Included as part of the "PRECAUTIONS" Section
Organ System Toxicity
RediTrex should be used only by physicians whose knowledge and experience include the use of antimetabolite therapy. Because of the possibility of serious toxic reactions (which can be fatal), RediTrex should be used only in patients with psoriasis or rheumatoid arthritis with severe, recalcitrant, disabling disease which is not adequately responsive to other forms of therapy.
Deaths have been reported with the use of methotrexate in the treatment of malignancy, psoriasis, and rheumatoid
arthritis. Patients should be closely monitored for bone marrow, liver, lung and kidney toxicities. RediTrex has the potential for serious toxicity. 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 RediTrex closely. Most adverse reactions are reversible if detected early. When such reactions do occur, the drug should be reduced in dosage or discontinued and appropriate corrective measures should be taken. If necessary, this could include the use of leucovorin calcium and/or acute, intermittent hemodialysis with a high-flux dialyzer [see OVERDOSE]. If RediTrex therapy is reinstituted, it should be carried out with caution, with adequate consideration of further need for the drug and 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 [see Use In Specific Populations].
Diarrhea and ulcerative stomatitis require interruption of therapy: otherwise, hemorrhagic enteritis and death from
intestinal perforation may occur.
If vomiting, diarrhea, or stomatitis occur, which may result in dehydration, RediTrex should be discontinued until
recovery occurs. RediTrex should be used with extreme caution in the presence of peptic ulcer disease or ulcerative
Unexpectedly severe (sometimes fatal) gastrointestinal toxicity has been reported with concomitant
administration of methotrexate (usually in high dosage) along with some nonsteroidal anti-inflammatory drugs
(NSAIDs) [see DRUG INTERACTIONS].
RediTrex can suppress hematopoiesis and cause anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, and/or thrombocytopenia. In patients with preexisting hematopoietic impairment, RediTrex should be used with caution, if at all. In controlled clinical trials conducted with another formulation of methotrexate in rheumatoid arthritis (n=128), leukopenia (WBC <3000/mm3) was seen in 2 patients, thrombocytopenia (platelets <100,000/mm3) in 6 patients, and pancytopenia in 2 patients.
RediTrex should be stopped immediately if there is a significant drop in blood counts. Patients with profound granulocytopenia and fever should be evaluated immediately and usually require parental broad-spectrum antibiotic therapy.
Unexpectedly severe (sometimes fatal) bone marrow suppression and aplastic anemia have been reported with concomitant administration of methotrexate (usually in high dosage) along with some nonsteroidal anti-inflammatory drugs (NSAIDs) [see DRUG INTERACTIONS].
RediTrex has the potential for acute (elevated transaminases) and chronic (fibrosis and cirrhosis) hepatotoxicity. Chronic toxicity is potentially fatal; it generally has occurred after prolonged use (generally two years or more) and after a total dose of at least 1.5 grams. In studies in psoriatic patients, hepatotoxicity appeared to be a function of total cumulative dose and appeared to be enhanced by alcoholism, obesity, diabetes and advanced age. An accurate incidence rate has not been determined; the rate of progression and reversibility of lesions is not known.
Special caution is indicated in the presence of preexisting liver damage or impaired hepatic function. In psoriasis, liver function tests, including serum albumin, should be performed periodically prior to dosing but are often normal in the face of developing fibrosis or cirrhosis. These lesions may be detectable only by biopsy. The usual recommendation is to obtain a liver biopsy at 1) pretherapy or shortly after initiation of therapy (2 to 4 months), 2) a total cumulative dose of 1.5 grams, and 3) after each additional 1.0 to 1.5 grams. Moderate fibrosis or any cirrhosis normally leads to discontinuation of the drug; mild fibrosis normally suggests a repeat biopsy in 6 months.
Milder histologic findings such as fatty change and low grade portal inflammation, are relatively common pretherapy. Although these mild changes are usually not a reason to avoid or discontinue RediTrex therapy, the drug should be used with caution.
In rheumatoid arthritis, age at first use of methotrexate and duration of therapy have been reported as risk factors for hepatotoxicity; other risk factors, similar to those observed in psoriasis, may be present in rheumatoid arthritis but have not been confirmed to date. Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis in this population. There is a combined reported experience in 217 rheumatoid arthritis patients with liver biopsies both before and during treatment (after a cumulative dose of at least 1.5 g) and in 714 patients with a biopsy only during treatment. There are 64 (7%) cases of fibrosis and 1 (0.1%) case of cirrhosis. Of the 64 cases of fibrosis, 60 were deemed mild. The reticulin stain is more sensitive for early fibrosis and its use may increase these figures. It is unknown whether even longer use will increase these risks.
Liver function tests should be performed at baseline at 4 to 8 week intervals in patients receiving RediTrex for rheumatoid arthritis. Pretreatment liver biopsy should be performed for patients with a history of excessive alcohol consumption, persistently abnormal baseline liver function test values or chronic hepatitis B or C infection. During therapy, liver biopsy should be performed if there are persistent liver function test abnormalities or there is a decrease in serum albumin below the normal range (in the setting of well controlled rheumatoid arthritis).
If the results of a liver biopsy show mild changes (Roenigk, grades I, II, IIIa), RediTrex may be continued and the patient monitored as per recommendations listed above. RediTrex should be discontinued in any patient who displays persistently abnormal liver function tests and refuses liver biopsy or in any patient whose liver biopsy shows moderate to severe changes (Roenigk grade IIIb or IV).
Infection Or Immunologic States
RediTrex should be used with extreme caution in the presence of active infection, and is contraindicated in patients
with overt or laboratory evidence of immunodeficiency syndromes.
Immunization may be ineffective when given during RediTrex therapy. Immunization with live virus vaccines is
generally not recommended. There have been reports of disseminated vaccinia infections after smallpox
immunizations in patients receiving methotrexate therapy.
Hypogammaglobulinemia has been reported rarely.
Potentially fatal opportunistic infections, especially Pneumocystis jiroveci pneumonia, may occur with RediTrex
therapy. When a patient presents with pulmonary symptoms, the possibility of Pneumocystis jiroveci pneumonia
should be considered.
There have been reports of leukoencephalopathy following intravenous administration of methotrexate to patients who have had craniospinal irradiation. Serious neurotoxicity, frequently manifested as generalized or focal seizures, has been reported with unexpectedly increased frequency among pediatric patients with acute lymphoblastic leukemia who were treated with intermediate-dose intravenous methotrexate (1 gm/m2).
Symptomatic patients were commonly noted to have leukoencephalopathy and/or microangiopathic calcifications on diagnostic imaging studies. Chronic leukoencephalopathy has also been reported in patients 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 dose regimens. Manifestations of this stroke-like encephalopathy may include confusion, hemiparesis, transient blindness, seizures and coma. The exact cause is unknown. After the intrathecal use of methotrexate, the central nervous system toxicity which may occur can be classified as follows: acute chemical arachnoiditis manifested by such symptoms as headache, back pain, nuchal rigidity, and fever; sub-acute myelopathy characterized by paraparesis/paraplegia associated with involvement with one or more spinal nerve roots; chronic leukoencephalopathy manifested by confusion, irritability, somnolence, ataxia, dementia, seizures and coma. This condition can be progressive and even fatal.
Methotrexate-induced lung disease, including acute or chronic interstitial pneumonitis, is a potentially dangerous lesion, which may occur acutely at any time during therapy and has been reported at low doses. It is not always fully reversible and fatalities have been reported.
Pulmonary symptoms (especially a dry nonproductive cough) or a non-specific pneumonitis occurring during RediTrex therapy may be indicative of a potentially dangerous lesion and require interruption of treatment and careful investigation. Although clinically variable, the typical patient with methotrexate induced lung disease presents with fever, cough, dyspnea, hypoxemia, and an infiltrate on chest X-ray; infection (including pneumonia) needs to be excluded. This lesion can occur at all dosages.
RediTrex may cause renal damage that may lead to acute renal failure. 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.
Severe, occasionally fatal, dermatologic reactions, including toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, and erythema multiforme, have been reported in children and adults, within days of oral, intramuscular, intravenous, or intrathecal methotrexate administration. Reactions were noted after single or multiple low, intermediate, or high doses of methotrexate in patients with neoplastic and non-neoplastic diseases.
Lesions of psoriasis may be aggravated by concomitant exposure to ultraviolet radiation. Radiation dermatitis and sunburn may be “recalled” by the use of methotrexate.
RediTrex should be used with extreme caution in the presence of debility.
Methotrexate exits slowly from third space compartments (e.g., 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.
Based on published reports and methotrexate’s mechanism of action, methotrexate can cause embryo-fetal toxicity and fetal death when administered to a pregnant woman. In pregnant women, methotrexate is contraindicated. Verify pregnancy status in females of reproductive potential prior to initiating RediTrex. Advise females of reproductive potential to use effective contraception during treatment with RediTrex and for 6 months after the final dose. Advise males of reproductive potential to use effective contraception during RediTrex treatment and for at least 3 months after the final dose [see CONTRAINDICATIONS, Use In Specific Populations, CLINICAL PHARMACOLOGY].
Effects On Reproduction
Based on published reports, methotrexate can cause impairment of fertility, oligospermia and menstrual dysfunction in humans. It is not known if the infertility is reversible in affected patients. Discuss the risk of effects on reproduction with female and male patients of reproductive potential [see Use In Specific Populations].
Patients undergoing RediTrex 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, monitoring of these parameters is recommended: hematology at least monthly, renal function and
liver function every 1 to 2 months [see Organ System Toxicity].
During initial or changing doses, or during periods of increased risk of elevated methotrexate blood levels (e.g.,
dehydration), more frequent monitoring may also be indicated.
Liver Function Tests
Transient liver function test abnormalities are observed frequently after methotrexate administration and are usually not cause for modification of methotrexate therapy. Persistent liver function test abnormalities, and/or depression of serum albumin may be indicators of serious liver toxicity and require evaluation [see Organ System Toxicity].
A relationship between abnormal liver function tests and fibrosis or cirrhosis of the liver has not been established for patients with psoriasis. Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis in the rheumatoid arthritis population.
Pulmonary Function Tests
Pulmonary function tests may be useful if methotrexate-induced lung disease is suspected, especially if baseline measurements are available [see Organ System Toxicity].
Risks From Improper Dosing
Both the physician and pharmacist should emphasize to the patient that RediTrex is administered weekly and that mistaken daily use has led to fatal toxicity [see DOSAGE AND ADMINISTRATION].
Patients With Impaired Renal Function, Ascites, Or Pleural Effusions
Methotrexate elimination is reduced in patients with impaired renal function, ascites, or pleural effusions. Such patients require especially careful monitoring for toxicity and require dose reduction or, in some cases, discontinuation of RediTrex administration.
Dizziness And Fatigue
Adverse reactions, such as dizziness and fatigue, may affect the ability to drive or operate machinery.
Non-Hodgkin’s lymphoma and other tumors have been reported in patients receiving low-dose oral methotrexate. However, there have been instances of malignant lymphoma arising during treatment with low-dose oral methotrexate, which have regressed completely following withdrawal of methotrexate, without requiring active anti-lymphoma treatment. Discontinue RediTrex first and, if the lymphoma does not regress, appropriate treatment should be instituted.
Tumor Lysis Syndrome
Like other cytotoxic drugs, methotrexate may induce “tumor lysis syndrome” in patients with rapidly growing tumors.
Concomitant Radiation Therapy
Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis.
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION and Instructions for Use).
Risk Of Organ Toxicity
Inform patients of the risks of organ toxicity, including gastrointestinal, hematologic, hepatic, infections, neurologic, pulmonary, renal and skin as well as possible signs and symptoms for which they should contact their healthcare provider. Advise patients of the need for close follow-up, including periodic laboratory tests to monitor toxicity [see WARNINGS AND PRECAUTIONS].
Importance Of Proper Dosing And Administration
Both the physician and pharmacist should emphasize to the patient that the recommended dose is taken weekly and that mistaken daily use of the recommended dose has led to fatal toxicity [see DOSING AND ADMINISTRATION].
RediTrex is intended for use under the guidance and supervision of a physician. Patients should not self-administer until they receive training from a healthcare professional. The patient’s or caregiver’s ability to administer RediTrex should be assessed.
Patients should be instructed to use administration sites on the abdomen or the thigh. Administration should not be made within 2 inches of the navel. Instruct patients not to administer RediTrex to the arms or any other areas of the body, as delineated in the RediTrex Instructions for Use [see Instructions for Use].
Advise females of reproductive potential that RediTrex can cause fetal harm and is contraindicated in pregnancy. Advise women of childbearing potential that RediTrex should not be started until pregnancy is excluded. Women should be fully counseled on the serious risk to the fetus should they become pregnant while undergoing treatment. Inform patients to contact their physician if they suspect that they are pregnant [see BOXED WARNING, CONTRAINDICATIONS, WARNING AND PRECAUTIONS, Use In Specific Populations].
Advise patients of reproductive potential that RediTrex may cause impairment of fertility, oligospermia, and
menstrual dysfunction [see WARNINGS AND PRECAUTIONS, Use In Specific Populations].
Advise females of reproductive potential to use effective contraception during RediTrex therapy and for 6 months
after the final dose [see Use In Specific Populations].
Advise males of reproductive potential to use effective contraception during RediTrex therapy and for 3 months
after final dose [see Use In Specific Populations].
Advise females not to breastfeed during therapy with RediTrex and for one week after final dose [see Use In Specific Populations].
Ability To Drive Or Operate Machinery
Inform patients that adverse reactions such as dizziness and fatigue may affect their ability to drive or operate machinery.
Proper Storage And Disposal
Advise patients to store RediTrex between 20°C to 25°C (68°F to 77°F), and to protect from light (keep in carton until the time of use).
Inform patients and caregivers of the need for proper disposal after use, including the use of a sharps disposal
Carcinogenesis, Mutagenesis, Impairment Of Fertility
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.
Data are available regarding the risks for pregnancy and for fertility in humans [see Use In Specific Populations].
Use In Specific Populations
Based on published reports and methotrexate’s mechanism of action, methotrexate can cause embryo-fetal toxicity and fetal death when administered to a pregnant woman [see Data and CLINICAL PHARMACOLOGY]. In pregnant women with non-malignant disease, RediTrex is contraindicated. There are no animal data that meet current standards for nonclinical developmental toxicity studies.
The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Published data from cases, literature reviews, and observational studies report that methotrexate exposure during pregnancy is associated with an increased risk of embryo-fetal toxicity and fetal death. Methotrexate exposure during the first trimester of pregnancy is associated with an increased incidence of spontaneous abortions and multiple adverse developmental outcomes, including skull anomalies, facial dysmorphism, central nervous system abnormalities, limb abnormalities, and sometimes cardiac anomalies and intellectual impairment. Adverse outcomes associated with exposure during second and third trimesters of pregnancy include intrauterine growth restriction and functional abnormalities. Because methotrexate is widely distributed and persists in the body for a prolonged period, there is a potential risk to the fetus from preconception methotrexate exposure.
A prospective multicenter study evaluated pregnancy outcomes in women taking methotrexate less than or equal to 30 mg/week after conception. The rate of miscarriage in pregnant women exposed to methotrexate was 42.5% (95% confidence interval [95% CI] 29.2-58.7), which was higher than in unexposed autoimmune disease comparators (22.5%, 95% CI 16.8-29.7) and unexposed nonautoimmune disease (17.3%, 95% CI 13-22.8). Of the live births, the rate of major birth defects in pregnant women exposed to methotrexate after conception was higher than in autoimmune disease (adjusted odds ratio (OR) 1.8 [95% CI 0.6-5.7]) and nonautoimmune disease (adjusted OR 3.1 [95% CI 1.03-9.5]). Major birth defects associated with pregnancies exposed to methotrexate after conception were not always consistent with methotrexate-associated adverse developmental outcomes.
Limited published literature report the presence of methotrexate in human milk in low amounts. The highest breast milk to plasma concentration ratio demonstrated was 0.08:1. No information is available on the effects of methotrexate on a breastfed infant or on milk production. Because of the potential for serious adverse reactions, including myelosuppression, from methotrexate in breastfed infants, advise women not to breastfeed during RediTrex therapy and for one week after final dose.
Females And Males Of Reproductive Potential
Verify the pregnancy status of females of reproductive potential prior to initiating RediTrex.
RediTrex can cause fetal harm when administered to a pregnant woman [see Pregnancy].
Advise females of reproductive potential to use effective contraception during and for 6 months after the final dose
Methotrexate can cause chromosomal damage to sperm cells. Advise males with female partners of reproductive
potential to use effective contraception during and for at least 3 months after the final dose of RediTrex.
Based on published reports of female infertility after treatment with methotrexate, advise females of reproductive
potential that RediTrex can cause impairment of fertility and menstrual dysfunction during and after cessation of therapy. It is not known if the infertility may be reversed in all affected females.
Based on published reports of male infertility after treatment with methotrexate, advise males of reproductive
potential that RediTrex can cause oligospermia or infertility during and after cessation of therapy. It is not known if the infertility may be reversed in all affected males.
The safety and effectiveness of methotrexate, including RediTrex, have not been established in pediatric patients with psoriasis.
The safety and effectiveness of RediTrex have not been established in pediatric patients with neoplastic diseases. The safety and effectiveness of methotrexate have been established in pediatric patients with polyarticular juvenile idiopathic arthritis [see Clinical Studies].
Published clinical studies evaluating the use of methotrexate in children and adolescents (i.e., patients 2 to 16 years of age) with pJIA demonstrated safety comparable to that observed in adults with rheumatoid arthritis [see ADVERSE REACTIONS].
RediTrex does not contain a preservative. However, methotrexate injectable formulations containing the preservative benzyl alcohol are not recommended for use in neonates. There have been reports of fatal ‘gasping syndrome’ in neonates (children less than one month of age) following the administrations of intravenous solutions containing the preservative benzyl alcohol. Symptoms include a striking onset of gasping respiration, hypotension, bradycardia, and cardiovascular collapse.
Serious neurotoxicity, frequently manifested as generalized or focal seizures, has been reported with unexpectedly increased frequency among pediatric patients with acute lymphoblastic leukemia who were treated with intermediate-dose intravenous methotrexate (1 gm/m2) [see WARNINGS AND PRECAUTIONS].
Clinical studies of methotrexate did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious reflecting the greater frequency of decreased hepatic and renal function, decreased folate stores, concomitant disease or other drug therapy (i.e., that interfere with renal function, methotrexate or folate metabolism) in this population [see WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS and Hepatic Impairment]. Since decline in renal function may be associated with increases in adverse reactions and serum creatinine measurements may over estimate renal function in the elderly, more accurate methods (i.e., creatinine clearance) should be considered. Serum methotrexate levels may also be helpful. Elderly patients should be closely monitored for early signs of hepatic, bone marrow and renal toxicity. In chronic use situations, certain toxicities may be reduced by folate supplementation. Post-marketing experience suggests that the occurrence of bone marrow suppression, thrombocytopenia, and pneumonitis may increase with age [see WARNINGS AND PRECAUTIONS].
Methotrexate elimination is reduced in patients with impaired renal function. Such patients require especially careful monitoring for toxicity and require dose reduction or, in some cases, discontinuation of RediTrex administration.
The effect of hepatic impairment on methotrexate pharmacokinetics has not been studied. RediTrex is contraindicated in patients with alcoholic liver disease or other chronic liver disease. Patients with obesity, diabetes, hepatic fibrosis or steatohepatitis are at increased risk for hepatic injury and fibrosis secondary to methotrexate, and should be monitored closely [see WARNINGS AND PRECAUTIONS].