The following information has been taken from the Physicians Desk Reference or other sources and is provided for informational purposes only. This page was last updated in 1998. As I no longer have an interest in pursuing treatments with drugs, this page is not updated. Please contact the Pemphigus Foundation for the latest information about possible drug and other treatments for pemphigus.
Prednisone is a glucocorticoid. Glucocorticoids are adrenocortical steroids, both naturally occurring and synthetic, which are readily absorbed from the gastrointestinal tract. Prednisone is a white to practically white, odorless, crystalline powder. It is very slightly soluble in water; slightly soluble in alcohol, in chloroform, in dioxane, and in methanol.
The chemical name for prednisone is pregna-1,4-diene-3,11,20-trione, 17,21- dihydroxy- and its molecular weight is 358.43.
ACTIONS/CLINICAL PHARMACOLOGY Naturally occurring Glucocorticoids (hydrocortisone and cortisone), which also have salt-retaining properties, are used as replacement therapy in adrenocortical deficiency states. Their synthetic analogs are primarily used for their potent anti-inflammatory effects in disorders of many organ systems.
Glucocorticoids cause profound and varied metabolic effects. In addition, they modify the body's immune responses to diverse stimuli.
INDICATIONS AND USAGE Prednisone Tablets are indicated in the following conditions:
Primary or secondary adrenocortical insufficiency (hydrocortisone or cortisone is the first choice; synthetic analogs may be used in conjunction with mineralocorticoids where applicable; in infancy mineralocorticoid supplementation is of particular importance)
Congenital adrenal hyperplasia
Hypercalcemia associated with cancer
Nonsuppurative thyroiditis
As adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in:
Psoriatic arthritis
Rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low-dose maintenance therapy)
Ankylosing spondylitis
Acute and subacute bursitis
Acute nonspecific tenosynovitis
Acute gouty arthritis
Post-traumatic osteoarthritis
Synovitis of osteoarthritis
Epicondylitis
During an exacerbation or as maintenance therapy in selected cases of:
Systemic lupus erythematosus
Systemic dermatomyositis (polymyositis)
Acute rheumatic carditis
Pemphigus
Bullous dermatitis herpetiformis
Severe erythema multiforme
(Stevens-Johnson syndrome)
Exfoliative dermatitis
Mycosis fungoides
Severe psoriasis
Severe seborrheic dermatitis
Control of severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment:
Seasonal or perennial allergic rhinitis
Bronchial asthma
Contact dermatitis
Atopic dermatitis
Serum sickness
Drug hypersensitivity reactions
Severe acute and chronic allergic and inflammatory processes involving the eye and its adnexa such as:
Allergic corneal marginal ulcers
Herpes zoster ophthalmicus
Anterior segment inflammation
Diffuse posterior uveitis and choroiditis
Sympathetic ophthalmia
Allergic conjunctivitis
Keratitis
Chorioretinitis
Optic neuritis
Iritis and iridocyclitis
Symptomatic sarcoidosis
Loeffler's syndrome not manageable by other means
Berylliosis
Fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate antituberculous chemotherapy
Aspiration pneumonitis
Idiopathic thrombocytopenic purpura in adults
Secondary thrombocytopenia in adults
Acquired (autoimmune) hemolytic anemia
Erythroblastopenia (RBC anemia)
Congenital (erythroid) hypoplastic anemia
For palliative management of:
Leukemias and lymphomas in adults
Acute leukemia of childhood
To induce a diuresis or remission of proteinuria in the nephritic syndrome, without uremia, of the idiopathic type or that due to lupus erythematosus
To tide the patient over a critical period of the disease in:
Ulcerative colitis
Regional enteritis
Acute exacerbations of multiple sclerosis
Tuberculous meningitis with subarachnoid block or impending block when used concurrently with appropriate antituberculous chemotherapy
Trichinosis with neurologic or myocardial involvement
CONTRAINDICATIONS Systemic fungal infections and known hypersensitivity to components.
WARNINGS In patients on corticosteroid therapy subjected to unusual stress, increased dosage of rapidly acting corticosteroids before, during, and after the stressful situation is indicated.
Corticosteroids may mask some signs of infection, and new infections may appear during their use. There may be decreased resistance and inability to localize infection when corticosteroids are used.
Prolonged use of corticosteroids may produce posterior subcapsular cataracts, glaucoma with possible damage to the optic nerves, and may enhance the establishment of secondary ocular infections due to fungi or viruses.
Usage In Pregnancy: Since adequate human reproduction studies have not been done with corticosteroids, the use of these drugs in pregnancy, nursing mothers or women of childbearing potential requires that the possible benefits of the drug be weighed against the potential hazards to the mother and embryo or fetus. Infants born of mothers who have received substantial doses of corticosteroids during pregnancy, should be carefully observed for signs of hypoadrenalism.
Average and large doses of hydrocortisone or cortisone can cause elevation of blood pressure, salt and water retention, and increased excretion of potassium. These effects are less likely to occur with the synthetic derivatives except when used in large doses. Dietary salt restriction and potassium supplementation may be necessary. All corticosteroids increase calcium excretion.
While on corticosteroid therapy patients should not be vaccinated against smallpox. Other immunization procedures should not be undertaken in patients who are on corticosteroids, especially on high dose, because of possible hazards of neurological complications and a lack of antibody response.
The use of Prednisone Tablets in active tuberculosis should be restricted to those cases of fulminating or disseminated tuberculosis in which the corticosteroid is used for the management of the disease in conjunction with an appropriate anti-tuberculous regimen.
If corticosteroids are indicated in patients with latent tuberculosis or tuberculin reactivity, close observation is necessary as reactivation of the disease may occur. During prolonged corticosteroid therapy, these patients should receive chemoprophylaxis.
Persons who are on drugs which suppress the immune system are more susceptible to infections than healthy individuals. Chicken pox and measles, for example, can have a more serious or even fatal course in non-immune children or adults on corticosteroids. In such children or adults who have not had these diseases, particular care should be taken to avoid exposure. How the dose, route and duration of corticosteroid administration affects the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed to chicken pox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobin (IG), may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chickenpox develops, treatment with antiviral agents may be considered.
Drug-induced secondary adrenocortical insufficiency may be minimized by gradual reduction of dosage. This type of relative insufficiency may persist for months after discontinuation of therapy; therefore, in any situation of stress occurring during that period, hormone therapy should be reinstituted. Since mineralocorticoid secretion may be impaired, salt and/or a mineralocorticoid should be administered concurrently.
There is an enhanced effect of corticosteroids on patients with hypothyroidism and in those with cirrhosis.
Corticosteroids should be used cautiously in patients with ocular herpes simplex because of possible corneal perforation.
The lowest possible dose of corticosteroid should be used to control the condition under treatment, and when reduction in dosage is possible, the reduction should be gradual.
Psychic derangements may appear when corticosteroids are used, ranging from euphoria, insomnia, mood swings, personality changes, and severe depression, to frank psychotic manifestations. Also, existing emotional instability or psychotic tendencies may be aggravated by corticosteroids.
Steroids should be used with caution in nonspecific ulcerative colitis, if there is a probability of impending perforation, abscess or other pyogenic infection; diverticulitis; fresh intestinal anastomoses; active or latent peptic ulcer; renal insufficiency; hypertension; osteoporosis; and myasthenia gravis.
Growth and development of infants and children on prolonged corticosteroid therapy should be carefully observed.
Although controlled clinical trials have shown corticosteroids to be effective in speeding the resolution of acute exacerbations of multiple sclerosis, they do not show that corticosteroids affect the ultimate outcome or natural history of the disease. The studies do show that relatively high doses of corticosteroids are necessary to demonstrate a significant effect. (See DOSAGE AND ADMINISTRATION).
Since complications of treatment with Glucocorticoids are dependent on the size of the dose and the duration of treatment, a risk/benefit decision must be made in each individual case as to dose and duration of treatment and as to whether daily or intermittent therapy should be used.
Convulsions have been reported with concurrent use of methyl prednisolone and cyclosporin. Since concurrent use of these agents results in a mutual inhibition of metabolism, it is possible that adverse events associated with the individual use of either drug may be more apt to occur.
The pharmacokinetic interactions listed below are potentially clinically important. Drugs that induce hepatic enzymes such as phenobarbital, phenytoin and rifampin may increased the clearance of corticosteroids and may require increases in corticosteroid dose to achieve the desired response. Drugs such as troleandomycin and ketoconazole may inhibit metabolism of corticosteroids and thus decrease their clearance. Therefore, the dose of corticosteroid should be titrated to avoid steroid toxicity. Corticosteroids may increase the clearance of high dose aspirin. This could lead to decreased salicylate serum levels or increase the risk of salicylate toxicity when corticosteroid is withdrawn. Aspirin should be used cautiously in conjunction with corticosteroids in patients suffering from hypoprothrombinemia. The effect of corticosteroids on oral anticoagulants is variable. There are reports of enhanced as well as diminished effects of anticoagulants when given concurrently with corticosteroids. Therefore, coagulation indices should be monitored to maintain the desired anticoagulant effect.
Persons who are on immuno suppressant doses of corticosteroids should be warned to avoid exposure to chicken pox or measles. Patients should also be advised that if they are exposed, medical advice should be sought without delay.
Aspirin should be used cautiously in conjunction with corticosteroids in hypoprothrombinemia.
Convulsions have been reported with concurrent use of methyl prednisolone and cyclosporin. Since concurrent use of these agents results in a mutual inhibition of metabolism, it is possible that adverse events associated with the individual use of either drug may be more apt to occur.
The pharmacokinetic interactions listed below are potentially clinically important. Drugs that induce hepatic enzymes such as phenobarbital, phenytoin and rifampin may increased the clearance of corticosteroids and may require increases in corticosteroid dose to achieve the desired response. Drugs such as troleandomycin and ketoconazole may inhibit metabolism of corticosteroids and thus decrease their clearance. Therefore, the dose of corticosteroid should be titrated to avoid steroid toxicity. Corticosteroids may increase the clearance of high dose aspirin. This could lead to decreased salicylate serum levels or increase the risk of salicylate toxicity when corticosteroid is withdrawn. Aspirin should be used cautiously in conjunction with corticosteroids in patients suffering from hypoprothrombinemia. The effect of corticosteroids on oral anticoagulants is variable. There are reports of enhanced as well as diminished effects of anticoagulants when given concurrently with corticosteroids. Therefore, coagulation indices should be monitored to maintain the desired anticoagulant effect.
Sodium retention
Fluid retention Congestive heart failure in susceptible patients
Potassium loss
Hypokalemic alkalosis
Hypertension
Muscle weakness
Steroid myopathy
Loss of muscle mass
Osteoporosis
Vertebral compression fractures
Aseptic necrosis of femoral and humeral heads
Pathologic fracture of long bones
Peptic ulcer with possible perforation and hemorrhage
Pancreatitis
Abdominal distention
Ulcerative esophagitis
Increases in alanine transaminase (ALT, SGPT), aspartate transaminase (AST, SGOT) and alkaline phosphatase have been observed following corticosteroid treatment. These changes are usually small, not associated with any clinical syndrome and are reversible upon discontinuation.
Impaired wound healing
Thin fragile skin
Petechiae and ecchymoses
Facial erythema
Increased sweating
May suppress reactions to skin tests
Negative nitrogen balance due to protein catabolism
Increased intra cranial pressure with papilledema (pseudo-tumor cerebri) usually after treatment
Convulsions
Vertigo
Headache
Menstrual irregularities
Development of Cushingoid state
Secondary adrenocortical and pituitary unresponsiveness, particularly in times of stress, as in trauma, surgery or illness.
Suppression of growth in children
Decreased carbohydrate tolerance
Manifestations of latent diabetes mellitus
Increased requirements for insulin or oral hypoglycemic agents in diabetics
Posterior subcapsular cataracts
Increased intra ocular pressure
Glaucoma
Exophthalmos
Urticaria and other allergic, anaphylactic or hypersensitivity reactions
DOSAGE AND ADMINISTRATION The initial dosage of Prednisone Tablets may vary from 5 mg to 60 mg of prednisone per day depending on the specific disease entity being treated. In situations of less severity lower doses will generally suffice while in selected patients higher initial doses may be required. The initial dosage should be maintained or adjusted until a satisfactory response is noted. If after a reasonable period of time there is a lack of satisfactory clinical response, Prednisone should be discontinued and the patient transferred to other appropriate therapy.
It should be emphasized that dosage requirements are variable and must be individualized on the basis of the disease under treatment and the response of the patient.
After a favorable response is noted, the proper maintenance dosage should be determined by decreasing the initial drug dosage in small decrements at appropriate time intervals until the lowest dosage which will maintain an adequate clinical response is reached. It should be kept in mind that constant monitoring is needed in regard to drug dosage. Included in the situations which may make dosage adjustments necessary are changes in clinical status secondary to remissions or exacerbations in the disease process, the patient's individual drug responsiveness, and the effect of patient exposure to stressful situations not directly related to the disease entity under treatment; in this latter situation, it may be necessary to increase the dosage of Prednisone for a period of time consistent with the patient's condition. If after long-term therapy the drug is to be stopped, it is recommended that it be withdrawn gradually rather than abruptly
In the treatment of acute exacerbations of multiple sclerosis daily doses of 200 mg of prednisolone for a week followed by 80 mg every other day for 1 month have been shown to be effective. (Dosage range is the same for prednisone and prednisolone).
ADT is a corticosteroid dosing regimen in which twice the usual daily dose of corticoid is administered every other morning. The purpose of this mode of therapy is to provide the patient requiring long-term pharmacologic dose treatment with the beneficial effects of corticoids while minimizing certain undesirable effects, including pituitary-adrenal suppression, the Cushingoid state, corticoid withdrawal symptoms, and growth suppression in children.
The rationale for this treatment schedule is based on two major premises: (a) the anti-inflammatory or therapeutic effect of corticoids persists longer than their physical presence and metabolic effects and (b) administration of the corticosteroid every other morning allows for re-establishment of more nearly normal hypothalamic-pituitary-adrenal (HPA) activity on the off-steroid day.
A brief review of the HPA physiology may be helpful in understanding this rationale. Acting primarily through the hypothalamus a fall in free cortisol stimulates the pituitary gland to produce increasing amounts of corticotropin (ACTH) while a rise in free cortisol inhibits ACTH secretion. Normally the HPA system is characterized by diurnal (circadian) rhythm. Serum levels of ACTH rise from a low point about 10 pm to a peak level about 6 am. Increasing levels of ACTH stimulate adrenocortical activity resulting in a rise in plasma cortisol with maximal levels occurring between 2 am and 8 am. This rise in cortisol dampens ACTH production and in turn adrenocortical activity. There is a gradual fall in plasma corticoids during the day with lowest levels occurring about midnight.
The diurnal rhythm of the HPA axis is lost in Cushing's disease, a syndrome of adrenocortical hyperfunction characterized by obesity with centripetal fat distribution, thinning of the skin with easy bruisability, muscle wasting with weakness, hypertension, latent diabetes, osteoporosis, electrolyte imbalance, etc. The same clinical findings of hyperadrenocorticism may be noted during long-term pharmacologic dose corticoid therapy administered in conventional daily divided doses. It would appear, then, that a disturbance in the diurnal cycle with maintenance of elevated corticoid values during the night may play a significant role in the development of undesirable corticoid effects. Escape from these constantly elevated plasma levels for even short periods of time may be instrumental in protecting against undesirable pharmacologic effects.
During conventional pharmacologic dose corticosteroid therapy, ACTH production is inhibited with subsequent suppression of cortisol production by the adrenal cortex. Recovery time for normal HPA activity is variable depending upon the dose and duration of treatment. During this time the patient is vulnerable to any stressful situation. Although it has been shown that there is considerably less adrenal suppression following a single morning dose of prednisolone (10 mg) as opposed to a quarter of that dose administered every 6 hours, there is evidence that some suppressive effect on adrenal activity may be carried over into the following day when pharmacologic doses are used. Further, it has been shown that a single dose of certain corticosteroids will produce adrenocortical suppression for two or more days. Other corticoids, including methyl prednisolone, hydrocortisone, prednisone, and prednisolone, are considered to be short acting (producing adrenocortical suppression for 1 1/4 to 1 ½ days following a single dose) and thus are recommended for alternate day therapy.
The following should be kept in mind when considering alternate day therapy:
1) Basic principles and indications for corticosteroid therapy should apply. The benefits of ADT should not encourage the indiscriminate use of steroids.
2) ADT is a therapeutic technique primarily designed for patients in whom long- term pharmacologic corticoid therapy is anticipated.
3) In less severe disease processes in which corticoid therapy is indicated, it may be possible to initiate treatment with ADT. More severe disease states usually will require daily divided high dose therapy for initial control of the disease process. The initial suppressive dose level should be continued until satisfactory clinical response is obtained, usually four to ten days in the case of many allergic and collagen diseases. It is important to keep the period of initial suppressive dose as brief as possible particularly when subsequent use of alternate day therapy is intended.
Once control has been established, two courses are available: (a) change to ADT and then gradually reduce the amount of corticoid given every other day OR (b) following control of the disease process reduce the daily dose of corticoid to the lowest effective level as rapidly as possible and then change over to an alternate day schedule. Theoretically, course (a) may be preferable.
4) Because of the advantages of ADT, it may be desirable to try patients on this form of therapy who have been on daily corticoids for long periods of time (eg, patients with rheumatoid arthritis). Since these patients may already have a suppressed HPA axis, establishing them on ADT may be difficult and not always successful. However, it is recommended that regular attempts be made to change them over. It may be helpful to triple or even quadruple the daily maintenance dose and administer this every other day rather than just doubling the daily dose if difficulty is encountered. Once the patient is again controlled, an attempt should be made to reduce this dose to a minimum.
5) As indicated above, certain corticosteroids, because of their prolonged suppressive effect on adrenal activity, are not recommended for alternate day therapy (eg, dexamethasone and betamethasone).
6) The maximal activity of the adrenal cortex is between 2 am and 8 am, and it is minimal between 4 pm and midnight. Exogenous corticosteroids suppress adrenocortical activity the least, when given at the time of maximal activity (am).
7) In using ADT it is important, as in all therapeutic situations to individualize and tailor the therapy to each patient. Complete control of symptoms will not be possible in all patients. An explanation of the benefits of ADT will help the patient to understand and tolerate the possible flare-up in symptoms which may occur in the latter part of the off-steroid day. Other symptomatic therapy may be added or increased at this time if needed.
8) In the event of an acute flare-up of the disease process, it may be necessary to return to a full suppressive daily corticoid dose for control. Once control is again established alternate day therapy may be re-instituted.
9) Although many of the undesirable features of corticosteroid therapy can be minimized by ADT, as in any therapeutic situation, the physician must carefully weigh the benefit-risk ratio for each patient in whom corticoid therapy is being considered.
Methotrexate
Methotrexate should be used only by physicians whose knowledge and experience includes the use of antimetabolite therapy. The use of methotrexate high-dose regimens recommended for osteosarcoma requires meticulous care (see dosage and administration). High-dosage regimens for other neoplastic diseases are investigational and a therapeutic advantage has not been established. Because of the possibility of serious toxic reactions, the patient should be informed by the physician of the risks involved and should be under a physician's constant supervision. Deaths have been reported with the use of methotrexate in the treatment of malignancy, psoriasis, and rheumatoid arthritis.
In the treatment of psoriasis or rheumatoid arthritis, methotrexate use should be restricted to patients with severe, recalcitrant, disabling disease, which is not adequately responsive to other forms of therapy, and only when the diagnosis has been established and after appropriate consultation.
Methotrexate has been reported to cause fetal death and/or congenital anomalies. Therefore, it is not recommended for women of childbearing potential unless there is clear medical evidence that the benefits can be expected to outweigh the considered risks. Pregnant patients with psoriasis or
rheumatoid arthritis should not receive methotrexate. (See CONTRAINDICATIONS.)
Periodic monitoring for toxicity, including CBC with differential and platelet counts, and liver and renal function tests is a mandatory part of methotrexate therapy. Periodic liver biopsies may be indicated in some situations. Patients at increased risk for impaired methotrexate elimination (eg, renal dysfunction, pleural effusions, or ascites) should be monitored more frequently. (See PRECAUTIONS.)
Methotrexate causes hepatotoxicity, fibrosis, and cirrhosis, but generally only after prolonged use. Acutely, liver enzyme elevations are frequently seen, these are usually transient and asymptomatic, and also do not appear predictive of subsequent hepatic disease. Liver biopsy after sustained use often shows histologic changes, and fibrosis and cirrhosis have been reported; these latter lesions often are not preceded by symptoms or abnormal liver function tests. (See PRECAUTIONS.)
Methotrexate-induced lung disease is a potentially dangerous lesion, which may occur acutely at any time during therapy and which has been reported at doses as low as 7.5 mg/week. It is not always fully reversible. Pulmonary symptoms (especially a dry, nonproductive cough) may require interruption of treatment and careful investigation.
Methotrexate may produce marked bone marrow depression, with resultant anemia, leukopenia, and/or thrombocytopenia.
Diarrhea and ulcerative stomatitis require interruption of therapy; otherwise, hemorrhagic enteritis and death from intestinal perforation may occur.
Methotrexate therapy in patients with impaired renal function should be undertaken with extreme caution, and at reduced dosages, because renal dysfunction will prolong methotrexate elimination.
Unexpectedly severe (sometimes fatal) marrow suppression and gastrointestinal toxicity have been reported with concomitant administration of methotrexate (usually in high dosage) along with some nonsteroidal anti-inflammatory drugs (NSAIDs).
(See PRECAUTIONS, DRUG INTERACTIONS.)
Methotrexate formulations and diluents containing preservatives must not be used for intrathecal or high-dose methotrexate therapy.
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.
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 2 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.
Methotrexate in high doses, followed by leucovorin rescue, is used as a part of the treatment of patients with nonmetastatic osteosarcoma. The original rationale for high- dose methotrexate therapy was based on the concept of selective rescue of normal tissues by leucovorin. More recent evidence suggests that high-dose methotrexate may also overcome methotrexate resistance caused by impaired active transport, decreased affinity of dihydrofolic acid reductase for methotrexate, increased levels of dihydrofolic acid reductase resulting from gene amplification, or decreased polyglutamation of methotrexate. The actual mechanism of action is unknown.
Two Pediatric Oncology Group studies (one randomized and one nonrandomized) demonstrated a significant improvement in relapse-free survival in patients with non-metastatic osteosarcoma, when high-dose methotrexate with leucovorin rescue was used in combination with other chemotherapeutic agents following surgical resection of the primary tumor. These studies were not designed to demonstrate the specific contribution of high dose methotrexate/leucovorin rescue therapy to the efficacy of the combination. However, a contribution can be inferred from the reports of objective responses to this therapy in patients with metastatic osteosarcoma, and from reports of extensive tumor necrosis following preoperative administration of this therapy to patients with non-metastatic osteosarcoma.
Absorption: In adults, oral absorption appears to be dose dependent. Peak serum levels are reached within 1 to 2 hours. At doses of 30 mg/m(squared) or less, methotrexate is generally well absorbed with a mean bioavailability of about 60%. The absorption of doses greater than 80 mg/m(squared) is significantly less, possibly due to a saturation effect. In leukemic children, oral absorption 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/m(squared) dose) has been reported. Significant inter individual variability has also been noted in time to peak concentration (Tmax: 0.67 to 4 hrs after a 15 mg/m(squared) dose) and fraction of dose absorbed. 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.
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 three- to fivefold 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 3 to 10 hours for patients receiving treatment for psoriasis, or rheumatoid arthritis or low-dose antineoplastic therapy (less than 30 mg/m(squared)). For patients receiving high doses of methotrexate, the terminal half-life is 8 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.
NEOPLASTIC DISEASES: Methotrexate is indicated in the treatment of gestational choriocarcinoma, chorioadenoma destruens, and hydatidiform mole.
In acute lymphocytic leukemia, methotrexate is indicated in the prophylaxis of meningeal leukemia and is used in maintenance therapy in combination with other chemotherapeutic agents. Methotrexate is also indicated in the treatment of meningeal leukemia.
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, 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 in high doses followed by leucovorin rescue in combination with other chemotherapeutic agents is effective in prolonging relapse-free survival in patients with nonmetastatic osteosarcoma who have undergone surgical resection or amputation for the primary tumor.
PSORIASIS: 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.
RHEUMATOID ARTHRITIS: Methotrexate is indicated in the management of selected adults with severe, active, classical, or definite rheumatoid arthritis (ARA criteria) who have had an insufficient therapeutic response to, or are intolerant of, an adequate trial of first-line therapy including full dose NSAIDs and usually a trial of at least one or more disease-modifying antirheumatic drugs.
Aspirin, nonsteroidal anti-inflammatory agents, 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 patients 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 3 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.
GENERAL
: Methotrexate has the potential for serious toxicity (see 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 (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, and liver and renal function every 1 to 3 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.
A relationship between abnormal liver function tests and fibrosis or cirrhosis of the liver has not been established. 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 just prior to dosing and/or depression of serum albumin may be indicators of serious liver toxicity and require evaluation. Pulmonary function tests may be useful if methotrexate-induced lung disease is suspected, especially if baseline measurements are available.
Nonsteroidal anti-inflammatory drugs should not be administered prior to or concomitantly with the high doses of methotrexate used in the treatment of osteosarcoma. 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 15 mg/week) 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. In the treatment of patients with osteosarcoma, caution must be exercised if high-dose methotrexate is administered in combination with a potentially nephrotoxic chemotherapeutic agent (eg, cisplatin).
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.
Vitamin preparations containing folic acid or its derivatives may decrease responses to systemically administered methotrexate. Preliminary animal and human studies have shown that small quantities of intravenously administered leucovorin enter the CSF primarily as 5-methyltetrahydrofolate and, in humans, remain 1 to 3 orders of magnitude lower than the usual methotrexate concentrations following intrathecal administration. However, high doses of leucovorin may reduce the efficacy of intrathecally administered methotrexate.
Folate deficiency states may increase methotrexate toxicity.
Trimethoprim/sulfamethoxazole 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. Assessment of the carcinogenic potential of methotrexate is complicated by conflicting evidence of an increased risk of certain tumors in rheumatoid arthritis. Benefit should be weighed against this potential risk before using methotrexate alone or in combination with other drugs, especially in children or young adults. Methotrexate causes embryo toxicity, 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.
PREGNANCY: Psoriasis and rheumatoid arthritis: Methotrexate is in Pregnancy Category X. See CONTRAINDICATIONS.
NURSING MOTHERS: See CONTRAINDICATIONS.
PEDIATRIC USE: Safety and effectiveness in children have not been established, other than in cancer chemotherapy.
ORGAN SYSTEM TOXICITY: 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, leukopenia, 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/mm(cubed)) was seen in two patients, thrombocytopenia (platelets <100,000/mm(cubed)) in six patients, and pancytopenia in two 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 2 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.
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.
In psoriasis, the usual recommendation is to obtain a liver biopsy at a total cumulative dose of 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.
Clinical experience with liver disease in rheumatoid arthritis is limited, but the same risk factors would be anticipated. Liver function tests are also usually not reliable predictors of histological changes in this population.
When to perform a liver biopsy in rheumatoid arthritis patients has not been established, either in terms of cumulative methotrexate dose or duration of therapy. 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 1500 mg) 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.
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.
Neurologic: There have been reports of leukoencephalopathy following intravenous administration of methotrexate to patients who have had craniospinal irradiation. Chronic leukoencephalopathy has also been reported in patients with osteosarcoma who received repeated doses of high-dose methotrexate with leucovorin rescue even without cranial irradiation. Discontinuation of methotrexate does not always result in complete recovery.
A transient acute neurologic syndrome has been observed in patients treated with high-dosage regimens. Manifestations of this neurologic disorder may include behavioral abnormalities, focal sensorimotor signs, and abnormal reflexes. The exact cause is unknown.
After the intrathecal use of methotrexate, the central nervous system toxicity which may occur can be classified as follows: chemical arachnoiditis manifested by such symptoms as headache, back pain, nuchal rigidity, and fever; paresis, usually transient, manifested by paraplegia associated with involvement with one or more spinal nerve roots; leukoencephalopathy manifested by confusion, irritability, somnolence, ataxia, dementia, and occasionally major convulsions. 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 needs to be excluded. This lesion can occur at all dosages.
Renal: High doses of methotrexate used in the treatment of osteosarcoma may cause renal damage leading 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.
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.
Nonsteroidal anti-inflammatory drugs should not be administered prior to or concomitantly with the high doses of methotrexate used in the treatment of osteosarcoma. 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 15 mg/week) 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. In the treatment of patients with osteosarcoma, caution must be exercised if high-dose methotrexate is administered in combination with a potentially nephrotoxic chemotherapeutic agent (eg, cisplatin).
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.
Vitamin preparations containing folic acid or its derivatives may decrease responses to systemically administered methotrexate. Preliminary animal and human studies have shown that small quantities of intravenously administered leucovorin enter the CSF primarily as 5-methyltetrahydrofolate and, in humans, remain 1 to 3 orders of magnitude lower than the usual methotrexate concentrations following intrathecal administration. However, high doses of leucovorin may reduce the efficacy of intrathecally administered methotrexate. Folate deficiency states may increase methotrexate toxicity.
Trimethoprim/sulfamethoxazole has been reported rarely to increase bone marrow suppression in patients receiving methotrexate, probably by an additive antifolate effect.
(See Also PRECAUTIONS)
In general, the incidence and severity of acute side effects are related to dose and frequency of administration. The most serious reactions are discussed above under organ system toxicity in the precautions section. That section should also be consulted when looking for information about adverse reactions with 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.
CENTRAL NERVOUS SYSTEM: Headaches, drowsiness, blurred vision. Aphasia, hemiparesis, paresis, and convulsions have also occurred following administration of methotrexate. Following low doses, occasional patients have reported transient subtle cognitive dysfunction, mood alteration, or unusual cranial sensations.
PULMONARY SYSTEM: Interstitial pneumonitis deaths have been reported, and chronic interstitial obstructive pulmonary disease has occasionally occurred.
SKIN: Erythematous rashes, pruritus, urticaria, photosensitivity, pigmentary changes, alopecia, ecchymoses, telangiectasia, acne, furunculosis.
UROGENITAL SYSTEM: Severe nephropathy or renal failure, azotemia, cystitis, hematuria; defective oogenesis or spermatogenesis, transient oligospermia, menstrual dysfunction and vaginal discharge; infertility, abortion, fetal defects.
Other rarer reactions related to or attributed to the use of methotrexate such as opportunistic infection, arthralgia/myalgia, loss of libido/impotence, diabetes, osteoporosis, and sudden death. A few cases of anaphylactoid reactions have been reported.
ADVERSE REACTIONS IN DOUBLE-BLIND RHEUMATOID ARTHRITIS STUDIES: 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.
Incidence greater than 10%: Elevated liver function tests 15%, nausea/vomiting 10%.
Incidence 3% to 10%: Stomatitis, thrombocytopenia (platelet count less than 100,000/mm(cubed)).
Incidence 1% to 3%: Rash/pruritus/dermatitis, diarrhea, alopecia, leukopenia (WBC <3000/mm(cubed)), pancytopenia, dizziness.
No pulmonary toxicity was seen in these two trials. Thus, the incidence is probably less than 2.5% (95% C.L.). Hepatic histology was not examined in these short-term studies (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.
ADVERSE REACTIONS IN PSORIASIS: 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 4 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.
Leucovorin is indicated to diminish the toxicity and counteract the effect of inadvertently administered over dosages 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 over dose, hydration and urinary alkalinization may be necessary to prevent the precipitation of methotrexate and/or its metabolites in the renal tubules. Neither hemodialysis nor peritoneal dialysis has been shown to improve methotrexate elimination.
NEOPLASTIC DISEASES: Oral administration in tablet form is often preferred when low doses are being administered since absorption is rapid and effective serum levels are obtained. Methotrexate sodium injection and for injection may be given by the intramuscular, intravenous, intra- arterial, or intrathecal route. However, the preserved formulation contains Benzyl Alcohol and must not be used for intrathecal or high-dose therapy. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Choriocarcinoma And Similar Trophoblastic Diseases: Methotrexate is administered orally or intramuscularly in doses of 15 to 30 mg daily for a 5-day course. Such courses are usually repeated for three to five times as required, with rest periods of 1 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/24h 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 children 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/m(squared) in combination with 60 mg/m(squared) 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 two times weekly either by mouth or intramuscularly in total weekly doses of 30 mg/m(squared). 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.
Meningeal Leukemia: In the treatment or prophylaxis of meningeal leukemia, methotrexate must be administered intrathecally. Preservative- free methotrexate is diluted to a concentration of 1 mg/mL in an appropriate sterile, preservative-free medium such as 0.9% Sodium Chloride Injection, USP. The cerebrospinal fluid volume is dependent on age and not on body surface area. The CSF is at 40% of the adult volume at birth and reaches the adult volume in several years.
Intrathecal methotrexate administration at a dose of 12 mg/m(squared) (maximum 15 mg) has been reported to result in low CSF methotrexate concentrations and reduced efficacy in children and high concentrations and neurotoxicity in adults. The following dosage regimen is based on age instead of body surface area:
In one study in patients under the age of 40, this dosage regimen appeared to result in more consistent CSF methotrexate concentrations and less neurotoxicity. Another study in children with acute lymphocytic leukemia compared this regimen to a dose of 12 mg/m(squared) (maximum 15mg). A significant reduction in the rate of CNS relapse was observed in the group whose dose was based on age.
Because the CSF volume and turnover may decrease with age, a dose reduction may be indicated in elderly patients.
For the treatment of meningeal leukemia, intrathecal methotrexate may be given at intervals of 2 to 5 days. However, administration at intervals of less than 1 week may result in increased subacute toxicity. Methotrexate is administered until the cell count of the cerebrospinal fluid returns to normal. At this point one additional dose is advisable. For prophylaxis against meningeal leukemia, the dosage is the same as for treatment except for the intervals of administration. On this subject, it is advisable for the physician to consult the medical literature.
Untoward side effects may occur with any given intrathecal injection and are commonly neurological in character. Large doses may cause convulsions. Methotrexate given by the intrathecal route appears significantly in the systemic circulation and may cause systemic methotrexate toxicity. Therefore, systemic antileukemic therapy with the drug should be appropriately adjusted, reduced, or discontinued. Focal leukemic involvement of the CNS may not respond to intrathecal chemotherapy and is best treated with radiotherapy. Lymphomas: In Burkitt's tumor, Stages I to 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 antitumor 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: Therapy with methotrexate appears to produce clinical remissions in one half of the cases treated. Dosage is usually 2.5 to 10 mg daily by mouth for weeks or months. Dose levels of drug and adjustment of dose regimen by reduction or cessation of drug are guided by patient response and hematologic monitoring. Methotrexate has also been given intramuscularly in doses of 50 mg once weekly or 25 mg two times weekly.
Osteosarcoma: An effective adjuvant chemotherapy regimen requires the administration of several cytotoxic chemotherapeutic agents. In addition to high-dose methotrexate with leucovorin rescue, these agents may include doxorubicin, cisplatin, and the combination of bleomycin, cyclophosphamide and dactinomycin (BCD) in the doses and schedule shown in the table below. The starting dose for high-dose methotrexate treatment is 12 grams/m(squared). If this dose is not sufficient to produce a peak serum methotrexate concentration of 1,000 micromolar (10(raised to the power of minus 3) mol/L) at the end of the methotrexate infusion, the dose may be escalated to 15 grams/m(squared) in subsequent treatments. If the patient is vomiting or is unable to tolerate oral medication, leucovorin is given IV or IM at the same dose and schedule.
Beclomethasone
Beclomethasone dipropionate, USP, the active component of Beclomethasone Inhaler, is an anti-inflammatory steroid having the chemical name 9-Chloro-11beta,17,21- trihydroxy-16beta-methylpregna-1,4-diene-3,20-dione 17,21-dipropionate.
ACTIONS/CLINICAL PHARMACOLOGY Beclomethasone 17,21-dipropionate is a diester of Beclomethasone, a synthetic corticosteroid which is chemically related to dexamethasone. Beclomethasone differs from dexamethasone only in having a chlorine at the 9-alpha in place of a fluorine and in having a 16beta-methyl group instead of a 16 alpha-methyl group. Animal studies showed that Beclomethasone dipropionate has potent anti- inflammatory activity. When administered systemically to mice, the anti- inflammatory activity was accompanied by other typical features of glucocorticoid action including thymic involution, liver glycogen deposition, and pituitary-adrenal suppression. However, after systemic administration to rats, the anti-inflammatory action was associated with little or no effect on other tests of glucocorticoid activity.
Beclomethasone dipropionate is sparingly soluble and is poorly mobilized from subcutaneous or intramuscular injection sites. However, systemic absorption occurs after all routes of administration. When given to animals in the form of an aerosolized suspension of the trichloromonofluoromethane clathrate, the drug is deposited in the mouth and nasal passages, the trachea and principal bronchi and in the lung; a considerable portion of the drug is also swallowed. Absorption occurs rapidly from all respiratory and gastrointestinal tissues, as indicated by the rapid clearance of radioactively labeled drug from local tissues and appearance of tracer in the circulation. There is no evidence of tissue storage of Beclomethasone dipropionate or its metabolites. Lung slices can metabolize Beclomethasone dipropionate rapidly to Beclomethasone 17 monopropionate and more slowly to free Beclomethasone (which has very weak anti inflammatory activity). However, irrespective of the route of administration (injection, oral, or aerosol), the principal route of excretion of the drug and its metabolites is the feces. Less than 10% of the drug and its metabolites is excreted in the urine. In humans, 12% to 15% of an orally administered dose of Beclomethasone dipropionate was excreted in the urine as both conjugated and free metabolites of the drug.
The mechanisms responsible for the anti-inflammatory action of Beclomethasone dipropionate are unknown. The precise mechanism of the aerosolized drug's action in the lung is also unknown.
Beclomethasone Inhaler is indicated only for patients who require chronic treatment with corticosteroids for control of the symptoms of bronchial asthma. Such patients would include those already receiving systemic corticosteroids, and selected patients who are inadequately controlled on a non-steroid regimen and in whom steroid therapy has been withheld because of concern over potential adverse effects.
Beclomethasone Inhaler is NOT indicated:
1. For relief of asthma which can be controlled by bronchodilators and other non-steroid medications.
2. In patients who require systemic corticosteroid treatment infrequently.
3. In the treatment of non-asthmatic bronchitis.
Beclomethasone Inhaler is contraindicated in the primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required.
Hypersensitivity to any of the ingredients of this preparation contraindicates its use.
Particular care is needed in patients who are transferred from systemically active corticosteroids to Beclomethasone Inhaler because deaths due to adrenal insufficiency have occurred in asthmatic patients during and after transfer from systemic corticosteroids to aerosol Beclomethasone dipropionate. After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic-pituitary-adrenal (HPA) function. During this period of HPA suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery or infections, particularly gastroenteritis. Although Beclomethasone Inhaler may provide control of asthmatic symptoms during these episodes, it does NOT provide the systemic steroid which is necessary for coping with these emergencies.
During periods of stress or a severe asthmatic attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume systemic steroids (in large doses) immediately and to contact their physician for further instruction. These patients should also be instructed to carry a warning card indicating that they may need supplementary systemic steroids during periods of stress or a severe asthma attack. To assess the risk of adrenal insufficiency in emergency situations, routine tests of adrenal cortical function, including measurement of early morning resting cortisol levels, should be performed periodically in all patients. An early morning resting cortisol level may be accepted as normal only if it falls at or near the normal mean level.
Localized infections with Candida Albicans or Aspergillus Niger have occurred frequently in the mouth and pharynx and occasionally in the larynx. Positive cultures for oral Candida may be present in up to 75% of patients. Although the frequency of clinically apparent infection is considerably lower, these infections may require treatment with appropriate antifungal therapy or discontinuance of treatment with Beclomethasone Inhaler.
Beclomethasone Inhaler is not to be regarded as a bronchodilator and is not indicated for rapid relief of bronchospasm.
Patients should be instructed to contact their physician immediately when episodes of asthma which are not responsive to bronchodilators occur during the course of treatment with Beclomethasone. During such episodes, patients may require therapy with systemic corticosteroids.
There is no evidence that control of asthma can be achieved by the administration of Beclomethasone in amounts greater than the recommended doses.
Transfer of patients from systemic steroid therapy to Beclomethasone Inhaler may unmask allergic conditions previously suppressed by the systemic steroid therapy, e.g., rhinitis, conjunctivitis, and eczema.
Persons who are on drugs which suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in non-immune children or adults on corticosteroids. In such children or adults who have not had these diseases, particular care should be taken to avoid exposure. How the dose, route and duration of corticosteroid administration affects the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed to chickenpox, prophylaxis with varicella-zoster immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information). If chickenpox develops, treatment with antiviral agents may be considered.
During withdrawal from oral steroids, some patients may experience symptoms of systemically active steroid withdrawal, e.g., joint and/or muscular pain, lassitude and depression, despite maintenance or even improvement of respiratory function
(See DOSAGE AND ADMINISTRATION for details).
In responsive patients, Beclomethasone dipropionate may permit control of asthmatic symptoms without suppression of HPA function, as discussed below (See CLINICAL STUDIES).
Since Beclomethasone dipropionate is absorbed into the circulation and can be systemically active, the beneficial effects of Beclomethasone Inhaler in minimizing or preventing HPA dysfunction may be expected only when recommended dosages are not exceeded.
The long-term effects of Beclomethasone dipropionate in human subjects are still unknown. In particular, the local effects of the agent on developmental or immunologic processes in the mouth, pharynx, trachea, and lung are unknown. There is also no information about the possible long-term systemic effects of the agent.
The potential effects of Beclomethasone on acute, recurrent, or chronic pulmonary infections, including active or quiescent tuberculosis, are not known. Similarly, the potential effects of long-term administration of the drug on lung or other tissues are unknown.
Pulmonary infiltrates with eosinophilia may occur in patients on Beclomethasone Inhaler therapy. Although it is possible that in some patients this state may become manifest because of systemic steroid withdrawal when inhalational steroids are administered, a causative role for Beclomethasone dipropionate and/or its vehicle cannot be ruled out.
Glucocorticoids are known teratogens in rodent species and Beclomethasone dipropionate is no exception.
Teratology studies were done in rats, mice, and rabbits treated with subcutaneous Beclomethasone dipropionate. Beclomethasone dipropionate was found to produce fetal resorptions, cleft palate, agnathia, microstomia, absence of tongue, delayed ossification and partial agenesis of the thymus. Well controlled trials relating to fetal risk in humans are not available. Glucocorticoids are secreted in human milk. It is not known whether Beclomethasone dipropionate would be secreted in human milk but it is safe to assume that it is likely. The use of Beclomethasone dipropionate in pregnancy, nursing mothers, or women of childbearing potential requires that the possible benefits of the drug be weighed against the potential hazards to the mother, embryo, or fetus. Infants born of mothers who have received substantial doses of corticosteroids during pregnancy should be carefully observed for hypoadrenalism.
Persons who are on immuno suppressant doses of corticosteroids should be warned to avoid exposure to chickenpox or measles. Patients should also be advised that if they are exposed, medical advice should be sought without delay.
Deaths due to adrenal insufficiency have occurred in asthmatic patients during and after transfer from systemic corticosteroids to aerosol Beclomethasone dipropionate (see warnings).
Suppression of HPA function (reduction of early morning plasma cortisol levels) has been reported in adult patients who received 1600 mcg daily doses of Beclomethasone for one month. A few patients on Beclomethasone have complained of hoarseness or dry mouth.
Rare cases of immediate and delayed hypersensitivity reactions, including urticaria, angioedema, rash and bronchospasm have been reported following the oral and intranasal inhalation of Beclomethasone.
Adults
: The usual recommended dosage is two inhalations (84 mcg) given three or four times a day. Alternatively, four inhalations (168 mcg) given twice daily has been shown to be effective in some patients. In patients with severe asthma it is advisable to start with 12 to 16 inhalations a day and adjust the dosage downward according to the response of the patient. The maximal daily intake should not exceed 20 inhalations, 840 mcg (0.84 mg), in adults.Children 6 to 12 years of age: the usual recommended dosage is one or two inhalations (42 to 84 mcg) given three or four times a day according to the response of the patient. Alternatively, four inhalations (168 mcg) given twice daily has been shown to be effective in some patients. The maximal daily intake should not exceed ten inhalations, 420 mcg (0.42 mg), in children 6 to 12 years of age. Insufficient clinical data exist with respect to the administration of Beclomethasone inhaler in children below the age of 6.
Rinsing the mouth after inhalation is advised.
Patients receiving bronchodilators by inhalation should be advised to use the bronchodilator before Beclomethasone Inhaler in order to enhance penetration of Beclomethasone dipropionate into the bronchial tree. After use of an aerosol bronchodilator, several minutes should elapse before use of the Beclomethasone Inhaler to reduce the potential toxicity from the inhaled fluorocarbon propellants in the two aerosols.
Patients not receiving systemic steroids:
The use of Beclomethasone Inhaler is straightforward in patients who are inadequately controlled with non-steroid medications but in whom systemic steroid therapy has been withheld because of concern over potential adverse reactions. In patients who respond to Beclomethasone, an improvement in pulmonary function is usually apparent within one to four weeks after the start of Beclomethasone Inhaler.Patients receiving systemic steroids: In those patients dependent on systemic steroids, transfer to Beclomethasone and subsequent management may be more difficult because recovery from impaired adrenal function is usually slow. Such suppression has been known to last for up to 12 months. Clinical studies, however, have demonstrated that Beclomethasone may be effective in the management of these asthmatic patients and may permit replacement or significant reduction in the dosage of systemic corticosteroids.
The patient's asthma should be reasonably stable before treatment with Beclomethasone Inhaler is started. Initially, the aerosol should be used concurrently with the patient's usual maintenance dose of systemic steroid. After approximately one week, gradual withdrawal of the systemic steroid is started by reducing the daily or alternate daily dose. The next reduction is made after an interval of one or two weeks, depending on the response of the patient. Generally, these decrements should not exceed 2.5 mg of prednisone or its equivalent. A slow rate of withdrawal cannot be overemphasized. During withdrawal, some patients may experience symptoms of systemically active steroid withdrawal, e.g., joint and/or muscular pain, lassitude and depression, despite maintenance or even improvement of respiratory function. Such patients should be encouraged to continue with the inhaler but should be watched carefully for objective signs of adrenal insufficiency, such as hypotension and weight loss. If evidence of adrenal insufficiency occurs, the systemic steroid dose should be boosted temporarily and thereafter further withdrawal should continue more slowly.
During periods of stress or a severe asthma attack, transfer patients will require supplementary treatment with systemic steroids. Exacerbations of asthma which occur during the course of treatment with Beclomethasone Inhaler should be treated with a short course of systemic steroid which is gradually tapered as these symptoms subside. There is no evidence that control of asthma can be achieved by administration of Beclomethasone in amounts greater than the recommended doses.
The effects of Beclomethasone dipropionate on hypothalamic-pituitary-adrenal (HPA) function have been evaluated in adult volunteers. There was no suppression of early morning plasma cortisol concentrations when Beclomethasone dipropionate was administered in a dose of 1000 mcg/day for one month as an aerosol or for three days by intramuscular injection. However, partial suppression of plasma cortisol concentration was observed when Beclomethasone dipropionate was administered in doses of 2000 mcg/day either intramuscularly or by aerosol. Immediate suppression of plasma cortisol concentrations was observed after single doses of 4000 mcg of Beclomethasone dipropionate.
In one study, the effects of Beclomethasone dipropionate on HPA function were examined in patients with asthma. There was no change in basal early morning plasma cortisol concentrations or in the cortisol responses to tetracosactrin (ACTH 1:24) stimulation after daily administration of 400, 800 or 1200 mcg of Beclomethasone dipropionate for 28 days. After daily administration of 1600 mcg each day for 28 days, there was a slight reduction in basal cortisol concentrations and a statistically significant (p <.01) reduction in plasma cortisol responses to tetracosactrin stimulation. The effects of a more prolonged period of Beclomethasone dipropionate administration on HPA function have not been evaluated. However, a number of investigators have noted that when systemic corticosteroid therapy in asthmatic subjects can be replaced with recommended doses of Beclomethasone dipropionate, there is gradual recovery of endogenous cortisol concentrations to the normal range. There is still no documented evidence of recovery from other adverse systemic corticosteroid- induced reactions during prolonged therapy of patients with Beclomethasone dipropionate.
Clinical experience has shown that some patients with bronchial asthma who require corticosteroid therapy for control of symptoms can be partially or completely withdrawn from systemic corticosteroid if therapy with Beclomethasone dipropionate aerosol is substituted. Beclomethasone dipropionate aerosol is not effective for all patients with bronchial asthma or at all stages of the disease in a given patient.
The early clinical experience has revealed several new problems which may be associated with the use of Beclomethasone dipropionate by inhalation for treatment of patients with bronchial asthma:
1. There is a risk of adrenal insufficiency when patients are transferred from systemic corticosteroids to aerosol Beclomethasone dipropionate. Although the aerosol may provide adequate control of asthma during the transfer period, it does not provide the systemic steroid which is needed during acute stress situations. Deaths due to adrenal insufficiency have occurred in asthmatic patients during and after transfer from systemic corticosteroids to aerosol Beclomethasone dipropionate. (See warnings.)
2. Transfer of patients from systemic steroid therapy to Beclomethasone dipropionate aerosol may unmask allergic conditions which were previously controlled by the systemic steroid therapy, e.g., rhinitis, conjunctivitis, and eczema.
3. Localized infections with Candida Albicans or Aspergillus Niger have occurred frequently in the mouth and pharynx and occasionally in the larynx. It has been reported that up to 75% of the patients who receive prolonged treatment with Beclomethasone dipropionate have positive oral cultures for Candida Albicans. The incidence of clinically apparent infection is considerably lower but may require therapy with appropriate antifungal agents or discontinuation of treatment with Beclomethasone dipropionate aerosol.
The long-term effects of Beclomethasone dipropionate in human subjects are still unknown. In particular, the local effects of the agent on developmental or immunologic processes in the mouth, pharynx, trachea and lung are unknown. There is also no information about the possible long-term systemic effects of the agent. The possible relevance of the data in animal studies to results in human subjects cannot be evaluated.
Azathioprine
Azathioprine , an immuno suppressive antimetabolite, is available in tablet form for oral administration and 100 mg vials for intravenous injection.
Azathioprine is chemically 6-((1-methyl-4-nitro-1H-imidazol-5-yl)thio)-H- purine. It is an imidazolyl derivative of 6-mercaptopurine (PURINETHOL) and many of its biological effects are similar to those of the parent compound.
Azathioprine is insoluble in water, but may be dissolved with addition of one molar equivalent of alkali. The sodium salt of azathioprine is sufficiently soluble to make a 10 mg/mL water solution which is stable for 24 hours at 59 deg to 77 F (15 deg to 25 C). Azathioprine is stable in solution at neutral or acid pH but hydrolysis to mercaptopurine occurs in excess sodium hydroxide (0.1N), especially on warming. Conversion to mercaptopurine also occurs in the presence of sulfhydryl compounds such as cysteine, glutathione, and hydrogen sulfide.
METABOLISM: Azathioprine is well absorbed following oral administration. Maximum serum radioactivity occurs at 1 to 2 hours after oral 35S-azathioprine and decays with a half-life of 5 hours. This is not an estimate of the half-life of azathioprine itself but is the decay rate for all 35S-containing metabolites of the drug. Because of extensive metabolism, only a fraction of the radioactivity is present as azathioprine. Usual doses produce blood levels of azathioprine, and of mercaptopurine derived from it, which are low (<1 mcg/mL). Blood levels are of little predictive value for therapy since the magnitude and duration of clinical effects correlate with thiopurine nucleotide levels in tissues rather than with plasma drug levels. Azathioprine and mercaptopurine are moderately bound to serum proteins (30%) and are partially dialyzable.
Azathioprine is cleaved in vivo to mercaptopurine. Both compounds are rapidly eliminated from blood and are oxidized or methylated in erythrocytes and liver; no azathioprine or mercaptopurine is detectable in urine after 8 hours. Conversion to inactive 6-thiouric acid by xanthine oxidase is an important degradative pathway, and the inhibition of this pathway in patients receiving allopurinol (ZYLOPRIM) is the basis for the azathioprine dosage reduction required in these patients (see PRECAUTIONS: Drug Interactions). Proportions of metabolites are different in individual patients, and this presumably accounts for variable magnitude and duration of drug effects. Renal clearance is probably not important in predicting biological effectiveness or toxicities, although dose reduction is practiced in patients with poor renal function.
Summary information from transplant centers and registries indicates relatively universal use of Azathioprine with or without other immuno suppressive agents. Although the use of azathioprine for inhibition of renal homograft rejection is well established, the mechanism(s) for this action are somewhat obscure. The drug suppresses hypersensitivities of the cell-mediated type and causes variable alterations in antibody production. Suppression of T-cell effects, including ablation of T-cell suppression, is dependent on the temporal relationship to antigenic stimulus or engraftment. This agent has little effect on established graft rejections or secondary responses.
Alterations in specific immune responses or immunologic functions in transplant recipients are difficult to relate specifically to immuno suppression by azathioprine. These patients have subnormal responses to vaccines, low numbers of T-cells, and abnormal phagocytosis by peripheral blood cells, but their mitogenic responses, serum immunoglobulins, and secondary antibody responses are usually normal.
Azathioprine suppresses disease manifestations as well as underlying pathology in animal models of autoimmune disease. For example, the severity of adjuvant arthritis is reduced by azathioprine.
The mechanisms whereby azathioprine affects autoimmune diseases are not known. Azathioprine is immuno suppressive, delayed hypersensitivity and cellular cytotoxicity tests being suppressed to a greater degree than are antibody responses. In the rat model of adjuvant arthritis, azathioprine has been shown to inhibit the lymph node hyperplasia which precedes the onset of the signs of the disease. Both the immuno suppressive and therapeutic effects in animal models are dose-related. Azathioprine is considered a slow-acting drug and effects may persist after the drug has been discontinued.
Azathioprine is indicated as an adjunct for the prevention of rejection in renal homotransplantation. It is also indicated for the management of severe, active rheumatoid arthritis unresponsive to rest, aspirin, or other nonsteroidal anti-inflammatory drugs, or to agents in the class of which gold is an example.
RENAL HOMOTRANSPLANTATION: Azathioprine is indicated as an adjunct for the prevention of rejection in renal homotransplantation. Experience with over 16,000 transplants shows a 5-year patient survival of 35% to 55%, but this is dependent on donor, match for HLA antigens, anti-donor or anti B-cell alloantigen antibody, and other variables. The effect of Azathioprine on these variables has not been tested in controlled trials.
RHEUMATOID ARTHRITIS: Azathioprine is indicated only in adult patients meeting criteria for classic or definite rheumatoid arthritis as specified by the American Rheumatism Association. Azathioprine should be restricted to patients with severe, active and erosive disease not responsive to conventional management including rest, aspirin, or other nonsteroidal drugs or to agents in the class of which gold is an example. Rest, physiotherapy, and salicylates should be continued while Azathioprine is given, but it may be possible to reduce the dose of corticosteroids in patients on Azathioprine. The combined use of Azathioprine with gold, antimalarials, or penicillamine has not been studied for either added benefit or unexpected adverse effects. The use of Azathioprine with these agents cannot be recommended.
Azathioprine should not be given to patients who have shown hypersensitivity to the drug.
Azathioprine should not be used for treating rheumatoid arthritis in pregnant women.
Patients with rheumatoid arthritis previously treated with alkylating agents (cyclophosphamide, chlorambucil, melphalan, or others) may have a prohibitive risk of neoplasia if treated with Azathioprine.
Chronic immuno suppression with this purine antimetabolite increases Risk Of Neoplasia in humans. Physicians using this drug should be very familiar with this risk as well as with the mutagenic potential to both men and women and with possible hematologic toxicities.
Severe Leukopenia And/Or Thrombocytopenia may occur in patients on Azathioprine. Macrocytic anemia and severe bone marrow depression may also occur. Hematologic toxicities are dose related and may be more severe in renal transplant patients whose homograft is undergoing rejection. It is suggested that patients on Azathioprine have complete blood counts, including platelet counts, weekly during the first month, twice monthly for the second and third months of treatment, then monthly or more frequently if dosage alterations or other therapy changes are necessary. Delayed hematologic suppression may occur. Prompt reduction in dosage or temporary withdrawal of the drug may be necessary if there is a rapid fall in, or persistently low leukocyte count or other evidence of bone marrow depression. Leukopenia does not correlate with therapeutic effect; therefore the dose should not be increased intentionally to lower the white blood cell count.
Serious Infections are a constant hazard for patients receiving chronic immuno suppression, especially for homograft recipients. Fungal, viral, bacterial and protozoal infections may be fatal and should be treated vigorously. Reduction of azathioprine dosage and/or use of other drugs should be considered.
Azathioprine is mutagenic in animals and humans, carcinogenic in animals, and may increase the patient's Risk Of Neoplasia. Renal transplant patients are known to have an increased risk of malignancy, predominantly skin cancer and reticulum cell or lymphomatous tumors. The risk of post-transplant lymphomas may be increased in patients who receive aggressive treatment with immuno suppressive drugs. The degree of immuno suppression is determined not only by the immuno suppressive regimen but also by a number of other patient factors. The number of immuno suppressive agents may not necessarily increase the risk of post-transplant lymphomas. However, transplant patients who receive multiple immuno suppressive agents may be at risk for over-immuno suppression; therefore, immuno suppressive drug therapy should be maintained at the lowest effective levels. Information is available on the spontaneous neoplasia risk in rheumatoid arthritis, and on neoplasia following immuno suppressive therapy of other autoimmune diseases. It has not been possible to define the precise risk of neoplasia due to Azathioprine. The data suggest the risk may be elevated in patients with rheumatoid arthritis, though lower than for renal transplant patients. However, acute myelogenous leukemia as well as solid tumors have been reported in patients with rheumatoid arthritis who have received azathioprine. Data on neoplasia in patients receiving Azathioprine can be found under ADVERSE REACTIONS.
Azathioprine has been reported to cause temporary depression in spermatogenesis and reduction in sperm viability and sperm count in mice at doses 10 times the human therapeutic dose; a reduced percentage of fertile matings occurred when animals received 5 mg/kg
PREGNANCY: Pregnancy Category D. Azathioprine can cause fetal harm when administered to a pregnant woman. Azathioprine should not be given during pregnancy without careful weighing of risk versus benefit. Whenever possible, use of Azathioprine in pregnant patients should be avoided. This drug should not be used for treating rheumatoid arthritis in pregnant women.
Azathioprine is teratogenic in rabbits and mice when given in doses equivalent to the human dose (5 mg/kg daily). Abnormalities included skeletal malformations and visceral anomalies.
Limited immunologic and other abnormalities have occurred in a few infants born of renal allograft recipients on Azathioprine. In a detailed case report, documented lymphopenia, diminished IgG and IgM levels, CMV infection, and a decreased thymic shadow were noted in an infant born to a mother receiving 150 mg azathioprine and 30 mg prednisone daily throughout pregnancy. At 10 weeks most features were normalized. DeWitte et al. 21 reported pancytopenia and severe immune deficiency in a preterm infant whose mother received 125 mg azathioprine and 12.5 mg prednisone daily. There have been two published reports of abnormal physical findings. Williamson and Karp. described an infant born with preaxial polydactyly whose mother received azathioprine 200 mg daily and prednisone 20 mg every other day during pregnancy. Tallent et al. described an infant with a large myelomeningocele in the upper lumbar region, bilateral dislocated hips, and bilateral talipes equinovarus. The father was on long-term azathioprine therapy.
Benefit versus risk must be weighed carefully before use of Azathioprine in patients of reproductive potential. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing age should be advised to avoid becoming pregnant.
GENERAL: A gastrointestinal hypersensitivity reaction characterized by severe nausea and vomiting has been reported. These symptoms may also be accompanied by diarrhea, rash, fever, malaise, myalgias, elevations in liver enzymes, and occasionally, hypotension. Symptoms of gastrointestinal toxicity most often develop within the first several weeks of Azathioprine therapy and are reversible upon discontinuation of the drug. The reaction can recur within hours after rechallenge with a single dose of Azathioprine.
Patients being started on Azathioprine should be informed of the necessity of periodic blood counts while they are receiving the drug and should be encouraged to report any unusual bleeding or bruising to their physician. They should be informed of the danger of infection while receiving Azathioprine and encouraged to report signs and symptoms of infection to their physician. Careful dosage instructions should be given to the patient, especially when Azathioprine is being administered in the presence of impaired renal function or concomitantly with allopurinol (see Drug Interactions subsection and DOSAGE AND ADMINISTRATION). Patients should be advised of the potential risks of the use of Azathioprine during pregnancy and during the nursing period. The increased risk of neoplasia following Azathioprine therapy should be explained to the patient.
See WARNINGS and ADVERSE REACTIONS sections.
USE WITH ALLOPURINOL: The principal pathway for detoxification of Azathioprine is inhibited by allopurinol. Patients receiving Azathioprine and allopurinol concomitantly should have a dose reduction of Azathioprine, to approximately 1/3 to 1/4 the usual dose.
USE WITH OTHER AGENTS AFFECTING MYELOPOESIS: Drugs which may affect leukocyte production, including co-trimoxazole, may lead to exaggerated leukopenia, especially in renal transplant recipients.
USE WITH ANGIOTENSIN CONVERTING ENZYME INHIBITORS: The use of angiotensin converting enzyme inhibitors to control hypertension in patients on azathioprine has been reported to induce anemia and severe leukopenia.
USE WITH WARFARIN: Azathioprine may inhibit the anticoagulant effect of warfarin.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY: See WARNINGS section.
PREGNANCY: TERATOGENIC EFFECTS: Pregnancy Category D. See WARNINGS section.
NURSING MOTHERS: The use of Azathioprine in nursing mothers is not recommended. Azathioprine or its metabolites are transferred at low levels, both transplacentally and in breast milk. Because of the potential for tumorigenicity shown for azathioprine, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
PEDIATRIC USE: Safety and efficacy of azathioprine in pediatric patients have not been established.
The principal and potentially serious toxic effects of Azathioprine are hematologic and gastrointestinal. The risks of secondary infection and neoplasia are also significant (see WARNINGS). The frequency and severity of adverse reactions depend on the dose and duration of Azathioprine as well as on the patient's underlying disease or concomitant therapies. The incidence of hematologic toxicities and neoplasia encountered in groups of renal homograft recipients is significantly higher than that in studies employing Azathioprine for rheumatoid arthritis.
Data on the rate and risk of neoplasia among persons with rheumatoid arthritis treated with azathioprine are limited. The incidence of lymphoproliferative disease in patients with RA appears to be significantly higher than that in the general population. In one completed study, the rate of lymphoproliferative disease in RA patients receiving higher than recommended doses of azathioprine (5 mg/kg/day) was 1.8 cases per 1000 patient years of follow-up, compared with 0.8 cases per 1000 patient years of follow-up in those not receiving azathioprine. However, the proportion of the increased risk attributable to the azathioprine dosage or to other therapies (i.e., alkylating agents) received by patients treated with azathioprine cannot be determined.
HEMATOLOGIC: Leukopenia and/or thrombocytopenia are dose dependent and may occur late in the course of therapy with Azathioprine. Dose reduction or temporary withdrawal allows reversal of these toxicities. Infection may occur as a secondary manifestation of bone marrow suppression or leukopenia, but the incidence of infection in renal homotransplantation is 30 to 60 times that in rheumatoid arthritis. Macrocytic anemia and/or bleeding have been reported.
There are rare individuals with an inherited deficiency of the enzyme thiopurine methyltransferase (TPMT) who may be unusually sensitive to the myelosuppressive effect of azathioprine and prone to developing rapid bone marrow suppression following the initiation of treatment with Azathioprine.
GASTROINTESTINAL: Nausea and vomiting may occur within the first few months of therapy with Azathioprine, and occurred in approximately 12% of 676 rheumatoid arthritis patients. The frequency of gastric disturbance often can be reduced by administration of the drug in divided doses and/or after meals. However, in some patients, nausea and vomiting may be severe and may be accompanied by symptoms such as diarrhea, fever, malaise, and myalgias (see PRECAUTIONS). Vomiting with abdominal pain may occur rarely with a hypersensitivity pancreatitis. Hepatotoxicity manifest by elevation of serum alkaline phosphatase, bilirubin, and/or serum transaminases is known to occur following azathioprine use, primarily in allograft recipients. Hepatotoxicity has been uncommon (less than 1%) in rheumatoid arthritis patients. Hepatotoxicity following transplantation most often occurs within 6 months of transplantation and is generally reversible after interruption of Azathioprine. A rare, but life-threatening hepatic veno- occlusive disease associated with chronic administration of azathioprine has been described in transplant patients and in one patient receiving Azathioprine for panuveitis. Periodic measurement of serum transaminases, alkaline phosphatase, and bilirubin is indicated for early detection of hepatotoxicity. If hepatic veno-occlusive disease is clinically suspected, Azathioprine should be permanently withdrawn.
OTHERS: Additional side effects of low frequency have been reported. These include skin rashes, alopecia, fever, arthralgias, diarrhea, steatorrhea, negative nitrogen balance, and reversible interstitial pneumonitis.
The oral LD50s for single doses of Azathioprine in mice and rats are 2500 mg/kg and 400 mg/kg, respectively. Very large doses of this antimetabolite may lead to marrow hypoplasia, bleeding, infection, and death. About 30% of Azathioprine is bound to serum proteins, but approximately 45% is removed during an 8-hour hemodialysis. A single case has been reported of a renal transplant patient who ingested a single dose of 7500 mg Azathioprine. The immediate toxic reactions were nausea, vomiting, and diarrhea, followed by mild leukopenia and mild abnormalities in liver function. The white blood cell count, SGOT, and bilirubin returned to normal 6 days after the overdose.
RENAL HOMOTRANSPLANTATION: The dose of Azathioprine required to prevent rejection and minimize toxicity will vary with individual patients; this necessitates careful management. The initial dose is usually 3 to 5 mg/kg daily, beginning at the time of transplant. Azathioprine is usually given as a single daily dose on the day of, and in a minority of cases 1 to 3 days before, transplantation. Azathioprine is often initiated with the intravenous administration of the sodium salt, with subsequent use of tablets (at the same dose level) after the post operative period. Intravenous administration of the sodium salt is indicated only in patients unable to tolerate oral medications. Dose reduction to maintenance levels of 1 to 3 mg/kg daily is usually possible. The dose of Azathioprine should not be increased to toxic levels because of threatened rejection. Discontinuation may be necessary for severe hematologic or other toxicity, even if rejection of the homograft may be a consequence of drug withdrawal.
RHEUMATOID ARTHRITIS: Azathioprine is usually given on a daily basis. The initial dose should be approximately 1.0 mg/kg (50 to 100 mg) given as a single dose or on a twice daily schedule. The dose may be increased, beginning at 6 to 8 weeks and thereafter by steps at 4-week intervals, if there are no serious toxicities and if initial response is unsatisfactory. Dose increments should be 0.5 mg/kg daily, up to a maximum dose of 2.5 mg/kg/day. Therapeutic response occurs after several weeks of treatment, usually 6 to 8; an adequate trial should be a minimum of 12 weeks. Patients not improved after 12 weeks can be considered refractory. Azathioprine may be continued long-term in patients with clinical response, but patients should be monitored carefully, and gradual dosage reduction should be attempted to reduce risk of toxicities.
Maintenance therapy should be at the lowest effective dose, and the dose given can be lowered decrementally with changes of 0.5 mg/kg or approximately 25 mg daily every 4 weeks while other therapy is kept constant. The optimum duration of maintenance Azathioprine has not been determined. Azathioprine can be discontinued abruptly, but delayed effects are possible.
USE IN RENAL DYSFUNCTION: Relatively oliguric patients, especially those with tubular necrosis in the immediate post-cadaveric transplant period, may have delayed clearance of Azathioprine or its metabolites, may be particularly sensitive to this drug, and are usually given lower doses.
Add 10 mL of Sterile Water for Injection, and swirl until a clear solution results. This solution, equivalent to 100 mg azathioprine, is for intravenous use only; it has a pH of approximately 9.6, and it should be used within 24 hours. Further dilution into sterile saline or dextrose is usually made for infusion; the final volume depends on time for the infusion, usually 30 to 60 minutes, but as short as 5 minutes and as long as 8 hours for the daily dose.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Procedures for proper handling and disposal of this immuno suppressive antimetabolite drug should be considered. Several guidelines on this subject have been published.
There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.
Dexamethasone
Glucocorticoids are adrenocortical steroids, both naturally occurring and synthetic, which are readily absorbed from the gastrointestinal tract.
Dexamethasone, a synthetic adrenocortical steroid, is a white to practically white, odorless, crystalline powder. It is stable in air. It is practically insoluble in water. The molecular weight is 392.47. It is designated chemically as 9-fluoro-11beta, 17, 21-trihydroxy-16alpha-methylpregna-1, 4-diene-3,20- dione.. The empirical formula is C22H29FO5.
Naturally occurring glucocorticoids (hydrocortisone and cortisone), which also have salt-retaining properties, are used as replacement therapy in adrenocortical deficiency states. Their synthetic analogs including dexamethasone are primarily used for their potent anti-inflammatory effects in disorders of many organ systems.
Glucocorticoids cause profound and varied metabolic effects. In addition, they modify the body's immune responses to diverse stimuli.
At equipotent anti-inflammatory doses, dexamethasone almost completely lacks the sodium-retaining property of hydrocortisone and closely related derivatives of hydrocortisone.
Primary or secondary adrenocortical insufficiency (hydrocortisone or cortisone is the first choice; synthetic analogs may be used in conjunction with mineralocorticoids where applicable; in infancy mineralocorticoid supplementation is of particular importance)
Congenital adrenal hyperplasia
Nonsuppurative thyroiditis
Hypercalcemia associated with cancer
As adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in:
Psoriatic arthritis
Rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low-dose maintenance therapy)
Ankylosing spondylitis
Acute and subacute bursitis
Acute nonspecific tenosynovitis
Acute gouty arthritis
Post-traumatic osteoarthritis
Synovitis of osteoarthritis
Epicondylitis
During an exacerbation or as maintenance therapy in selected cases of:
Systemic lupus erythematosus
Acute rheumatic carditis
Pemphigus
Bullous dermatitis herpetiformis
Severe erythema multiforme (Stevens-Johnson syndrome)
Exfoliative dermatitis
Mycosis fungoides
Severe psoriasis
Severe seborrheic dermatitis
Control of severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment:
Seasonal or perennial allergic rhinitis
Bronchial asthma
Contact dermatitis
Atopic dermatitis
Serum sickness
Drug hypersensitivity reactions
Severe acute and chronic allergic and inflammatory processes involving the eye and its adnexa, such as:
Allergic conjunctivitis
Keratitis
Allergic corneal marginal ulcers
Herpes zoster ophthalmicus
Iritis and iridocyclitis
Chorioretinitis
Anterior segment inflammation
Diffuse posterior uveitis and choroiditis
Optic neuritis
Sympathetic ophthalmia
Symptomatic sarcoidosis
Loeffler's syndrome not manageable by other means
Berylliosis
Fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate antituberculous chemotherapy
Aspiration pneumonitis
Idiopathic thrombocytopenic purpura in adults
Secondary thrombocytopenia in adults
Acquired (autoimmune) hemolytic anemia
Erythroblastopenia (RBC anemia)
Congenital (erythroid) hypoplastic anemia
For palliative management of:
Leukemias and lymphomas in adults
Acute leukemia of childhood
To induce a diuresis or remission of proteinuria in the nephrotic syndrome, without uremia, of the idiopathic type or that due to lupus erythematosus
To tide the patient over a critical period of the disease in:
Ulcerative colitis
Regional enteritis
Use in cerebral edema is not a substitute for careful neurosurgical evaluation and definitive management such as neurosurgery or other specific therapy.
Tuberculous meningitis with subarachnoid block or impending block when used concurrently with appropriate antituberculous chemotherapy
Trichinosis with neurologic or myocardial involvement
Systemic fungal infections
Hypersensitivity to this drug
In patients on corticosteroid therapy subjected to unusual stress, increased dosage of rapidly acting corticosteroids before, during, and after the stressful situation is indicated.
Drug-induced secondary adrenocortical insufficiency may result from too rapid withdrawal of corticosteroids and may be minimized by gradual reduction of dosage. This type of relative insufficiency may persist for months after discontinuation of therapy; therefore, in any situation of stress occurring during that period, hormone therapy should be reinstituted. If the patient is
receiving steroids already, dosage may have to be increased. Since mineralocorticoid secretion may be impaired, salt and/or a mineralocorticoid should be administered concurrently.
Corticosteroids may mask some signs of infection, and new infections may appear during their use. There may be decreased resistance and inability to localize infection when corticosteroids are used. Moreover, corticosteroids may affect the nitroblue-tetrazolium test for bacterial infection and produce false negative results.
In cerebral malaria, a double-blind trial has shown that the use of corticosteroids is associated with prolongation of coma and a higher incidence of pneumonia and gastrointestinal bleeding.
Corticosteroids may activate latent amebiasis. Therefore, it is recommended that latent or active amebiasis be ruled out before initiating corticosteroid therapy in any patient who has spent time in the tropics or any patient with unexplained diarrhea.
Prolonged use of corticosteroids may produce posterior subcapsular cataracts, glaucoma with possible damage to the optic nerves, and may enhance the establishment of secondary ocular infections due to fungi or viruses.
Usage In Pregnancy: Since adequate human reproduction studies have not been done with corticosteroids, use of these drugs in pregnancy or in women of childbearing potential requires that the anticipated benefits be weighed against the possible hazards to the mother and embryo or fetus. Infants born of mothers who have received substantial doses of corticosteroids during pregnancy should be carefully observed for signs of hypoadrenalism.
Corticosteroids appear in breast milk and could suppress growth, interfere with endogenous corticoste