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RHEUMATREX DOSE PACK- methotrexate tablet
Par Pharmaceutical
PATIENTS SHOULD BE CLOSELY MONITORED FOR BONE MARROW, LIVER, LUNG AND KIDNEY TOXICITIES. (See PRECAUTIONS.)
Methotrexate (formerly Amethopterin) is an antimetabolite used in the treatment of certain neoplastic diseases, severe psoriasis, and adult rheumatoid arthritis.
Chemically methotrexate is N-[4-[[(2,4-diamino-6-pteridinyl)methyl]methylamino]benzoyl]-L-glutamic acid. The structural formula is:
Molecular weight: 454.45 C20H22N8O5
Methotrexate Tablets, USP for oral administration are available in a packaging system designated as the RHEUMATREX® Methotrexate Tablets, USP Dose Pack for therapy with a weekly dosing schedule of 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg and 20 mg. Methotrexate Tablets, USP contain an amount of methotrexate sodium equivalent to 2.5 mg of methotrexate and the following inactive ingredients: Lactose, Magnesium Stearate and Pregelatinized Starch.
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 non-steroidal 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.
Absorption - In adults, oral absorption appears to be dose dependent. Peak serum levels are reached within one to two hours. At doses of 30 mg/m2 or less, methotrexate is generally well absorbed with a mean bioavailability of about 60%. The absorption of doses greater than 80 mg/m2 is significantly less, possibly due to a saturation effect.
In leukemic pediatric patients, oral absorption of methotrexate also appears to be dose dependent and has been reported to vary widely (23% to 95%). A twenty fold difference between highest and lowest peak levels (Cmax: 0.11 to 2.3 micromolar after a 20 mg/m2 dose) has been reported. Significant interindividual variability has also been noted in time to peak concentration (Tmax: 0.67 to 4 hrs after a 15 mg/m2 dose) and fraction of dose absorbed. The absorption of doses greater than 40 mg/m2 has been reported to be significantly less than that of lower doses. Food has been shown to delay absorption and reduce peak concentration. Methotrexate is generally completely absorbed from parenteral routes of injection. After intramuscular injection, peak serum concentrations occur in 30 to 60 minutes. As in leukemic pediatric patients, a wide interindividual variability in the plasma concentrations of methotrexate has been reported in pediatric patients with JRA. Following oral administration of methotrexate in doses of 6.4 to 11.2 mg/m2/week in pediatric patients with JRA, mean serum concentrations were 0.59 micromolar (range, 0.03 to 1.40) at 1 hour, 0.44 micromolar (range, 0.01 to 1.00) at 2 hours, and 0.29 micromolar (range 0.06 to 0.58) at 3 hours. In pediatric patients receiving methotrexate for acute lymphocytic leukemia (6.3 to 30 mg/m2), or for JRA (3.75 to 26.2 mg/m2), the terminal half-life has been reported to range from 0.7 to 5.8 hours or 0.9 to 2.3 hours, respectively.
Distribution - After intravenous administration, the initial volume of distribution is approximately 0.18 L/kg (18% of body weight) and steady-state volume of distribution is approximately 0.4 to 0.8 L/kg (40% to 80% of body weight). Methotrexate competes with reduced folates for active transport across cell membranes by means of a single carrier-mediated active transport process. At serum concentrations greater than 100 micromolar, passive diffusion becomes a major pathway by which effective intracellular concentrations can be achieved. Methotrexate in serum is approximately 50% protein bound. Laboratory studies demonstrate that it may be displaced from plasma albumin by various compounds including sulfonamides, salicylates, tetracyclines, chloramphenicol, and phenytoin.
Methotrexate does not penetrate the blood-cerebrospinal fluid barrier in therapeutic amounts when given orally or parenterally. High CSF concentrations of the drug may be attained by intrathecal administration.
In dogs, synovial fluid concentrations after oral dosing were higher in inflamed than uninflamed joints. Although salicylates did not interfere with this penetration, prior prednisone treatment reduced penetration into inflamed joints to the level of normal joints.
Metabolism - After absorption, methotrexate undergoes hepatic and intracellular metabolism to polyglutamated forms which can be converted back to methotrexate by hydrolase enzymes. These polyglutamates act as inhibitors of dihydrofolate reductase and thymidylate synthetase. Small amounts of methotrexate polyglutamates may remain in tissues for extended periods. The retention and prolonged drug action of these active metabolites vary among different cells, tissues and tumors. A small amount of metabolism to 7-hydroxymethotrexate may occur at doses commonly prescribed. Accumulation of this metabolite may become significant at the high doses used in osteogenic sarcoma. The aqueous solubility of 7-hydroxymethotrexate is 3 to 5 fold lower than the parent compound. Methotrexate is partially metabolized by intestinal flora after oral administration.
Half-Life - The terminal half-life reported for methotrexate is approximately three to ten hours for patients receiving treatment for psoriasis, or rheumatoid arthritis or low dose antineoplastic therapy (less than 30 mg/m2). For patients receiving high doses of methotrexate, the terminal half-life is eight to 15 hours.
Excretion - Renal excretion is the primary route of elimination and is dependent upon dosage and route of administration. With IV administration, 80% to 90% of the administered dose is excreted unchanged in the urine within 24 hours. There is limited biliary excretion amounting to 10% or less of the administered dose. Enterohepatic recirculation of methotrexate has been proposed.
Renal excretion occurs by glomerular filtration and active tubular secretion. Nonlinear elimination due to saturation of renal tubular reabsorption has been observed in psoriatic patients at doses between 7.5 and 30 mg. Impaired renal function, as well as concurrent use of drugs such as weak organic acids that also undergo tubular secretion, can markedly increase methotrexate serum levels. Excellent correlation has been reported between methotrexate clearance and endogenous creatinine clearance.
Methotrexate clearance rates vary widely and are generally decreased at higher doses. Delayed drug clearance has been identified as one of the major factors responsible for methotrexate toxicity. It has been postulated that the toxicity of methotrexate for normal tissues is more dependent upon the duration of exposure to the drug rather than the peak level achieved. When a patient has delayed drug elimination due to compromised renal function, a third space effusion, or other causes, methotrexate serum concentrations may remain elevated for prolonged periods.
The potential for toxicity from high dose regimens or delayed excretion is reduced by the administration of leucovorin calcium during the final phase of methotrexate plasma elimination. Pharmacokinetic monitoring of methotrexate serum concentrations may help identify those patients at high risk for methotrexate toxicity and aid in proper adjustment of leucovorin dosing. Guidelines for monitoring serum methotrexate levels, and for adjustment of leucovorin dosing to reduce the risk of methotrexate toxicity, are provided below in DOSAGE AND ADMINISTRATION.
Methotrexate has been detected in human breast milk. The highest breast milk to plasma concentration ratio reached was 0.08:1.
Methotrexate is indicated in the treatment of gestational choriocarcinoma, chorio-adenoma destruens and hydatidiform mole.
Methotrexate is used in maintenance therapy in combination with other chemotherapeutic agents.
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.
Methotrexate is 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.
Methotrexate is indicated in the management of selected adults with severe, active, rheumatoid arthritis (ACR 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.
Methotrexate can cause fetal death or teratogenic effects when administered to a pregnant woman. Methotrexate is contraindicated in pregnant women with psoriasis or rheumatoid arthritis and should be used in the treatment of neoplastic diseases only when the potential benefit outweighs the risk to the fetus. Women of childbearing potential should not be started on methotrexate until pregnancy is excluded and should be fully counseled on the serious risk to the fetus (See PRECAUTIONS) should they become pregnant while undergoing treatment. Pregnancy should be avoided if either partner is receiving methotrexate; during and for a minimum of three months after therapy for male patients, and during and for at least one ovulatory cycle after therapy for female patients. (See Boxed WARNINGS.)
Because of the potential for serious adverse reactions from methotrexate in breast fed infants, it is contraindicated in nursing mothers.
Patients with psoriasis or rheumatoid arthritis with alcoholism, alcoholic liver disease or other chronic liver disease should not receive methotrexate.
Patients with psoriasis or rheumatoid arthritis who have overt or laboratory evidence of immunodeficiency syndromes should not receive methotrexate.
Patients with psoriasis or rheumatoid arthritis who have preexisting blood dyscrasias, such as bone marrow hypoplasia, leukopenia, thrombocytopenia or significant anemia, should not receive methotrexate.
Patients with a known hypersensitivity to methotrexate should not receive the drug.
Methotrexate formulations and diluents containing preservatives must not be used for intrathecal or high dose methotrexate therapy.
Methotrexate has the potential for serious toxicity. (See Boxed WARNINGS.) Toxic effects may be related in frequency and severity to dose or frequency of administration but have been seen at all doses. Because they can occur at any time during therapy, it is necessary to follow patients on methotrexate closely. Most adverse reactions are reversible if detected early. When such reactions do occur, the drug should be reduced in dosage or discontinued and appropriate corrective measures should be taken. If necessary, this could include the use of leucovorin calcium and/or acute, intermittent hemodialysis with a high-flux dialyzer. (See OVERDOSAGE.) If methotrexate therapy is reinstituted, it should be carried out with caution, with adequate consideration of further need for the drug and with increased alertness as to possible recurrence of toxicity.
The clinical pharmacology of methotrexate has not been well studied in older individuals. Due to diminished hepatic and renal function as well as decreased folate stores in this population, relatively low doses should be considered, and these patients should be closely monitored for early signs of toxicity.
Patients should be informed of the early signs and symptoms of toxicity, of the need to see their physician promptly if they occur, and the need for close follow-up, including periodic laboratory tests to monitor toxicity.
Both the physician and pharmacist should emphasize to the patient that the recommended dose is taken weekly in rheumatoid arthritis and psoriasis, and that mistaken daily use of the recommended dose has led to fatal toxicity. Patients should be encouraged to read the Patient Instructions sheet within the Dose Pack. Prescriptions should not be written or refilled on a PRN basis.
Patients should be informed of the potential benefit and risk in the use of methotrexate. The risk of effects on reproduction should be discussed with both male and female patients taking methotrexate.
Patients undergoing methotrexate therapy should be closely monitored so that toxic effects are detected promptly. Baseline assessment should include a complete blood count with differential and platelet counts, hepatic enzymes, renal function tests, and a chest X-ray. During therapy of rheumatoid arthritis and psoriasis, monitoring of these parameters is recommended: hematology at least monthly, renal function and liver function every 1 to 2 months. More frequent monitoring is usually indicated during antineoplastic therapy. During initial or changing doses, or during periods of increased risk of elevated methotrexate blood levels (eg, dehydration), more frequent monitoring may also be indicated.
Transient liver function test abnormalities are observed frequently after methotrexate administration and are usually not cause for modification of methotrexate therapy. Persistent liver function test abnormalities, and/or depression of serum albumin may be indicators of serious liver toxicity and require evaluation. (See PRECAUTIONS, Organ System Toxicity, Hepatic.)
A relationship between abnormal liver function tests and fibrosis or cirrhosis of the liver has not been established for patients with psoriasis. Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis in the rheumatoid arthritis population.
Pulmonary function tests may be useful if methotrexate-induced lung disease is suspected, especially if baseline measurements are available.
Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate levels, resulting in deaths from severe hematologic and gastrointestinal toxicity.
Caution should be used when NSAIDs and salicylates are administered concomitantly with lower doses of methotrexate. These drugs have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity.
Despite the potential interactions, studies of methotrexate in patients with rheumatoid arthritis have usually included concurrent use of constant dosage regimens of NSAIDs, without apparent problems. It should be appreciated, however, that the doses used in rheumatoid arthritis (7.5 to 20 mg/wk) are somewhat lower than those used in psoriasis and that larger doses could lead to unexpected toxicity.
Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by certain drugs, such as salicylates, phenylbutazone, phenytoin, and sulfonamides. Renal tubular transport is also diminished by probenecid; use of methotrexate with this drug should be carefully monitored.
Oral antibiotics such as tetracycline, chloramphenicol, and nonabsorbable broad spectrum antibiotics, may decrease intestinal absorption of methotrexate or interfere with the enterohepatic circulation by inhibiting bowel flora and suppressing metabolism of the drug by bacteria.
Penicillins may reduce the renal clearance of methotrexate; increased serum concentrations of methotrexate with concomitant hematologic and gastrointestinal toxicity have been observed with methotrexate. Use of methotrexate with penicillins should be carefully monitored.
The potential for increased hepatotoxicity when methotrexate is administered with other hepatotoxic agents has not been evaluated. However, hepatotoxicity has been reported in such cases. Therefore, patients receiving concomitant therapy with methotrexate and other potential hepatotoxins (eg, azathioprine, retinoids, sulfa-salazine) should be closely monitored for possible increased risk of hepatotoxicity.
Methotrexate may decrease the clearance of theophylline; theophylline levels should be monitored when used concurrently with methotrexate.
Certain side effects such as mouth sores may be reduced by folate supplementation with methotrexate.
Trimethoprim/sulfa-methoxazole has been reported rarely to increase bone marrow suppression in patients receiving methotrexate, probably by an additive antifolate effect.
No controlled human data exist regarding the risk of neoplasia with methotrexate. Methotrexate has been evaluated in a number of animal studies for carcinogenic potential with inconclusive results. Although there is evidence that methotrexate causes chromosomal damage to animal somatic cells and human bone marrow cells, the clinical significance remains uncertain. Non-Hodgkin's lymphoma and other tumors have been reported in patients receiving low-dose oral methotrexate. However, there have been instances of malignant lymphoma arising during treatment with low-dose oral methotrexate, which have regressed completely following withdrawal of methotrexate, without requiring active anti-lymphoma treatment. Benefits should be weighed against the potential risks before using methotrexate alone or in combination with other drugs, especially in pediatric patients or young adults. Methotrexate causes embryotoxicity, abortion, and fetal defects in humans. It has also been reported to cause impairment of fertility, oligospermia and menstrual dysfunction in humans, during and for a short period after cessation of therapy.
Psoriasis and rheumatoid arthritis: Methotrexate is in Pregnancy Category X.
See CONTRAINDICATIONS.
See CONTRAINDICATIONS.
Safety and effectiveness in pediatric patients have been established only in cancer chemotherapy and in polyarticular-course juvenile rheumatoid arthritis.
Published clinical studies evaluating the use of methotrexate in children and adolescents (ie, patients 2 to 16 years of age) with JRA demonstrated safety comparable to that observed in adults with rheumatoid arthritis. (See CLINICAL PHARMACOLOGY, ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION.)
Clinical studies of methotrexate did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious reflecting the greater frequency of decreased hepatic and renal function, decreased folate stores, concomitant disease or other drug therapy (ie, that interfere with renal function, methotrexate or folate metabolism) in this population (See PRECAUTIONS, Drug Interactions). Since decline in renal function may be associated with increases in adverse events and serum creatinine measurements may over estimate renal function in the elderly, more accurate methods (ie, creatine clearance) should be considered. Serum methotrexate levels may also be helpful. Elderly patients should be closely monitored for early signs of hepatic, bone marrow and renal toxicity. In chronic use situations, certain toxicities may be reduced by folate supplementation. Post-marketing experience suggests that the occurence of bone marrow suppression, thrombocytopenia, and pneumonitis may increase with age. See Boxed WARNINGS and ADVERSE REACTIONS.
Gastrointestinal: If vomiting, diarrhea, or stomatitis occur, which may result in dehydration, methotrexate should be discontinued until recovery occurs. Methotrexate should be used with extreme caution in the presence of peptic ulcer disease or ulcerative colitis.
Hematologic: Methotrexate can suppress hematopoiesis and cause anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, and/or thrombocytopenia. In patients with malignancy and preexisting hematopoietic impairment, the drug should be used with caution, if at all. In controlled clinical trials in rheumatoid arthritis (n=128), leukopenia (WBC <3000/mm3) was seen in 2 patients, thrombocytopenia (platelets <100,000/mm3) in 6 patients, and pancytopenia in 2 patients.
In psoriasis and rheumatoid arthritis, methotrexate should be stopped immediately if there is a significant drop in blood counts. In the treatment of neoplastic diseases, methotrexate should be continued only if the potential benefit warrants the risk of severe myelosuppression. Patients with profound granulocytopenia and fever should be evaluated immediately and usually require parenteral broad-spectrum antibiotic therapy.
Hepatic: Methotrexate has the potential for acute (elevated transaminases) and chronic (fibrosis and cirrhosis) hepatotoxicity. Chronic toxicity is potentially fatal; it generally has occurred after prolonged use (generally two years or more) and after a total dose of at least 1.5 grams. In studies in psoriatic patients, hepatotoxicity appeared to be a function of total cumulative dose and appeared to be enhanced by alcoholism, obesity, diabetes and advanced age. An accurate incidence rate has not been determined; the rate of progression and reversibility of lesions is not known. Special caution is indicated in the presence of preexisting liver damage or impaired hepatic function.
In psoriasis, liver function tests, including serum albumin, should be performed periodically prior to dosing but are often normal in the face of developing fibrosis or cirrhosis. These lesions may be detectable only by biopsy. The usual recommendation is to obtain a liver biopsy at 1) pretherapy or shortly after initiation of therapy (2 - 4 months), 2) a total cumulative dose of 1.5 grams, and 3) after each additional 1.0 to 1.5 grams. Moderate fibrosis or any cirrhosis normally leads to discontinuation of the drug; mild fibrosis normally suggests a repeat biopsy in 6 months. Milder histologic findings such as fatty change and low grade portal inflammation are relatively common pretherapy. Although these mild changes are usually not a reason to avoid or discontinue methotrexate therapy, the drug should be used with caution.
In rheumatoid arthritis, age at first use of methotrexate and duration of therapy have been reported as risk factors for hepatotoxicity; other risk factors, similar to those observed in psoriasis, may be present in rheumatoid arthritis but have not been confirmed to date. Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis in this population. There is a combined reported experience in 217 rheumatoid arthritis patients with liver biopsies both before and during treatment (after a cumulative dose of at least 1.5 g) and in 714 patients with a biopsy only during treatment. There are 64 (7%) cases of fibrosis and 1 (0.1%) case of cirrhosis. Of the 64 cases of fibrosis, 60 were deemed mild. The reticulin stain is more sensitive for early fibrosis and its use may increase these figures. It is unknown whether even longer use will increase these risks.
Liver function tests should be performed at baseline and at 4-8 week intervals in patients receiving methotrexate for rheumatoid arthritis. Pretreatment liver biopsy should be performed for patients with a history of excessive alcohol consumption, persistently abnormal baseline liver function test values or chronic hepatitis B or C infection. During therapy, liver biopsy should be performed if there are persistent liver function test abnormalities or there is a decrease in serum albumin below the normal range (in the setting of well controlled rheumatoid arthritis).
If the results of a liver biopsy show mild changes (Roenigk grades I, II, IIIa), methotrexate may be continued and the patient monitored as per recommendations listed above. Methotrexate should be discontinued in any patient who displays persistently abnormal liver function tests and refuses liver biopsy or in any patient whose liver biopsy shows moderate to severe changes (Roenigk grade IIIb or IV).
Infection or Immunologic States: Methotrexate should be used with extreme caution in the presence of active infection, and is usually contraindicated in patients with overt or laboratory evidence of immunodeficiency syndromes. Immunization may be ineffective when given during methotrexate therapy. Immunization with live virus vaccines is generally not recommended. There have been reports of disseminated vaccinia infections after smallpox immunization in patients receiving methotrexate therapy.
Hypogammaglobulinemia has been reported rarely.
Potentially fatal opportunistic infections, especially Pneumocystis carinii pneumonia, may occur with methotrexate therapy. When a patient presents with pulmonary symptoms, the possibility of Pneumocystis carinii pneumonia should be considered.
Pulmonary: Pulmonary symptoms (especially a dry nonproductive cough) or a nonspecific pneumonitis occurring during methotrexate therapy may be indicative of a potentially dangerous lesion and require interruption of treatment and careful investigation. Although clinically variable, the typical patient with methotrexate induced lung disease presents with fever, cough, dyspnea, hypoxemia, and an infiltrate on chest X-ray; infection (including pneumonia) needs to be excluded. This lesion can occur at all dosages.
Renal: Methotrexate may cause renal damage that may lead to acute renal failure. Nephrotoxicity is due primarily to the precipitation of methotrexate and 7-hydroxymethotrexate in the renal tubules. Close attention to renal function including adequate hydration, urine alkalinization and measurement of serum methotrexate and creatinine levels are essential for safe administration.
Skin: Severe, occasionally fatal, dermatologic reactions, including toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, and erythema multiforme, have been reported in children and adults, within days of oral, intramuscular, intravenous, or intrathecal methotrexate administration. Reactions were noted after single or multiple, low, intermediate or high doses of methotrexate in patients with neoplastic and non-neoplastic diseases.
Other Precautions: Methotrexate should be used with extreme caution in the presence of debility.
Methotrexate exits slowly from third space compartments (eg, pleural effusions or ascites). This results in a prolonged terminal plasma half-life and unexpected toxicity. In patients with significant third space accumulations, it is advisable to evacuate the fluid before treatment and to monitor plasma methotrexate levels.
Lesions of psoriasis may be aggravated by concomitant exposure to ultraviolet radiation. Radiation dermatitis and sunburn may be "recalled" by the use of methotrexate.
The most frequently reported adverse reactions include ulcerative stomatitis, leukopenia, nausea, and abdominal distress. Other frequently reported adverse effects are malaise, undue fatigue, chills and fever, dizziness and decreased resistance to infection.
Other adverse reactions that have been reported with methotrexate are listed below by organ system. In the oncology setting, concomitant treatment and the underlying disease make specific attribution of a reaction to methotrexate difficult.
Alimentary System: gingivitis, pharyngitis, stomatitis, anorexia, nausea, vomiting, diarrhea, hematemesis, melena, gastrointestinal ulceration and bleeding, enteritis, pancreatitis.
Blood and Lymphatic System Disorders: suppressed hematopoiesis causing anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia and/or thrombocytopenia, lymphadenopathy and lymphoproliferative disorders (including reversible). Hypogammaglobulinemia has been reported rarely.
Cardiovascular: pericarditis, pericardial effusion, hypotension, and thromboembolic events (including arterial thrombosis, cerebral thrombosis, deep vein thrombosis, retinal vein thrombosis, thrombophlebitis, and pulmonary embolus).
Central Nervous System: headaches, drowsiness, blurred vision, transient blindness, speech impairment including dysarthria and aphasia, hemiparesis, paresis and convulsions have also occurred following administration of methotrexate. Following low doses, there have been occasional reports of transient subtle cognitive dysfunction, mood alteration, unusual cranial sensations, leukoencephalopathy, or encephalopathy.
Hepatobiliary: disorders, hepatotoxicity, acute hepatitis, chronic fibrosis and cirrhosis, decrease in serum albumin, liver enzyme elevations.
Infection: There have been case reports of sometimes fatal opportunistic infections in patients receiving methotrexate therapy for neoplastic and non-neoplastic diseases. Pneumocystis carinii pneumonia was the most common opportunistic infection. There have also been reports of infections, pneumonia, sepsis, nocardiosis, histoplasmosis, cryptococcosis, herpes zoster, H. simplex hepatitis, and disseminated H. simplex.
Musculoskeletal System: stress fracture.
Ophthalmic: conjunctivitis, serious visual changes of unknown etiology.
Pulmonary System: respiratory fibrosis, respiratory failure, interstitial pneumonitis; deaths have been reported, and chronic interstitial obstructive pulmonary disease has occasionally occurred.
Skin: erythematous rashes, pruritus, urticaria, photosensitivity, pigmentary changes, alopecia, ecchymosis, telangiectasia, acne, furunculosis, erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson Syndrome, skin necrosis, skin ulceration, and exfoliative dermatitis.
Urogenital System: severe nephropathy or renal failure, azotemia, cystitis, hematuria; defective oogenesis or spermatogenesis, transient oligospermia, menstrual dysfunction, vaginal discharge, and gynecomastia; infertility, abortion, fetal defects.
Other rarer reactions related to or attributed to the use of methotrexate such as nodulosis, vasculitis, arthralgia/myalgia, loss of libido/impotence, diabetes, osteoporosis, sudden death, reversible lymphomas, tumor lysis syndrome, soft tissue necrosis and osteonecrosis. Anaphylactoid reactions have been reported.
The approximate incidences of methotrexate attributed (ie, placebo rate subtracted) adverse reactions in 12 to 18 week double-blind studies of patients (n=128) with rheumatoid arthritis treated with low-dose oral (7.5 to 15 mg/week) pulse methotrexate, are listed below. Virtually all of these patients were on concomitant nonsteroidal anti-inflammatory drugs and some were also taking low dosages of corticosteroids. Hepatic histology was not examined in these short-term studies. (See PRECAUTIONS.)
Incidence greater than 10%: Elevated liver function tests 15%, nausea/vomiting 10%.
Incidence 3% to 10%: Stomatitis, thrombocytopenia, (platelet count less than 100,000/mm3).
Incidence 1% to 3%: Rash/pruritus/dermatitis, diarrhea, alopecia, leukopenia (WBC less than 3000/mm3), pancytopenia, dizziness.
Two other controlled trials of patients (n=680) with Rheumatoid Arthritis on 7.5 mg – 15 mg/wk oral doses showed an incidence of interstitial pneumonitis of 1%. (See PRECAUTIONS.)
Other less common reactions included decreased hematocrit, headache, upper respiratory infection, anorexia, arthralgias, chest pain, coughing, dysuria, eye discomfort, epistaxis, fever, infection, sweating, tinnitus, and vaginal discharge.
There are no recent placebo-controlled trials in patients with psoriasis. There are two literature reports (Roenigk, 1969 and Nyfors, 1978) describing large series (n=204, 248) of psoriasis patients treated with methotrexate. Dosages ranged up to 25 mg per week and treatment was administered for up to four years. With the exception of alopecia, photosensitivity, and "burning of skin lesions" (each 3% to 10%), the adverse reaction rates in these reports were very similar to those in the rheumatoid arthritis studies. Rarely, painful plaque erosions may appear.
The approximate incidences of adverse reactions reported in pediatric patients with JRA treated with oral, weekly doses of methotrexate (5 to 20 mg/m2/wk or 0.1 to 0.65 mg/kg/wk) were as follows (virtually all patients were receiving concomitant nonsteroidal anti-inflammatory drugs, and some also were taking low doses of cortico-steroids): elevated liver function tests, 14%; gastrointestinal reactions (eg, nausea, vomiting, diarrhea), 11%; stomatitis, 2%; leukopenia, 2%; headache, 1.2%; alopecia, 0.5%; dizziness, 0.2%; and rash, 0.2%. Although there is experience with dosing up to 30 mg/m2/wk in JRA, the published data for doses above 20 mg/m2/wk are too limited to provide reliable estimates of adverse reaction rates.
Leucovorin is indicated to diminish the toxicity and counteract the effect of inadvertently administered overdosages of methotrexate. Leucovorin administration should begin as promptly as possible. As the time interval between methotrexate administration and leucovorin initiation increases, the effectiveness of leucovorin in counteracting toxicity decreases. Monitoring of the serum methotrexate concentration is essential in determining the optimal dose and duration of treatment with leucovorin.
In cases of massive overdosage, hydration and urinary alkalinization may be necessary to prevent the precipitation of methotrexate and/or its metabolites in the renal tubules. Generally speaking, neither hemodialysis nor peritoneal dialysis have been shown to improve methotrexate elimination. However, effective clearance of methotrexate has been reported with acute, intermittent hemodialysis using a high-flux dialyzer (Wall, SM et al: Am J Kidney Dis 28(6): 846-854, 1996).
In postmarketing experience, overdose with methotrexate has generally occurred with oral and intrathecal administration, although intravenous and intramuscular overdose have also been reported.
Reports of oral overdose often indicate accidental daily administration instead of weekly (single or divided doses). Symptoms commonly reported following oral overdose include those symptoms and signs reported at pharmacologic doses, particularly hematologic and gastrointestinal reaction. For example, leukopenia, thrombocytopenia, anemia, pancytopenia, bone marrow suppression, mucositis, stomatitis, oral ulceration, nausea, vomiting, gastrointestinal ulceration, gastrointestinal bleeding. In some cases, no symptoms were reported. There have been reports of death following overdose. In these cases, events such as sepsis or septic shock, renal failure, and aplastic anemia were also reported.
Oral administration in tablet form is often preferred when low doses are being administered since absorption is rapid and effective serum levels are obtained.
Choriocarcinoma and similar trophoblastic diseases: Methotrexate is administered orally or intramuscularly in doses of 15 to 30 mg daily for a five-day course. Such courses are usually repeated for 3 to 5 times as required, with rest periods of one or more weeks interposed between courses, until any manifesting toxic symptoms subside. The effectiveness of therapy is ordinarily evaluated by 24 hour quantitative analysis of urinary chorionic gonadotropin (hCG), which should return to normal or less than 50 IU/24 hr usually after the third or fourth course and usually be followed by a complete resolution of measurable lesions in 4 to 6 weeks. One to two courses of methotrexate after normalization of hCG is usually recommended. Before each course of the drug careful clinical assessment is essential. Cyclic combination therapy of methotrexate with other antitumor drugs has been reported as being useful.
Since hydatidiform mole may precede choriocarcinoma, prophylactic chemotherapy with methotrexate has been recommended.
Chorioadenoma destruens is considered to be an invasive form of hydatidiform mole. Methotrexate is administered in these disease states in doses similar to those recommended for choriocarcinoma.
Leukemia: Acute lymphoblastic leukemia in pediatric patients and young adolescents is the most responsive to present day chemotherapy. In young adults and older patients, clinical remission is more difficult to obtain and early relapse is more common.
Methotrexate alone or in combination with steroids was used initially for induction of remission in acute lymphoblastic leukemias. More recently corticosteroid therapy, in combination with other antileukemic drugs or in cyclic combinations with methotrexate included, has appeared to produce rapid and effective remissions. When used for induction, methotrexate in doses of 3.3 mg/m2 in combination with 60 mg/m2 of prednisone, given daily, produced remissions in 50% of patients treated, usually within a period of 4 to 6 weeks. Methotrexate in combination with other agents appears to be the drug of choice for securing maintenance of drug-induced remissions. When remission is achieved and supportive care has produced general clinical improvement, maintenance therapy is initiated, as follows: Methotrexate is administered 2 times weekly either by mouth or intramuscularly in total weekly doses of 30 mg/m2. It has also been given in doses of 2.5 mg/kg intravenously every 14 days. If and when relapse does occur, reinduction of remission can again usually be obtained by repeating the initial induction regimen.
A variety of combination chemotherapy regimens have been used for both induction and maintenance therapy in acute lymphoblastic leukemia. The physician should be familiar with the new advances in antileukemic therapy.
Lymphomas: In Burkitt's tumor, Stages I-II, methotrexate has produced prolonged remissions in some cases. Recommended dosage is 10 to 25 mg/day orally for 4 to 8 days. In Stage III, methotrexate is commonly given concomitantly with other anti-tumor agents. Treatment in all stages usually consists of several courses of the drug interposed with 7 to 10 day rest periods. Lymphosarcomas in Stage III may respond to combined drug therapy with methotrexate given in doses of 0.625 to 2.5 mg/kg daily.
Mycosis Fungoides (cutaneous T cell lymphoma): Therapy with methotrexate as a single agent appears to produce clinical responses in up to 50% of patients treated. Dosage in early stages is usuallly 5 to 50 mg once weekly. Dose reduction or cessation is guided by patient response and hematologic monitoring. Methotrexate has also been administered twice weekly in doses ranging from 15 to 37.5 mg in patients who have responded poorly to weekly therapy.
Adult Rheumatoid Arthritis: Recommended Starting Dosage Schedules
Polyarticular-Course Juvenile Rheumatoid Arthritis: The recommended starting dose is 10 mg/m2 given once weekly.
For either adult RA or polyarticular-course JRA dosages may be adjusted gradually to achieve an optimal response. Limited experience shows a significant increase in the incidence and severity of serious toxic reactions, especially bone marrow suppression, at doses greater than 20 mg/wk in adults. Although there is experience with doses up to 30 mg/m2/wk in children, there are too few published data to assess how doses over 20 mg/m2/wk might affect the risk of serious toxicity in children. Experience does suggest, however, that children receiving 20 to 30 mg/m2/wk (0.65 to 1.0 mg/kg/wk) may have better absorption and fewer gastrointestinal side effects if methotrexate is administered either intramuscularly or subcutaneously.
Therapeutic response usually begins within 3 to 6 weeks and the patient may continue to improve for another 12 weeks or more.
The optimal duration of therapy is unknown. Limited data available from long-term studies in adults indicate that the initial clinical improvement is maintained for at least two years with continued therapy. When methotrexate is discontinued, the arthritis usually worsens within 3 to 6 weeks.
The patient should be fully informed of the risks involved and should be under constant supervision of the physician. (See Information for Patients under PRECAUTIONS.) Assessment of hematologic, hepatic, renal, and pulmonary function should be made by history, physical examination, and laboratory tests before beginning, periodically during, and before reinstituting methotrexate therapy. (See PRECAUTIONS.) Appropriate steps should be taken to avoid conception during methotrexate therapy. (See PRECAUTIONS and CONTRAINDICATIONS.)
Weekly therapy may be instituted with the RHEUMATREX® Methotrexate Tablets, USP, 2.5 mg Dose Packs which are designed to provide doses over a range of 5 mg to 20 mg administered as a single weekly dose. The dose packs are not recommended for administration of methotrexate in weekly doses greater than 20 mg. All schedules should be continually tailored to the individual patient. An initial test dose may be given prior to the regular dosing schedule to detect any extreme sensitivity to adverse effects. (See ADVERSE REACTIONS.) Maximal myelosuppression usually occurs in seven to ten days.
Psoriasis: Recommended Starting Dose Schedules
Dosages in each schedule may be gradually adjusted to achieve optimal clinical response; 30 mg/week should not ordinarily be exceeded.
Once optimal clinical response has been achieved, each dosage schedule should be reduced to the lowest possible amount of drug and to the longest possible rest period. The use of methotrexate may permit the return to conventional topical therapy, which should be encouraged.
Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-5 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.
Methotrexate Tablets, USP contain an amount of methotrexate sodium equivalent to 2.5 mg of methotrexate and are round, convex, yellow tablets, scored in half on one side, engraved with M above the score, and 1 below.
RHEUMATREX® Methotrexate Tablets, USP, 2.5 mg Dose Packs - (each tablet equivalent to 2.5 mg of methotrexate)
| RHEUMATREX® Methotrexate Tablets, USP Dose Pack –
4 cards each containing two 2.5 mg tablets, i.e., 5 mg per week.
| RHEUMATREX® Methotrexate Tablets, USP Dose Pack –
4 cards each containing three 2.5 mg tablets, i.e., 7.5 mg per week.
| RHEUMATREX® Methotrexate Tablets, USP Dose Pack –
4 cards each containing four 2.5 mg tablets, i.e., 10 mg per week.
| RHEUMATREX® Methotrexate Tablets, USP Dose Pack –
4 cards each containing five 2.5 mg tablets, i.e., 12.5 mg per week.
| RHEUMATREX® Methotrexate Tablets, USP Dose Pack –
4 cards each containing six 2.5 mg tablets, i.e., 15 mg per week.
| RHEUMATREX® Methotrexate Tablets, USP Dose Pack –
4 cards each containing seven 2.5 mg tablets, i.e., 17.5 mg per week.
| RHEUMATREX® Methotrexate Tablets, USP Dose Pack –
4 cards each containing eight 2.5 mg tablets, i.e., 20 mg per week.
Manufactured For:
DAVA Pharmaceuticals, Inc.
Fort Lee, NJ 07024 USA
EXCELLA GmbH
Feucht, Germany
Rev. 01/16
|Patient Information
Rheumatrex® DOSE PACK®
(Methotrexate Tablets)
|Read the Patient Instructions that come with RHEUMATREX® before you start using it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your doctor about your condition.
What is the most important information I should know about RHEUMATREX® ?
What is RHEUMATREX®?
RHEUMATREX® is a prescription medicine used in treating certain cancers, severe rheumatoid arthritis including polyarticular juvenile rheumatoid arthritis, and severe psoriasis.
Who should not take RHEUMATREX® ?
Do not take RHEUMATREX® if:
Before using RHEUMATREX® tell your doctor:
How should I take RHEUMATREX®?
What should I avoid while taking RHEUMATREX®?
Do not:
What are the possible or reasonably likely side effects of RHEUMATREX®?
RHEUMATREX® can cause serious and life-threatening problems including (see "What is the most important information I should know about RHEUMATREX®?):
The most common side effects of RHEUMATREX® include:
Stop taking RHEUMATREX® and call your doctor right away if you get diarrhea, mouth sores, a fever, dehydration, cough, bleeding, shortness of breath, any signs of infection, or a skin rash. If you have any questions about these or other side effects, talk to your doctor. These are not all the side effects of RHEUMATREX®. Ask your doctor or pharmacist for more information.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store RHEUMATREX®?
General information about RHEUMATREX®
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use RHEUMATREX® for a condition for which it was not prescribed. Do not give RHEUMATREX® to other people, even if they have the same symptoms that you have. It may harm them.
This leaflet summarizes the most important information about RHEUMATREX®. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about RHEUMATREX® that is written for healthcare professionals.
For additional information, please contact DAVA Pharmaceuticals, Inc. at our toll free number: 800-444-4011.
What are the ingredients in RHEUMATREX®?
Manufactured for:
|This Patient Information has been approved by the U.S. Food and Drug Administration.
Revised: January/2016
Rheumatrex® DOSE PACK®
each tablet contains an amount of methotrexate sodium equivalent to 2.5 mg of methotrexate
15 mg Per Week (6 tablets)
one week therapy
DOSAGE: See prescription label.
Rx only
Store at 20° - 25°C (68° - 77°F).
[See USP Controlled Room Temperature.]
Manufactured for: DAVA Pharmaceuticals, Inc., Fort Lee, NJ 07024, USA
By: Excella GmbH, Feucht, Germany
Rev. 07/09
4x6 Tablets NDC 67253-580-46
Rheumatrex® DOSE PACK®
each tablet contains an amount of methotrexate sodium equivalent to 2.5 mg of methotrexate
15 mg Per Week (6 tablets)
4 week dose pack
Rx only
Store at 20° - 25°C (68° - 77°F).
[See USP Controlled Room Temperature.]
Manufactured for: DAVA Pharmaceuticals, Inc., Fort Lee, NJ 07024, USA
By: Excella GmbH, Feucht, Germany
Rev. 07/09
PHARMACIST: See attached circular.
Label should read:
Take 6 tablets in single dose. Same time, same day, each week.
Take all tablets on card within a 24-hour period on the same day each week as directed by physician.
methotrexate tablet
|Labeler - Par Pharmaceutical (172202025)
|Business Operations
|Excella GmbH


text:
Backflow Testing Sausalito CA
Sausalito Backflow preventer testing and Plumbing
What is a backflow and Backflow preventer testing Sausalito CA?
What is a backflow and Backflow preventer testing in Sausalito CA? A backflow is when dirty or toxic waste water has reversed flow direction backwards, "back flow", and begins to enter your clean water source. Backflow toxic contamination likely can happen at the "cross connection" plumbing area. The cross connection pipes are located between the clean and dirty water lines plumbing area. A backflow stops working because pressure changed happened. Backflow pressure inside plumbing pipes can change from either a back pressure or back siphonage. Backflow pressure may change inside your plumbing because of a burst pipe pushing or sucking a change in plumbing water pressure, a leaking water pipe line, or burst water line main. Pressure change then can allow toxic materials, such as human feces, and nasty chemicals, to come backwards in to your pipe, and then into your clean water. That can be harmful to you. That is why you have a plumber in Sausalito do backflow testing. For a Sausalito plumber Backflow preventer testing CALL BACKFLOW-TESTS.com 1-877-637-0530
What is a plumbing backflow preventer testing Sausalito CA?
What is a backflow preventer Sausalito? Here in Sausalito CA a backflow preventer plumbing water safety device may be installed in your plumbing water main line. You may not know what it is, or that it exists. The water backflow preventer prevents the pressure of plumbing water to back flow backwards. A backflow preventer in Sausalito stops contaminated water from flowing backwards into your clean water system. Backflow prevention can be a life saver for you, since you probably don't want sewage to back flow into your clean water. When changes in water pressure happen inside your plumbing pipe line, your back flow prevention device will stop filthy water, from back flowing into your clean water system. Over time all things break down or leak water, including your backflow and plumbing pipes. Your backflow pipe may have a simple water leak and you don't know? When a backflow does fail, it could allow hazardous material, feces, or chemicals, into you clean water lines. This is why you call Sausalito Backflow preventer testing plumber service company, to fix, repair, or perform a backflow testing. CALL NOW BACKFLOW-TESTS.com 1-877-637-0530.
24 Hour Emergency Backflow and Plumbing Near Me
Emergency 24 hour Backflow preventer testing Sausalito CA Near Me. Backflow pipe leak and plumber repair and backflow testing is available throughout the state of CA. Backflow-Tests.com can connect you with some Certified and Affordable plumberBackflow preventer testing in Sausalito CA.
CALL BACKFLOW-TESTS.com for Affordable plumbing, Certified backflow repair, and plumber in Sausalito
BACKFLOW-TESTS.com plumber Backflow preventer testing Sausalito CA.

subset: commoncrawl


text:
Notice: this Wiki will be going read only early in 2024 and edits will no longer be possible. Please see: https://gitlab.eclipse.org/eclipsefdn/helpdesk/-/wikis/Wiki-shutdown-plan for the plan.
Difference between revisions of "Stardust/FAQ"
(→What Libraries does Stardust depend on?)
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===== How can I get the Source Code?
 =====
===== How can I get the Source Code?
 =====
Please see: [[Stardust/Source Code|http://wiki.eclipse.org/Stardust/Source_Code]]

Please see: [[Stardust/Source Code|http://wiki.eclipse.org/Stardust/Source_Code]]

===== What Libraries does Stardust depend on?
 =====
===== What Libraries does Stardust depend on?
 =====
The Stardust dependencies are managed via [http://maven.apache.org/ Apache Maven]. Maven POM files describing the dependencies for your target environment and configuration are can be found in our [http://archive.eclipse.org/stardust/maven/3rdparty Maven repository].
Please see [[Stardust/Knowledge Base/Build and Change Management/Maven|Maven page in the Stardust Knowledge Base]] for more details.

The Stardust dependencies are managed via [http://maven.apache.org/ Apache Maven]. Maven POM files describing the dependencies for your target environment and configuration are can be found in our [http://archive.eclipse.org/stardust/maven/3rdparty Maven repository].
Please see [[Stardust/Knowledge Base/Build and Change Management/Maven|Maven page in the Stardust Knowledge Base]] for more details.

===== Which Jars do I need for a Java Client? =====
===== Which Jars do I need for a Java Client? =====
Please check the [https://infinity.sungard.com/documentation/stardust product documentaton] chapter which suitable for your environment (Spring, EJB). Maven project for Spring and EJB client environements can be generated using the [[
Please check the [https://infinity.sungard.com/documentation/stardust product documentaton] chapter which suitable for your environment (Spring, EJB). Maven project for Spring and EJB client environements can be generated using the [[Stardust///Maven|Maven archetype]]
== Internationalization (i18n) ==
== Internationalization (i18n) ==
Revision as of 05:05, 6 May 2013
- 1 General Questions
- 2 Supported Platforms
- 3 Bug Reporting & Contributing
- 4 Build, Dependencies & Source Code
- 5 Internationalization (i18n)
- 6 Troubleshooting
- 7 Other
- 8 References
General Questions
What is the Eclipse Process Manager / Stardust?
Stardust is Business Process Management (BPM) for Eclipse.
Stardust is a comprehensive Business Process Management Suites (BPMS) which supports the whole process life cycle of process modeling, simulation, execution, monitoring and reporting. It allows you to model business processes in Eclipse, integrate them with your application services and UI components, run them in the process engine and to access workflow functionality and document management capabilities in the browser portal.
Stardust is a mature BPMS who's code base has been developed over more than 10 years. It has a proven track record in the industry with more than 1,500 customers on all 5 continents and is embedded in many solutions in mission critical, partially high throughput environments.
Where did Stardust come from?
Stardust is a code contribution from SunGard based on the Process Platform (IPP).
Initially the Infinity Process Platform was developed by the CARNOT AG and sold under the name CARNOT. In November 2006 SunGard acquired the CARNOT AG and included the rebranded product in its Infinity technology stack. Since then the BPMS has been widely adopted across SunGard. It is integrated in many of the company's products and solutions and also offered in a SAAS deliver model named Infinity on Demand.
Please see the pages on how to get access and how to install.
Who is building commercial Products based on Stardust?
Stardust is an open source product under the Eclipse Public License and does not include any liability or commercial support. The Infinity Process Platform is Stardust under a commercial license including commercial support provided by SunGard. All of the source code was submitted to Eclipse as open source and the code bases are synchronized on a regular basis.
Offerings that are based on the Infinity Process Platform are currently sold by SunGard, its national distribution partners and by SunGard customers who are reselling IPP-based solutions to their customer base.
Offerings from other vendors which are based on Stardust can only be expected after the open sourcing is completed and the platform is fully availabe under the EPL.
How is Stardust licensed?
Stardust is licensed under the Eclipse Public License. The Infinity Process Platform is Stardust under a commercial license including commercial support provided by SunGard.
How can I get Help?
Please check the knowledge base, contact us via the forum or send an email to the Stardust developer mailing list.
Can I get commercial Support?
SunGard offers commercial support for the Infinity Process Platform which is Stardust under a commercial license including commercial support.
Supported Platforms
On which Java Versions can I use Stardust?
On version 6.0.x the following Java runtimes are supported
| Vendor
| Supported Version
| Oracle
| 32 Bit JRE 6.0 (in combination with WebSphere 7)
| BEA/Oracle
| JRockit JDK 6.0 (in combination with Weblogic 11g)
Does Stardust work on IBM's / JRockit JDK?
IBM JDK is supported in combination with the supported IBM Websphere version.
JRockit is supported in combination with the supported Weblogic version.
Also see the answers regarding supported Java runtimes and supported Application Servers.
Which Application Server does Stardust support?
On version 6.0.x the following application servers are supported
| Server
| Version
| IBM WebSphere
| 7, 8
| BEA / Oracle WebLogic
| 10.3.3
| 5.1
| Apache Tomcat
| 6.0.32
Which Databases does Stardust support?
On version 6.0.x the following database servers are supported:
|Supported Versions
|10g, 11g R1 (22.214.171.124.0), 11g R2 (22.214.171.124.0)
|9.5, 9.7
|5.0, 5.1
|Sybase ASE
|SQL Server
|2005, 2008
There is no official testing for other databases, but some project have reported that they are successfully using other DBMS or other version, e.g. PostgreSQL.
Which Environments can Stardust run in?
Stardust can be deployed in EJB and Spring environments.The EJB mode requires a full-blown application server with EJB 2 support (JBOSS, Weblogic, Websphere). Currently the Stardust EJB services are only available as EJB 2 services. EJB 3 support is planned. A Spring deployment is supported in all supported application servers and on Apache Tomcat.
Can I use Stardust from a .NET environement?
The complete Stardust Java API functionality is also accessible from .NET via Stardust's Web Servcie API. The Web Service API has been tested for .NET compatibility and several proucts and customers projects have implemented custom .NET clients based on this API. Example code is availe in the Knowledge Base.
Bug Reporting & Contributing
How do I report a Bug in Stardust?
If you are not completely sure that it is a bug then please consult the forum first. Bugs can be reported via the Eclipse Bugzilla system for Stardust.
How can I search the existing List of Bugs in Stardust?
You can log into Eclipse Bugzilla system for Stardust and browse the reported issues. Also consider consulting the forum.
How can I contribute to Startdust?
Build, Dependencies & Source Code
How can I get the Source Code?
Please see: http://wiki.eclipse.org/Stardust/Source_Code
What Libraries does Stardust depend on?
The Stardust dependencies are managed via Apache Maven. Maven POM files describing the dependencies for your target environment and configuration are can be found in our Maven repository.
Please see Maven page in the Stardust Knowledge Base for more details.
Which Jars do I need for a Java Client?
Please check the product documentaton chapter which suitable for your environment (Spring, EJB). Maven project for Spring and EJB client environements can be generated using the Maven archetype
Internationalization (i18n)
What languages are supported?
The supported languages are English, German, and simplified Chinese.
Can I get Stardust in another language?
Stardust's portal, error messages and Eclipse plugins are fully i18ned and can be translated by anyone into additional languages. One only has to create and translate the corresponding resource bundles. We found a convenient way to do this using the Java.net excelbundle project. A compiled version of excelbundle is available on Maven Central repository. We create a script to make the rountrip (translation-update-review-adjustment) easier. This way also non technical people can work on the translation in an Excel sheet.
How can I prevent OutOfMemoryErrors on Tomcat?
The default Tomcat settings (in a RAD scenario) do not allocate much memory. Hence the application may run often out of memory quite frequently. The console log will often throw a java.lang.OutOfMemoryError exception. To avoid this, just add a different memory settings in the Tomcat launch configuration:
Servers > Open Launch Configuration > Arguments > VM arguments > at the very bottom add >
-Xms128m -Xmx512m -XX:MaxPermSize=128m
On a standalone server (outside eclipse RAD environment) start tomcat using:
set JAVA_OPTS=-Xms128m -Xmx512m -XX:MaxPermSize=128m
catalina.bat run
Why is my Completion Method invoked twice?
You most probably defined the completion method once in the application element which is connected to your activity and a second time in the access point of an out data mapping.
To perform the intended operation the application's completion method is invoked first. After the processing is done, the results can be mapped into the process context via outdata mappings. In the access point fields of the outdata mappings one has to select the getter methods which will return the data. When the mappings are executed, the engine will invoke the (getter) methods specified in the access points of the outdata mappings to fetch the values. (If any, it will also evaluate the specified access paths on returned objects.) If the completion method has a return value which should be mapped to a process data, then the access point of the outdata mapping should not use the completion method (again). This would result in a second invocation. To get the reurn value of the completion method use the "return value" access point.
To which Directory is my Web Application published in the RAD Environment?
If you checked the Tomcat installation which you use for the RAD environment, you saw that Eclipse leaves this installation unmodified. The stardust dynamic web project is not published to the server's webapps folder. Instead it is published to a temporary folder which, if you don't change the configuration, is created inside your workspace under:
When troubleshooting it can be helpful to browser this folder to see what Eclipse actually published to the server.
How to change the default Port on Oracle XE?
c:\> sqlplus '/ as sysdba'
SQL> EXEC DBMS_XDB.SETHTTPPOR SQL> SELECT dbms_xdb.gethttpport, dbms_xdb.getftpport FROM dual;T(8081);[1]
How can I browse the Jackrabbit Repository Contents?
The easiest way to browse the Jackrabbit repository is to use WebDAV and configure the repository as a network drive under Windows. You will need to ensure that the WebDAV servlets (Simple WebDAV and JCR over WebDAV) are configured properly in the web.xml of your web application. You can then use a command like the following to map the repository as a network drive:
net use t: "http://<hostname>:<port>/<context-root>/jackrabbit/repository/default/ipp-repository" /User:<jcr-user> <jcr-password>
The <jcr-user> and <jcr-password> can be obtained by looking up the values specified in the jackrabbit-jcr-context.xml file.
To browse the Jackrabbit tree and look up the node property values you can use a tool like JCR Browser (http://sourceforge.net/projects/jcrbrowser). This tool provides options to connect to the repository over RMI/WebDAV etc.
How can I configure the DMS / Content Repository / Jackrabbit to ...?
For Jackrabbit configuration, tuning options and more please see the Jackrabbit wiki.


text:
Perfect cleaning service and nice personnel. Not epic surroundings but really close to bus station and the beaches as well. Would absolutely recommend.
Stuff helpful and friendly, Location was great, Breakfast was really good.
1.2. The information contained in this website is offered for the convenience of users. This information may contain inaccuracies, errors, omissions and / or mistakes, so that the owner does not guarantee the reliability, accuracy and / or safety of the contents.
1.3. The information contained on the website is current at the date of the last update. The owner reserves the right to make, at any time, changes, updates and / or deletions as may be necessary.
1.4. The website owner is not responsible for any damage that may result from interference, interruptions, computer viruses and / or disconnections in the operational functioning of this electronic system, neither of which can be caused by third parties through illegal interference in the system.
1.5. The user undertakes to use the website and the services available to them according to law, morals and good customs, refraining from using it for illicit purposes contrary to the provisions of these rules, or in any manner that may harm third or impede the normal use by other users.
1.6. The services are collected and provided through the Web are designed for adults so that users who take service through this website should be legally of age. No request or collect any information on children.
1.7. The owner is not responsible for the contents, products and / or services that may be obtained through advertising or links to third party websites (links) through this website. The presence of links is for informational purposes only and does not imply any relationship between the owner and the owners of web pages that can be accessed through these links.
1.8. The content of this website is intended for personal use, so you may not copy, reproduce, distribute, communicate, publish, transfer, process, sell or use the content of this website for public or commercial purposes.
1.9. The holder may withdraw or suspend at any time without prior notice provision of services to users who have infringed the provisions of this document, or incurred in violation of the law, morality or public order. The exclusion of the user does not constitute a waiver of any legal action relevant to accountability.
The owner reserves the right to exclude temporarily or permanently the users of this website are given if any of the following circumstances:
• Failure of any of the General Conditions set out in this document.
• Failure to comply with the law, morality and public order.
In any case, the user exclusion constitute a waiver to perform the legal actions, and possible indemnity payments.
For the purposes of Article 27 of the LSSICE, the contractual process conducted by www.hotelmarfil.com be done through the following steps:
• First Choice Hotel, offer, package or other hotel services on the home page via the search parameters, and the dates of stay.
• Second: Choosing the type of room, number of them, and number of people.
• Third: selection of supplements and additional services shows the final price. Insert both of personal data relating to the reserve, as well as the bank card used to guarantee the reservation and acceptance of general conditions of booking.
• Fourth: Formalizing the booking confirmation page sample.
• Fifth: Sending email booking confirmation with details of the same.
Upon reservation will generate an electronic document subsequently incorporated into its holder files. The user will always have full access to and knowledge of it by sending an email with the content at the end of the booking process.
Once you have completed the booking, the customer is requested to review the content of it so you can identify possible errors in data entry, in case of correction needed, the user can call the central reservations phone (+34) 971341005 or send an email to email@example.com providing identifying details of the reservation.
4.1. In reservation service "on line" guarantees the security and confidentiality of transactions.
4.2. The transactional service connection is made through a secure server. This is the standard technology in Internet security, Secure Socket Layer (SSL), which uses an encryption system to provide maximum confidentiality of data that it transmitted. The information is transmitted encrypted to ensure that it is intelligible only to the client computer and the server of the website owner.
4.3. Verification that the connection is made through a secure server can be checked by any of the following systems:
- Using the address (www.hotelabrat.com) of the server, since a secure server begins with https.
Through an indication on your browser that displays a whole key to a closed padlock on the bottom of the screen.
Following the entry into the main site and in the linked pages may incorporate cookies to your computer. If the users are not interested in it, must set your browser to prevent the incorporation of cookies on your computer.
The relationship between the owner of the website and users shall be governed by Spanish law
Shall have jurisdiction in any dispute between the parties the courts of Ibiza (Spain), expressly waiving any other jurisdiction that may app
Perfect cleaning service and nice personnel. Not epic surroundings but really close to bus station and the beaches as well. Would absolutely recommend.
Stuff helpful and friendly, Location was great, Breakfast was really good.


text:
21 783
>War 4< free xp
ta mapa jest skopiowana XD
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ta mapa jest skopiowana XD


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SCOTTSDALE, Ariz. — Researchers from Mayo Clinic and the University of Arizona are shedding light on a mechanism in the human body that may result in more effective treatments for conditions such as autoimmune disorders, cancer, allergies and chronic inflammation. The team has discovered a novel function of a protein previously believed to only help with blood clotting. The researchers found that this protein can prevent the immune system from going out of control – a condition that can ultimately harm the body.
The findings are published in the journal Immunity.
The protein is believed to work this way: When the body is attacked by viruses or bacteria, the immune system rallies to provide a defense mechanism. This is known as inflammation. While inflammation is needed to fight off viruses and other pathogens, it can also cause damage – and the immune system has to find the right balance so levels of inflammation are not too high or too low.
The question has always been, how does the immune system maintain that balance?
"Our discovery explains this," says co-author Sourav Ghosh, Ph.D., assistant professor in the Department of Cellular and Molecular Medicine at the UA College of Medicine in Tucson.
The researchers focused on two cells that control mediation of the body's immune response, with regulating inflammation the goal. They targeted specific immune responses in laboratory models to determine levels of inflammation and compared their findings with blood from patients with inflammatory bowel diseases such as ulcerative colitis and Crohn's disease.
The researchers found that patients experiencing increased inflammation had lower levels of a specific protein produced by cells than did healthy study participants.
The findings could result in more targeted treatments for the inflammatory bowel diseases, which can be especially promising because current treatment is limited at this time, and colon cancer is a significant risk for such patients, says co-author Jonathan Leighton, M.D., chair of Gastroenterology at Mayo Clinic in Arizona.
Dr. Leighton says, "From a clinical standpoint, we think that three factors predispose to inflammatory bowel disease – genetics, environment and the immune system. The immune system is a critical factor because it controls inflammation, and the results from our research provide insight on how to better control this inflammation."
The study was funded by the National Institutes of Health, the Crohn's and Colitis Foundation, the American Heart Association, the American Asthma Foundation, the Lupus Research Foundation and a Gershon-Trudeau Postdoctoral Fellowship.
Mayo Clinic doctors are using innovation to improve the lives of people who suffer from congestive heart failure and other chronic heart conditions. The Organ ...
Mayo Clinic is celebrating 60 years of helping patients receive the gift of life through organ transplants. Over the past six decades, Mayo Clinic has ...
Many parts of the U.S. – and the world — will soon "fall back" as daylight saving time ends and clocks fall back one hour. ...


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The WordPress.com stats helper monkeys prepared a 2012 annual report for this blog.
Here's an excerpt:
The new Boeing 787 Dreamliner can carry about 250 passengers. This blog was viewed about 1,800 times in 2012. If it were a Dreamliner, it would take about 7 trips to carry that many people.


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Naperville, IL -- (SBWIRE) -- 07/05/2013 -- Reportstack, provider of premium market research reports announces the addition of Anxiety Disorders - Pipeline Review, H1 2013 market report to its offering
Anxiety Disorders - Pipeline Review, H1 2013
Global Markets Direct's, 'Anxiety Disorders - Pipeline Review, H1 2013', provides an overview of the indication's therapeutic pipeline. This report provides information on the therapeutic development for Anxiety Disorders, complete with latest updates, and special features on late-stage and discontinued projects. It also reviews key players involved in the therapeutic development for Anxiety Disorders. Anxiety Disorders - Pipeline Review, Half Year is built using data and information sourced from Global Markets Direct's proprietary databases, Company/University websites, SEC filings, investor presentations and featured press releases from company/university sites and industry-specific third party sources, put together by Global Markets Direct's team.
Note*: Certain sections in the report may be removed or altered based on the availability and relevance of data for the indicated disease.
- A snapshot of the global therapeutic scenario for Anxiety Disorders.
- A review of the Anxiety Disorders products under development by companies and universities/research institutes based on information derived from company and industry-specific sources.
- Coverage of products based on various stages of development ranging from discovery till registration stages.
- A feature on pipeline projects on the basis of monotherapy and combined therapeutics.
- Coverage of the Anxiety Disorders pipeline on the basis of route of administration and molecule type.
- Key discontinued pipeline projects.
- Latest news and deals relating to the products.
Reasons to buy
- Identify and understand important and diverse types of therapeutics under development for Anxiety Disorders.
- Identify emerging players with potentially strong product portfolio and design effective counter-strategies to gain competitive advantage.
- Plan mergers and acquisitions effectively by identifying players of the most promising pipeline.
- Devise corrective measures for pipeline projects by understanding Anxiety Disorders pipeline depth and focus of Indication therapeutics.
- Develop and design in-licensing and out-licensing strategies by identifying prospective partners with the most attractive projects to enhance and expand business potential and scope.
- Modify the therapeutic portfolio by identifying discontinued projects and understanding the factors that drove them from pipeline.
To view the table of contents for this market research report please visit


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Halloween cards
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It's that time again. Time to dust off that witch's cap or that set of Frankenstein neck bolts, time to practice that Vincent Price voice or give your best rendition of "Fly My pretties!" And while you're at it, don't forget to pick up some dry ice and brain-shaped lollipops at the supermarket, along with a Halloween card to send to a friend. It's Halloween! While one might think at first that mixing scary movie imagery with excessive amounts of candy would be a recipe for disaster, Halloween has turned out to be one of America's most beloved pastimes. Arriving every October 31st, Halloween is a time for kids and adults alike to dress up as something scary – though the grown ups generally prefer costume parties to trick or treating. But no matter how old you are, it's a good time to think of friends and perhaps send them a gift, some candy or a Halloween card. Just remember not to send any fake blood, it might give the wrong idea.
The history of Halloween dates back to medieval England, since any country that can produce someone like Henry VIII is bound to have a scary side. While candy is the primary way to show your holiday spirit, sending Halloween cards has become more and more popular. The traditions of Halloween result from a mixture of a Roman seed planting festival and the Celtic festival honoring the end of summer; the end of summer being such an awful thing for the Celts that it's no surprise it ended up being associated with monsters. But the name itself comes from the fact that Halloween comes immediately before All Hallows Day. As far as trick or treating goes, it emerged as a tradition for children and adults alike to ask for a blessing on their souls; today, it serves the equally important purpose of getting the kids out of the house for a while. There are plenty of other important traditions on Halloween as well, such as pumpkin carving, apple bobbing, and trying to get the leaves off your front lawn so you can put up that giant tarantula decoration you love so much. But don't forget to look out for the well being of your fellow spooks this Halloween; a Halloween card, poem or gift for loved ones will keep them from frightening you with a petulant reaction later on.


text: Alright, first report from the show–we'll start easy. Caspian has some new components, and Wilson Combat is the beneficiary of one of these items. This, of course, relates to Caspian's new 1911 single-stack Recon frame with tactical light-mounting rail. So, for Wilson Combat customers that want a 1911 with integral light-mounting rail, things are looking pretty good. Caspian is also …Read More »


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In Belarus, arriving flights are served by the following airports


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