcutaneous Administration for Adult RA :
After a single intravenous infusion as a loading dose (as per body weight categories above), 125 mg administered by a subcutaneous injection should be given within a day, followed by 125 mg subcutaneously once a week.

Patients who are unable to receive an infusion may initiate weekly injections of subcutaneous ORENCIA without an intravenous loading dose.
Patients transitioning from ORENCIA intravenous therapy to subcutaneous administration should administer the first subcutaneous dose instead of the next scheduled intravenous dose.

Juvenile Idiopathic Arthritis:
Pediatric patients weighing less than 75 kg receive 10 mg/kg intravenously based on the patient's body weight. Pediatric patients weighing 75 kg or more should be administered ORENCIA following the adult intravenous dosing regimen, not to exceed a maximum dose of 1000 mg.

General Dosing Information for Intravenous Administration:
Administer as a 30-minute intravenous infusion.
Following initial dose, give at 2 and 4 weeks, then every 4 weeks.
Prepare ORENCIA using only the silicone-free disposable syringe.
Use only sterile water to reconstitute the powder.
The reconstituted product must be administered using a filter.

DOSAGE FORMS AND STRENGTHS:
-250 mg lyophilized powder in a single-use vial for intravenous infusion
-125 mg/mL solution in a single-dose prefilled syringe

CONTRAINDICATIONS:
None

WARNINGS AND PRECAUTIONS
-Concomitant use with a TNF antagonist can increase the risk of infections and serious infections.
-Hypersensitivity, anaphylaxis, and anaphylactoid reactions.
-Patients with a history of recurrent infections or underlying conditions predisposing to infections may experience more infections.
-Discontinue if a serious infection develops.
-Screen for latent TB infection prior to initiating therapy. Patients testing positive should be treated prior to initiating ORENCIA.
-Live vaccines should not be given concurrently or within 3 months of discontinuation.
-Patients with juvenile idiopathic arthritis should be brought up to date with all immunizations prior to ORENCIA therapy.
-Based on its mechanism of action, ORENCIA may blunt the effectiveness of some immunizations.
-COPD patients may develop more frequent respiratory adverse events.

ADVERSE REACTIONS
Most common adverse events (>/=10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea.

To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

adalimumab  (Humira ®):  top of page icon

 WARNING: SERIOUS INFECTIONS AND MALIGNANCY
See full prescribing information for complete boxed warning.
Increased risk of serious infections leading to hospitalization or death, including tuberculosis (TB), bacterial sepsis, .....    Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers including 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
HUMIRA is a tumor necrosis factor (TNF) blocker indicated for treatment of:
Rheumatoid Arthritis (RA):
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 RA.
Juvenile Idiopathic Arthritis (JIA):
Reducing signs and symptoms of moderately to severely active polyarticular JIA in pediatric patients 4 years of age and older.

Psoriatic Arthritis (PsA):
Reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in adult patients with active PsA.

Ankylosing Spondylitis (AS):
Reducing signs and symptoms in adult patients with active AS.

Crohn’s Disease (CD):
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. Reducing signs and symptoms and inducing clinical remission in these patients if they have also lost response to or are intolerant to infliximab.

Ulcerative Colitis (UC):
Inducing and sustaining clinical remission in adult patients with moderately to severely active ulcerative colitis who have had an inadequate response to immunosuppressants such as corticosteroids, azathioprine or 6-mercaptopurine (6-MP). The effectiveness of HUMIRA has not been established in patients who have lost response to or were intolerant to TNF blockers.

Plaque Psoriasis (Ps):
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.

DOSAGE AND ADMINISTRATION
Administered by subcutaneous injection.

Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis:
40 mg every other week.
Some patients with RA not receiving methotrexate may benefit from increasing the frequency to 40 mg every week.

Juvenile Idiopathic Arthritis:
15 kg (33 lbs) to < 30 kg (66 lbs): 20 mg every other week
geq 30 kg (66 lbs): 40 mg every other week

Crohn's Disease and Ulcerative Colitis:
Initial dose (Day 1): 160 mg (four 40 mg injections in one day or two 40 mg injections per day for two consecutive days)
Second dose two weeks later (Day 15): 80 mg
Two weeks later (Day 29): Begin a maintenance dose of 40 mg every other week.
For patients with Ulcerative Colitis only: Only continue HUMIRA in patients who have shown evidence of clinical remission by eight weeks (Day 57) of therapy.

Plaque Psoriasis:
80 mg initial dose, followed by 40 mg every other week starting one week after initial dose.

How Supplied
Injection: 40 mg/0.8 mL in a single-use prefilled pen (HUMIRA Pen)
Injection: 40 mg/0.8 mL in a single-use prefilled glass syringe
Injection: 20 mg/0.4 mL in a single-use prefilled glass syringe

anakinra  (Kineret ®)  top of page icon

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 ®)  top of page icon

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 ®)  top of page icon

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 ® ) top of page icon

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 TNFalpha and TNFbeta (lymphotoxin alpha [LTalpha]) 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 ®)  top of page icon

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 ® ) top of page icon

WARNING: SERIOUS INFECTIONS AND MALIGNANCY
See full prescribing information for complete boxed warning.
Increased risk of serious infections leading to hospitalization or death, including tuberculosis (TB), bacterial sepsis, .....    Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers including infiximab.


INDICATIONS AND USAGE
REMICADE is a tumor necrosis factor (TNF) blocker indicated for:

Crohn's Disease:
reducing signs and symptoms and inducing and maintaining clinical remission in adult patients with moderately to severely active disease who have had an inadequate response to conventional therapy.
reducing the number of draining enterocutaneous and rectovaginal fistulas and maintaining fistula closure in adult patients with fistulizing disease.

Pediatric Crohn's Disease:
reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients with moderately to severely active disease who have had an inadequate response to conventional therapy.

Ulcerative Colitis:
reducing signs and symptoms, inducing and maintaining clinical remission and mucosal healing, and eliminating corticosteroid use in adult patients with moderately to severely active disease who have had an inadequate response to conventional therapy.

Pediatric Ulcerative Colitis:
reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients with moderately to severely active disease who have had an inadequate response to conventional therapy.

Rheumatoid Arthritis in combination with methotrexate:
reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in patients with moderately to severely active disease.

Ankylosing Spondylitis:
reducing signs and symptoms in patients with active disease.

Psoriatic Arthritis:
reducing signs and symptoms of active arthritis, inhibiting the progression of structural damage, and improving physical function.

Plaque Psoriasis:
treatment of adult patients with chronic severe (i.e., extensive and /or disabling) plaque psoriasis who are candidates for systemic therapy and when other systemic therapies are medically less appropriate.

DOSAGE AND ADMINISTRATION
REMICADE is administered by intravenous infusion over a period of not less than 2 hours.

Crohn's Disease
5 mg/kg at 0, 2 and 6 weeks, then every 8 weeks. Some adult patients who initially respond to treatment may benefit from increasing the dose to 10 mg/kg if they later lose their response.

Pediatric Crohn's Disease
5 mg/kg at 0, 2 and 6 weeks, then every 8 weeks.

Ulcerative Colitis
5 mg/kg at 0, 2 and 6 weeks, then every 8 weeks.

Pediatric Ulcerative Colitis
5 mg/kg at 0, 2 and 6 weeks, then every 8 weeks.

Rheumatoid Arthritis
In conjunction with methotrexate, 3 mg/kg at 0, 2 and 6 weeks, then every 8 weeks. Some patients may benefit from increasing the dose up to 10 mg/kg or treating as often as every 4 weeks.

Ankylosing Spondylitis
5 mg/kg at 0, 2 and 6 weeks, then every 6 weeks.

Psoriatic Arthritis and Plaque Psoriasis
5 mg/kg at 0, 2 and 6 weeks, then every 8 weeks.


DOSAGE FORMS AND STRENGTHS
100 mg of lyophilized infliximab in a 20 mL vial for intravenous infusion.

leflunomide  (Arava ®)  top of page icon

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 ®)  top of page icon

OTREXUP™ (methotrexate) injection (below)

-------------
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)

Drug UPDATES:   OTREXUP™ (methotrexate) injection, for subcutaneous use
[Drug information  /  PDF]  
Dosing:  Click (+) next to Dosage and Administration section (drug info link)

Initial U.S. Approval:  2013

Mechanism of Action: 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.

The mechanism of action in rheumatoid arthritis is unknown; it may affect immune function.

INDICATIONS AND USAGE:  Otrexup is a folate analog metabolic inhibitor indicated for the:
• Management of patients with severe, active rheumatoid arthritis (RA) and polyarticular juvenile idiopathic arthritis (pJIA), who are intolerant of or had an inadequate response to first-line therapy (1.1)
• Symptomatic control of severe, recalcitrant, disabling psoriasis in adults who are not adequately responsive to other forms of therapy (1.2)

Limitation of Use
Otrexup is not indicated for the treatment of neoplastic diseases

HOW SUPPLIED: Injection: Single-dose auto-injector delivering 0.4 mL of methotrexate in the following dosage strengths: 7.5 mg, 10 mg, 15 mg, 20mg, and 25 mg

Drug UPDATESRASUVO (methotrexate) injection, for subcutaneous use
Initial U.S. Approval: 1953
[Drug information  /  PDF]  
Dosing:  Click (+) next to Dosage and Administration section (drug info link)

U.S. Approval:  2014

Mechanism of Action: 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.

The mechanism of action in rheumatoid arthritis is unknown; it may affect immune function.

INDICATIONS AND USAGE
Rasuvo is a folate analog metabolic inhibitor indicated for the:
Management of patients with severe, active rheumatoid arthritis (RA) and polyarticular juvenile idiopathic arthritis (pJIA), who are intolerant of or had an inadequate response to first-line therapy (1.1)
Symptomatic control of severe, recalcitrant, disabling psoriasis in adults who are not adequately responsive to other forms of therapy (1.2)

Limitation of Use:
Rasuvo is not indicated for the treatment of neoplastic diseases
HOW SUPPLIED:  Injection: Single-dose manually-triggered auto-injector delivering methotrexate in the following dosage strengths: 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg, and 30 mg.

sulfasalazine  (Azulfidine ®)  top of page icon

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

tocilizumab -ACTEMRA® top of page icon

Local monograph

tofacitinib - XELJANZ ® tablets: top of page


Drug UPDATES
XELJANZ ® (tofacitinib) tablets, for oral use
XELJANZ ® XR (tofacitinib) extended release tablets, for oral use

[Drug information  /  PDF]     REVIEW PACKAGE INSERT FOR POSSIBLE UPDATES
PACKAGE INSERT -Dosing:  Click (+) next to Dosage and Administration section (drug info link)
BOXED WARNING
WARNING: SERIOUS INFECTIONS AND MALIGNANCY See full prescribing information for complete boxed warning.

Serious infections leading to hospitalization or death, including tuberculosis and bacterial, invasive fungal, viral, and other opportunistic infections, have occurred in patients receiving XELJANZ. (5.1)
If a serious infection develops, interrupt XELJANZ/XELJANZ XR until the infection is controlled. (5.1)
Prior to starting XELJANZ/XELJANZ XR, perform a test for latent tuberculosis; if it is positive, start treatment for tuberculosis prior to starting XELJANZ/XELJANZ XR. (5.1)
Monitor all patients for active tuberculosis during treatment, even if the initial latent tuberculosis test is negative. (5.1)
Lymphoma and other malignancies have been observed in patients treated with XELJANZ. Epstein Barr Virus-associated post-transplant lymphoproliferative disorder has been observed at an increased rate in renal transplant patients treated with XELJANZ and concomitant immunosuppressive medications. (5.2)


Initial U.S. Approval:  2016

Mechanism of Action: Tofacitinib is a Janus kinase (JAK) inhibitor. JAKs are intracellular enzymes which transmit signals arising from cytokine or growth factor-receptor interactions on the cellular membrane to influence cellular processes of hematopoiesis and immune cell function. Within the signaling pathway, JAKs phosphorylate and activate Signal Transducers and Activators of Transcription (STATs) which modulate intracellular activity including gene expression. Tofacitinib modulates the signaling pathway at the point of JAKs, preventing the phosphorylation and activation of STATs. JAK enzymes transmit cytokine signaling through pairing of JAKs (e.g., JAK1/JAK3, JAK1/JAK2, JAK1/TyK2, JAK2/JAK2). Tofacitinib inhibited the in vitro activities of JAK1/JAK2, JAK1/JAK3, and JAK2/JAK2 combinations with IC50 of 406, 56, and 1377 nM, respectively. However, the relevance of specific JAK combinations to therapeutic effectiveness is not known.

INDICATIONS AND USAGE:
XELJANZ/XELJANZ XR is an inhibitor of Janus kinases (JAKs) indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate. It may be used as monotherapy or in combination with methotrexate or other nonbiologic disease-modifying antirheumatic drugs (DMARDs).

Limitations of Use: Use of XELJANZ/XELJANZ XR in combination with biologic DMARDs or potent immunosuppressants such as azathioprine and cyclosporine is not recommended.


DOSAGE AND ADMINISTRATION: PDF
Rheumatoid Arthritis
Recommended dose of XELJANZ is 5 mg twice daily. (2.1)
Recommended dose of XELJANZ XR is 11 mg once daily. (2.1)
Recommended dose in patients with moderate and severe renal impairment and moderate hepatic impairment is XELJANZ 5 mg once daily. (2.4, 8.6, 8.7)
Use of XELJANZ/XELJANZ XR in patients with severe hepatic impairment is not recommended. (2.4, 8.7)

HOW SUPPLIED:
XELJANZ Tablets: 5 mg
XELJANZ XR Tablets: 11 mg
 

Reference(s)

National Institutes of Health, U.S. National Library of Medicine, DailyMed Database.
Provides access to the latest drug monographs submitted to the Food and Drug Administration (FDA). Please review the latest applicable package insert for additional information and possible updates.  A local search option of this data can be found here.

Disclaimer

Listed dosages are for - Adult patients ONLY. PLEASE READ THE DISCLAIMER CAREFULLY BEFORE ACCESSING OR USING THIS SITE. BY ACCESSING OR USING THIS SITE, YOU AGREE TO BE BOUND BY THE TERMS AND CONDITIONS SET FORTH IN THE DISCLAIMER. GlobalRPH does not directly or indirectly practice medicine or provide medical services and therefore assumes no liability whatsoever of any kind for the information and data accessed through the Service or for any diagnosis or treatment made in reliance thereon.

David F. McAuley, Pharm.D., R.Ph.  GlobalRPh Inc.
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