Dosage & Administration
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Rasuvo Prescribing Information
Rasuvo 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), Rasuvo 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.
Rasuvo 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 Rasuvo 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
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, Rasuvo should be discontinued until recovery occurs. Rasuvo should be used with extreme caution in the presence of peptic ulcer disease or ulcerative colitis.
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
Rasuvo can suppress hematopoiesis and cause anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, and/or thrombocytopenia. In patients with preexisting hematopoietic impairment, Rasuvo 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.
Rasuvo 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 parenteral 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
Rasuvo 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 Rasuvo therapy, the drug should be used with caution.
In rheumatoid arthritis, age at first use of methotrexate and duration of therapy have been reported as risk factors for hepatotoxicity; other risk factors, similar to those observed in psoriasis, may be present in rheumatoid arthritis but have not been confirmed to date. Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis in this population. There is a combined reported experience in 217 rheumatoid arthritis patients with liver biopsies both before and during treatment (after a cumulative dose of at least 1.5 g) and in 714 patients with a biopsy only during treatment. There are 64 (7%) cases of fibrosis and 1 (0.1%) case of cirrhosis. Of the 64 cases of fibrosis, 60 were deemed mild. The reticulin stain is more sensitive for early fibrosis and its use may increase these figures. It is unknown whether even longer use will increase these risks.
Liver function tests should be performed at baseline and at 4 to 8 week intervals in patients receiving Rasuvo 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), Rasuvo may be continued and the patient monitored as per recommendations listed above. Rasuvo 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).
Rasuvo 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 Rasuvo 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
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 Rasuvo 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.
Rasuvo 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.
Rasuvo 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.
1. Methotrexate can cause embryo-fetal toxicity, including fetal death. Use is contraindicated during pregnancy. Verify the pregnancy status of females of reproductive potential prior to initiating therapy. Advise females and males of reproductive potential to use effective contraception during and after treatment with Rasuvo [see,5.2 Embryo-Fetal ToxicityBased on published reports and methotrexate's mechanism of action, methotrexate can cause embryo-fetal toxicity, including fetal death when administered to a pregnant woman. In pregnant women Rasuvo is contraindicated. Verify the pregnancy status of females of reproductive potential prior to initiating Rasuvo. Advise females of reproductive potential to use effective contraception during treatment with Rasuvo and for 6 months after the final dose. Advise males of reproductive potential to use effective contraception during Rasuvo treatment and for 3 months after the final dose [see
Contraindications (4), Use in Specific Populations (8.1, 8.3), Clinical Pharmacology (12.1)]., and4 CONTRAINDICATIONSRasuvo is contraindicated in the following:
- Pregnancy
- Alcoholism or liver disease
- Immunodeficiency syndromes
- Preexisting blood dyscrasias
- Hypersensitivity to methotrexate
•
Pregnancy
Rasuvo can cause embryo-fetal toxicity and fetal death when administered during pregnancy. [seeWarnings and Precautions (5.2)and Use in Specific Populations (8.1)].•
Alcoholism or Liver Disease
Patients with alcoholism, alcoholic liver disease or other chronic liver disease [seeWarnings and Precautions (5.1)].•
Immunodeficiency Syndromes
Patients who have overt or laboratory evidence of immunodeficiency syndromes [seeWarnings and Precautions (5.1)].•
Preexisting Blood Dyscrasias
Patients who have preexisting blood dyscrasias, such as bone marrow hypoplasia, leukopenia, thrombocytopenia, or significant anemia [seeWarnings and Precautions (5.1)].•
Hypersensitivity
Patients with a known hypersensitivity to methotrexate. Severe hypersensitivity reactions have been observed with methotrexate use [seeWarnings and Precautions (5.1)andAdverse Reactions (6.1and6.2)].].,8.1 PregnancyRisk SummaryBased 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
Dataand Clinical Pharmacology (12.1)]. In pregnant women with psoriasis or rheumatoid arthritis, Rasuvo is contraindicated [seeContraindications (4)]. 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.
DataHuman DataPublished 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 patients with autoimmune disease (22.5%, 95% CI 16.8-29.7) and unexposed patients with non-autoimmune 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 unexposed patients with autoimmune disease (adjusted odds ratio (OR) 1.8 [95% CI 0.6-5.7]) and unexposed patients with non-autoimmune disease (adjusted OR 3.1 [95% CI 1.03-9.5]) (2.9%).Major birth defects associated with pregnancies exposed to methotrexate after conception were not always consistent with methotrexate-associated adverse developmental outcomes.
8.3 Females and Males of Reproductive PotentialPregnancy TestingVerify the pregnancy status of females of reproductive potential prior to initiating Rasuvo
.ContraceptionFemalesRasuvo can cause fetal harm when administered to a pregnant woman
[see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during and for 6 months after the final dose of Rasuvo.MalesMethotrexate 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 Rasuvo.
InfertilityFemalesBased on the published reports of female infertility after treatment with methotrexate, advise females of reproductive potential that Rasuvo 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.
MalesBased on published reports of male infertility after treatment with methotrexate, advise males of reproductive potential that Rasuvo can cause infertility or oligospermia during and after cessation of therapy. It is not known if the infertility may be reversed in all affected males.
2. Methotrexate elimination is reduced in patients with impaired renal functions, ascites, or pleural effusions. Such patients require especially careful monitoring for toxicity, and require dose reduction or, in some cases, discontinuation of Rasuvo administration [see].5.6 Patients with Impaired Renal Function, Ascites, or Pleural EffusionsMethotrexate 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 Rasuvo administration.
3. Unexpectedly severe (sometimes fatal) bone marrow suppression, aplastic anemia, and gastrointestinal toxicity have been reported with concomitant administration of methotrexate (usually in high dosage) along with some nonsteroidal anti-inflammatory drugs (NSAIDs) [seeand5.1 Organ System ToxicityRasuvo 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), Rasuvo 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.
Rasuvo 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 Rasuvo closely. Most adverse reactions are reversible if detected early. When such reactions do occur, the drug should be reduced in dosage or discontinued and appropriate corrective measures should be taken. If necessary, this could include the use of leucovorin calcium and/or acute, intermittent hemodialysis with a high-flux dialyzer [see
Overdosage (10)]. If Rasuvo 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 [seeUse in Specific Populations (8.5)].Gastrointestinal: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, Rasuvo should be discontinued until recovery occurs. Rasuvo should be used with extreme caution in the presence of peptic ulcer disease or ulcerative colitis.
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 (7.1)].Hematologic:Rasuvo can suppress hematopoiesis and cause anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, and/or thrombocytopenia. In patients with preexisting hematopoietic impairment, Rasuvo 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.
Rasuvo 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 parenteral 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 (7.1)].Hepatic:Rasuvo 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 Rasuvo therapy, the drug should be used with caution.
In rheumatoid arthritis, age at first use of methotrexate and duration of therapy have been reported as risk factors for hepatotoxicity; other risk factors, similar to those observed in psoriasis, may be present in rheumatoid arthritis but have not been confirmed to date. Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis in this population. There is a combined reported experience in 217 rheumatoid arthritis patients with liver biopsies both before and during treatment (after a cumulative dose of at least 1.5 g) and in 714 patients with a biopsy only during treatment. There are 64 (7%) cases of fibrosis and 1 (0.1%) case of cirrhosis. Of the 64 cases of fibrosis, 60 were deemed mild. The reticulin stain is more sensitive for early fibrosis and its use may increase these figures. It is unknown whether even longer use will increase these risks.
Liver function tests should be performed at baseline and at 4 to 8 week intervals in patients receiving Rasuvo 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), Rasuvo may be continued and the patient monitored as per recommendations listed above. Rasuvo 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:Rasuvo 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 Rasuvo 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 jirovecipneumonia, may occur with Rasuvo therapy. When a patient presents with pulmonary symptoms, the possibility ofPneumocystis jirovecipneumonia should be considered.Neurologic: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.
Pulmonary: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 Rasuvo therapy may be indicative of a potentially dangerous lesion and require interruption of treatment and careful investigation. Although clinically variable, the typical patient with methotrexate induced lung disease presents with fever, cough, dyspnea, hypoxemia, and an infiltrate on chest X-ray; infection (including pneumonia) needs to be excluded. This lesion can occur at all dosages.
Renal:Rasuvo 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.
Skin:Severe, occasionally fatal, dermatologic reactions, including toxic epidermal necrolysis, Stevens- Johnson syndrome, exfoliative dermatitis, skin necrosis, and erythema multiforme, have been reported in children and adults, within days of oral, intramuscular, intravenous, or intrathecal methotrexate administration. Reactions were noted after single or multiple low, intermediate, or high doses of methotrexate in patients with neoplastic and non-neoplastic diseases.
Lesions of psoriasis may be aggravated by concomitant exposure to ultraviolet radiation.
Radiation dermatitis and sunburn may be "recalled" by the use of methotrexate.
Other precautions:Rasuvo 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.
].7.1 Aspirin, Nonsteroidal Anti-Inflammatory Drugs, and SteroidsNonsteroidal anti-inflammatory drugs (NSAIDs) should not be administered prior to or concomitantly with the high doses of methotrexate, such as 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 [see
Warnings and Precautions (5.1)].Caution should be used when NSAIDs and salicylates are administered concomitantly with lower doses of methotrexate, including Rasuvo. 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. Aspirin, NSAIDs, and/or low dose steroids may be continued, although the possibility of increased toxicity with concomitant use of NSAIDs including salicylates has not been fully explored. Steroids may be reduced gradually in patients who respond to methotrexate.
4. 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 may not be preceded by symptoms or abnormal liver function tests in the psoriasis population. For this reason, periodic liver biopsies are usually recommended for psoriatic patients who are under long-term treatment. Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis in the rheumatoid arthritis population [see].5.1 Organ System ToxicityRasuvo 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), Rasuvo 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.
Rasuvo 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 Rasuvo closely. Most adverse reactions are reversible if detected early. When such reactions do occur, the drug should be reduced in dosage or discontinued and appropriate corrective measures should be taken. If necessary, this could include the use of leucovorin calcium and/or acute, intermittent hemodialysis with a high-flux dialyzer [see
Overdosage (10)]. If Rasuvo 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 [seeUse in Specific Populations (8.5)].Gastrointestinal: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, Rasuvo should be discontinued until recovery occurs. Rasuvo should be used with extreme caution in the presence of peptic ulcer disease or ulcerative colitis.
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 (7.1)].Hematologic:Rasuvo can suppress hematopoiesis and cause anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, and/or thrombocytopenia. In patients with preexisting hematopoietic impairment, Rasuvo 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.
Rasuvo 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 parenteral 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 (7.1)].Hepatic:Rasuvo 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 Rasuvo therapy, the drug should be used with caution.
In rheumatoid arthritis, age at first use of methotrexate and duration of therapy have been reported as risk factors for hepatotoxicity; other risk factors, similar to those observed in psoriasis, may be present in rheumatoid arthritis but have not been confirmed to date. Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis in this population. There is a combined reported experience in 217 rheumatoid arthritis patients with liver biopsies both before and during treatment (after a cumulative dose of at least 1.5 g) and in 714 patients with a biopsy only during treatment. There are 64 (7%) cases of fibrosis and 1 (0.1%) case of cirrhosis. Of the 64 cases of fibrosis, 60 were deemed mild. The reticulin stain is more sensitive for early fibrosis and its use may increase these figures. It is unknown whether even longer use will increase these risks.
Liver function tests should be performed at baseline and at 4 to 8 week intervals in patients receiving Rasuvo 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), Rasuvo may be continued and the patient monitored as per recommendations listed above. Rasuvo 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:Rasuvo 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 Rasuvo 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 jirovecipneumonia, may occur with Rasuvo therapy. When a patient presents with pulmonary symptoms, the possibility ofPneumocystis jirovecipneumonia should be considered.Neurologic: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.
Pulmonary: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 Rasuvo therapy may be indicative of a potentially dangerous lesion and require interruption of treatment and careful investigation. Although clinically variable, the typical patient with methotrexate induced lung disease presents with fever, cough, dyspnea, hypoxemia, and an infiltrate on chest X-ray; infection (including pneumonia) needs to be excluded. This lesion can occur at all dosages.
Renal:Rasuvo 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.
Skin:Severe, occasionally fatal, dermatologic reactions, including toxic epidermal necrolysis, Stevens- Johnson syndrome, exfoliative dermatitis, skin necrosis, and erythema multiforme, have been reported in children and adults, within days of oral, intramuscular, intravenous, or intrathecal methotrexate administration. Reactions were noted after single or multiple low, intermediate, or high doses of methotrexate in patients with neoplastic and non-neoplastic diseases.
Lesions of psoriasis may be aggravated by concomitant exposure to ultraviolet radiation.
Radiation dermatitis and sunburn may be "recalled" by the use of methotrexate.
Other precautions:Rasuvo 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.
5. 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) may require interruption of treatment and careful investigation [see].5.1 Organ System ToxicityRasuvo 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), Rasuvo 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.
Rasuvo 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 Rasuvo closely. Most adverse reactions are reversible if detected early. When such reactions do occur, the drug should be reduced in dosage or discontinued and appropriate corrective measures should be taken. If necessary, this could include the use of leucovorin calcium and/or acute, intermittent hemodialysis with a high-flux dialyzer [see
Overdosage (10)]. If Rasuvo 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 [seeUse in Specific Populations (8.5)].Gastrointestinal: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, Rasuvo should be discontinued until recovery occurs. Rasuvo should be used with extreme caution in the presence of peptic ulcer disease or ulcerative colitis.
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 (7.1)].Hematologic:Rasuvo can suppress hematopoiesis and cause anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, and/or thrombocytopenia. In patients with preexisting hematopoietic impairment, Rasuvo 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.
Rasuvo 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 parenteral 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 (7.1)].Hepatic:Rasuvo 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 Rasuvo therapy, the drug should be used with caution.
In rheumatoid arthritis, age at first use of methotrexate and duration of therapy have been reported as risk factors for hepatotoxicity; other risk factors, similar to those observed in psoriasis, may be present in rheumatoid arthritis but have not been confirmed to date. Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis in this population. There is a combined reported experience in 217 rheumatoid arthritis patients with liver biopsies both before and during treatment (after a cumulative dose of at least 1.5 g) and in 714 patients with a biopsy only during treatment. There are 64 (7%) cases of fibrosis and 1 (0.1%) case of cirrhosis. Of the 64 cases of fibrosis, 60 were deemed mild. The reticulin stain is more sensitive for early fibrosis and its use may increase these figures. It is unknown whether even longer use will increase these risks.
Liver function tests should be performed at baseline and at 4 to 8 week intervals in patients receiving Rasuvo 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), Rasuvo may be continued and the patient monitored as per recommendations listed above. Rasuvo 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:Rasuvo 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 Rasuvo 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 jirovecipneumonia, may occur with Rasuvo therapy. When a patient presents with pulmonary symptoms, the possibility ofPneumocystis jirovecipneumonia should be considered.Neurologic: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.
Pulmonary: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 Rasuvo therapy may be indicative of a potentially dangerous lesion and require interruption of treatment and careful investigation. Although clinically variable, the typical patient with methotrexate induced lung disease presents with fever, cough, dyspnea, hypoxemia, and an infiltrate on chest X-ray; infection (including pneumonia) needs to be excluded. This lesion can occur at all dosages.
Renal:Rasuvo 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.
Skin:Severe, occasionally fatal, dermatologic reactions, including toxic epidermal necrolysis, Stevens- Johnson syndrome, exfoliative dermatitis, skin necrosis, and erythema multiforme, have been reported in children and adults, within days of oral, intramuscular, intravenous, or intrathecal methotrexate administration. Reactions were noted after single or multiple low, intermediate, or high doses of methotrexate in patients with neoplastic and non-neoplastic diseases.
Lesions of psoriasis may be aggravated by concomitant exposure to ultraviolet radiation.
Radiation dermatitis and sunburn may be "recalled" by the use of methotrexate.
Other precautions:Rasuvo 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.
6. Diarrhea and ulcerative stomatitis require interruption of therapy: otherwise, hemorrhagic enteritis and death from intestinal perforation may occur [see].5.1 Organ System ToxicityRasuvo 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), Rasuvo 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.
Rasuvo 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 Rasuvo closely. Most adverse reactions are reversible if detected early. When such reactions do occur, the drug should be reduced in dosage or discontinued and appropriate corrective measures should be taken. If necessary, this could include the use of leucovorin calcium and/or acute, intermittent hemodialysis with a high-flux dialyzer [see
Overdosage (10)]. If Rasuvo 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 [seeUse in Specific Populations (8.5)].Gastrointestinal: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, Rasuvo should be discontinued until recovery occurs. Rasuvo should be used with extreme caution in the presence of peptic ulcer disease or ulcerative colitis.
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 (7.1)].Hematologic:Rasuvo can suppress hematopoiesis and cause anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, and/or thrombocytopenia. In patients with preexisting hematopoietic impairment, Rasuvo 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.
Rasuvo 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 parenteral 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 (7.1)].Hepatic:Rasuvo 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 Rasuvo therapy, the drug should be used with caution.
In rheumatoid arthritis, age at first use of methotrexate and duration of therapy have been reported as risk factors for hepatotoxicity; other risk factors, similar to those observed in psoriasis, may be present in rheumatoid arthritis but have not been confirmed to date. Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis in this population. There is a combined reported experience in 217 rheumatoid arthritis patients with liver biopsies both before and during treatment (after a cumulative dose of at least 1.5 g) and in 714 patients with a biopsy only during treatment. There are 64 (7%) cases of fibrosis and 1 (0.1%) case of cirrhosis. Of the 64 cases of fibrosis, 60 were deemed mild. The reticulin stain is more sensitive for early fibrosis and its use may increase these figures. It is unknown whether even longer use will increase these risks.
Liver function tests should be performed at baseline and at 4 to 8 week intervals in patients receiving Rasuvo 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), Rasuvo may be continued and the patient monitored as per recommendations listed above. Rasuvo 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:Rasuvo 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 Rasuvo 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 jirovecipneumonia, may occur with Rasuvo therapy. When a patient presents with pulmonary symptoms, the possibility ofPneumocystis jirovecipneumonia should be considered.Neurologic: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.
Pulmonary: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 Rasuvo therapy may be indicative of a potentially dangerous lesion and require interruption of treatment and careful investigation. Although clinically variable, the typical patient with methotrexate induced lung disease presents with fever, cough, dyspnea, hypoxemia, and an infiltrate on chest X-ray; infection (including pneumonia) needs to be excluded. This lesion can occur at all dosages.
Renal:Rasuvo 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.
Skin:Severe, occasionally fatal, dermatologic reactions, including toxic epidermal necrolysis, Stevens- Johnson syndrome, exfoliative dermatitis, skin necrosis, and erythema multiforme, have been reported in children and adults, within days of oral, intramuscular, intravenous, or intrathecal methotrexate administration. Reactions were noted after single or multiple low, intermediate, or high doses of methotrexate in patients with neoplastic and non-neoplastic diseases.
Lesions of psoriasis may be aggravated by concomitant exposure to ultraviolet radiation.
Radiation dermatitis and sunburn may be "recalled" by the use of methotrexate.
Other precautions:Rasuvo 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.
7. Malignant lymphomas, which may regress following withdrawal of methotrexate, may occur in patients receiving low-dose methotrexate and, thus, may not require cytotoxic treatment. Discontinue Rasuvo first and, if the lymphoma does not regress, appropriate treatment should be instituted [see].5.8 Malignant LymphomasNon-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 Rasuvo first and, if the lymphoma does not regress, appropriate treatment should be instituted.
8. Like other cytotoxic drugs, methotrexate may induce "tumor lysis syndrome" in patients with rapidly growing tumors [see].5.9 Tumor Lysis SyndromeLike other cytotoxic drugs, methotrexate may induce "tumor lysis syndrome" in patients with rapidly growing tumors.
9. Severe, occasionally fatal, skin reactions have been reported following single or multiple doses of methotrexate. Reactions have occurred within days of oral, intramuscular, intravenous, or intrathecal methotrexate administration. Recovery has been reported with discontinuation of therapy [see].5.1 Organ System ToxicityRasuvo 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), Rasuvo 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.
Rasuvo 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 Rasuvo closely. Most adverse reactions are reversible if detected early. When such reactions do occur, the drug should be reduced in dosage or discontinued and appropriate corrective measures should be taken. If necessary, this could include the use of leucovorin calcium and/or acute, intermittent hemodialysis with a high-flux dialyzer [see
Overdosage (10)]. If Rasuvo 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 [seeUse in Specific Populations (8.5)].Gastrointestinal: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, Rasuvo should be discontinued until recovery occurs. Rasuvo should be used with extreme caution in the presence of peptic ulcer disease or ulcerative colitis.
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 (7.1)].Hematologic:Rasuvo can suppress hematopoiesis and cause anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, and/or thrombocytopenia. In patients with preexisting hematopoietic impairment, Rasuvo 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.
Rasuvo 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 parenteral 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 (7.1)].Hepatic:Rasuvo 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 Rasuvo therapy, the drug should be used with caution.
In rheumatoid arthritis, age at first use of methotrexate and duration of therapy have been reported as risk factors for hepatotoxicity; other risk factors, similar to those observed in psoriasis, may be present in rheumatoid arthritis but have not been confirmed to date. Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis in this population. There is a combined reported experience in 217 rheumatoid arthritis patients with liver biopsies both before and during treatment (after a cumulative dose of at least 1.5 g) and in 714 patients with a biopsy only during treatment. There are 64 (7%) cases of fibrosis and 1 (0.1%) case of cirrhosis. Of the 64 cases of fibrosis, 60 were deemed mild. The reticulin stain is more sensitive for early fibrosis and its use may increase these figures. It is unknown whether even longer use will increase these risks.
Liver function tests should be performed at baseline and at 4 to 8 week intervals in patients receiving Rasuvo 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), Rasuvo may be continued and the patient monitored as per recommendations listed above. Rasuvo 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:Rasuvo 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 Rasuvo 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 jirovecipneumonia, may occur with Rasuvo therapy. When a patient presents with pulmonary symptoms, the possibility ofPneumocystis jirovecipneumonia should be considered.Neurologic: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.
Pulmonary: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 Rasuvo therapy may be indicative of a potentially dangerous lesion and require interruption of treatment and careful investigation. Although clinically variable, the typical patient with methotrexate induced lung disease presents with fever, cough, dyspnea, hypoxemia, and an infiltrate on chest X-ray; infection (including pneumonia) needs to be excluded. This lesion can occur at all dosages.
Renal:Rasuvo 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.
Skin:Severe, occasionally fatal, dermatologic reactions, including toxic epidermal necrolysis, Stevens- Johnson syndrome, exfoliative dermatitis, skin necrosis, and erythema multiforme, have been reported in children and adults, within days of oral, intramuscular, intravenous, or intrathecal methotrexate administration. Reactions were noted after single or multiple low, intermediate, or high doses of methotrexate in patients with neoplastic and non-neoplastic diseases.
Lesions of psoriasis may be aggravated by concomitant exposure to ultraviolet radiation.
Radiation dermatitis and sunburn may be "recalled" by the use of methotrexate.
Other precautions:Rasuvo 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.
10. Potentially fatal opportunistic infections, especially Pneumocystis jiroveci pneumonia, may occur with methotrexate therapy [see].5.1 Organ System ToxicityRasuvo 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), Rasuvo 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.
Rasuvo 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 Rasuvo closely. Most adverse reactions are reversible if detected early. When such reactions do occur, the drug should be reduced in dosage or discontinued and appropriate corrective measures should be taken. If necessary, this could include the use of leucovorin calcium and/or acute, intermittent hemodialysis with a high-flux dialyzer [see
Overdosage (10)]. If Rasuvo 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 [seeUse in Specific Populations (8.5)].Gastrointestinal: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, Rasuvo should be discontinued until recovery occurs. Rasuvo should be used with extreme caution in the presence of peptic ulcer disease or ulcerative colitis.
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 (7.1)].Hematologic:Rasuvo can suppress hematopoiesis and cause anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, and/or thrombocytopenia. In patients with preexisting hematopoietic impairment, Rasuvo 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.
Rasuvo 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 parenteral 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 (7.1)].Hepatic:Rasuvo 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 Rasuvo therapy, the drug should be used with caution.
In rheumatoid arthritis, age at first use of methotrexate and duration of therapy have been reported as risk factors for hepatotoxicity; other risk factors, similar to those observed in psoriasis, may be present in rheumatoid arthritis but have not been confirmed to date. Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis in this population. There is a combined reported experience in 217 rheumatoid arthritis patients with liver biopsies both before and during treatment (after a cumulative dose of at least 1.5 g) and in 714 patients with a biopsy only during treatment. There are 64 (7%) cases of fibrosis and 1 (0.1%) case of cirrhosis. Of the 64 cases of fibrosis, 60 were deemed mild. The reticulin stain is more sensitive for early fibrosis and its use may increase these figures. It is unknown whether even longer use will increase these risks.
Liver function tests should be performed at baseline and at 4 to 8 week intervals in patients receiving Rasuvo 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), Rasuvo may be continued and the patient monitored as per recommendations listed above. Rasuvo 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:Rasuvo 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 Rasuvo 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 jirovecipneumonia, may occur with Rasuvo therapy. When a patient presents with pulmonary symptoms, the possibility ofPneumocystis jirovecipneumonia should be considered.Neurologic: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.
Pulmonary: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 Rasuvo therapy may be indicative of a potentially dangerous lesion and require interruption of treatment and careful investigation. Although clinically variable, the typical patient with methotrexate induced lung disease presents with fever, cough, dyspnea, hypoxemia, and an infiltrate on chest X-ray; infection (including pneumonia) needs to be excluded. This lesion can occur at all dosages.
Renal:Rasuvo 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.
Skin:Severe, occasionally fatal, dermatologic reactions, including toxic epidermal necrolysis, Stevens- Johnson syndrome, exfoliative dermatitis, skin necrosis, and erythema multiforme, have been reported in children and adults, within days of oral, intramuscular, intravenous, or intrathecal methotrexate administration. Reactions were noted after single or multiple low, intermediate, or high doses of methotrexate in patients with neoplastic and non-neoplastic diseases.
Lesions of psoriasis may be aggravated by concomitant exposure to ultraviolet radiation.
Radiation dermatitis and sunburn may be "recalled" by the use of methotrexate.
Other precautions:Rasuvo 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.
11. Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis [see].5.10 Concomitant Radiation TherapyMethotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis.
Rasuvo is a folate analog metabolic inhibitor indicated for the:
- Management of patients with severe, active rheumatoid arthritis (RA) and polyarticular juvenile idiopathic arthritis (pJIA), who are intolerant of or had an inadequate response to first-line therapy ()
1.1 Rheumatoid Arthritis including Polyarticular Juvenile Idiopathic ArthritisRasuvo is indicated in the management of selected adults with severe, active rheumatoid arthritis (RA) (ACR criteria), or children with active polyarticular juvenile idiopathic arthritis (pJIA), who have had an insufficient therapeutic response to, or are intolerant of, an adequate trial of first-line therapy including full dose non-steroidal anti-inflammatory agents (NSAIDs).
- Symptomatic control of severe, recalcitrant, disabling psoriasis in adults who are not adequately responsive to other forms of therapy ()
1.2 PsoriasisRasuvo is indicated in adults for 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.
Rasuvo is not indicated for the treatment of neoplastic diseases (
Rasuvo is not indicated for the treatment of neoplastic diseases.
- Rasuvo is for once weekly subcutaneous use only.
- Administer Rasuvo in the abdomen or thigh. ()
2.1 Important Dosing InformationRasuvo is a single-dose manually-triggered auto-injector for once-weekly subcutaneous use only [see
Warnings and Precautions (5.5)]. Administer Rasuvo in the abdomen or the thigh. Rasuvo is only available in doses between 7.5 to 30 mg in 2.5 mg increments. Use another formulation of methotrexate for alternative dosing in patients who require oral, intramuscular, intravenous, intra-arterial, or intrathecal dosing, doses less than 7.5 mg per week, doses more than 30 mg per week, high-dose regimens, or dose adjustments of less than 2.5 mg increments. - Use another formulation of methotrexate for patients requiring oral, intramuscular, intravenous, intra-arterial, or intrathecal dosing, doses less than 7.5 mg per week, doses above 30 mg per week, high-dose regimens, or dose adjustments of less than 2.5 mg increments ()
2.1 Important Dosing InformationRasuvo is a single-dose manually-triggered auto-injector for once-weekly subcutaneous use only [see
Warnings and Precautions (5.5)]. Administer Rasuvo in the abdomen or the thigh. Rasuvo is only available in doses between 7.5 to 30 mg in 2.5 mg increments. Use another formulation of methotrexate for alternative dosing in patients who require oral, intramuscular, intravenous, intra-arterial, or intrathecal dosing, doses less than 7.5 mg per week, doses more than 30 mg per week, high-dose regimens, or dose adjustments of less than 2.5 mg increments. - Starting doses of methotrexate:
- RA: 7.5 mg once weekly of an oral or subcutaneous formulation ()
2.2 Rheumatoid Arthritis including Polyarticular Juvenile Idiopathic ArthritisRecommended starting dose of methotrexate:
Adult RA:7.5 mg as a single oral or subcutaneous dose once weekly.pJIA:10 mg/m2once weekly.For patients switching from oral methotrexate to Rasuvo, consider any differences in bioavailability between oral and subcutaneously administered methotrexate [see
Clinical Pharmacology (12.3)].Dosages may be adjusted gradually to achieve an optimal response. Limited experience shows a significant increase in the incidence and severity of serious toxic reactions, especially bone marrow suppression, at doses greater than 20 mg/wk in adults. Although there is experience with doses up to 30 mg/m2/wk in children, there are too few published data to assess how doses over 20 mg/m2/wk might affect the risk of serious toxicity in children. Experience does suggest, however, that children receiving 20 to 30 mg/m2/wk (0.65 to 1.0 mg/kg/wk) may have better absorption and fewer gastrointestinal side effects if methotrexate is administered either intramuscularly or subcutaneously.
Therapeutic response usually begins within 3 to 6 weeks and the patient may continue to improve for another 12 weeks or more.
The optimal duration of therapy is unknown. Limited data available from long-term studies in adults indicate that the initial clinical improvement is maintained for at least two years with continued therapy. When methotrexate is discontinued, the arthritis usually worsens within 3 to 6 weeks.
The patient should be fully informed of the risks involved and should be under constant supervision of the physician.Assessment of hematologic, hepatic, renal, and pulmonary function should be made by history, physical examination, and laboratory tests before beginning, periodically during, and before reinstituting Rasuvo therapy [seeWarnings and Precautions (5.4)]. Females of childbearing potential should not be started on Rasuvo until pregnancy is excluded [seeContraindications (4)andWarnings and Precautions (5.2)].All schedules should be continually tailored to the individual patient. An initial test dose may be given prior to the regular dosing schedule to detect any extreme sensitivity to adverse effects.
Maximal myelosuppression usually occurs in seven to ten days.
- pJIA: 10 mg/m2 once weekly ()
2.2 Rheumatoid Arthritis including Polyarticular Juvenile Idiopathic ArthritisRecommended starting dose of methotrexate:
Adult RA:7.5 mg as a single oral or subcutaneous dose once weekly.pJIA:10 mg/m2once weekly.For patients switching from oral methotrexate to Rasuvo, consider any differences in bioavailability between oral and subcutaneously administered methotrexate [see
Clinical Pharmacology (12.3)].Dosages may be adjusted gradually to achieve an optimal response. Limited experience shows a significant increase in the incidence and severity of serious toxic reactions, especially bone marrow suppression, at doses greater than 20 mg/wk in adults. Although there is experience with doses up to 30 mg/m2/wk in children, there are too few published data to assess how doses over 20 mg/m2/wk might affect the risk of serious toxicity in children. Experience does suggest, however, that children receiving 20 to 30 mg/m2/wk (0.65 to 1.0 mg/kg/wk) may have better absorption and fewer gastrointestinal side effects if methotrexate is administered either intramuscularly or subcutaneously.
Therapeutic response usually begins within 3 to 6 weeks and the patient may continue to improve for another 12 weeks or more.
The optimal duration of therapy is unknown. Limited data available from long-term studies in adults indicate that the initial clinical improvement is maintained for at least two years with continued therapy. When methotrexate is discontinued, the arthritis usually worsens within 3 to 6 weeks.
The patient should be fully informed of the risks involved and should be under constant supervision of the physician.Assessment of hematologic, hepatic, renal, and pulmonary function should be made by history, physical examination, and laboratory tests before beginning, periodically during, and before reinstituting Rasuvo therapy [seeWarnings and Precautions (5.4)]. Females of childbearing potential should not be started on Rasuvo until pregnancy is excluded [seeContraindications (4)andWarnings and Precautions (5.2)].All schedules should be continually tailored to the individual patient. An initial test dose may be given prior to the regular dosing schedule to detect any extreme sensitivity to adverse effects.
Maximal myelosuppression usually occurs in seven to ten days.
- Psoriasis: 10 to 25 mg once weekly of an oral, intramuscular, subcutaneous, or intravenous formulation ()
2.3 PsoriasisRecommended starting dose of methotrexate:
Psoriasis: 10-25 mg as a single oral, intramuscular, subcutaneous, or intravenous dose once weekly.For patients switching from oral methotrexate to Rasuvo, consider any differences in bioavailability between oral and subcutaneously administered methotrexate [see
Clinical Pharmacology (12.3)].Dosage may be gradually adjusted to achieve optimal clinical response; 30 mg/week should not ordinarily be exceeded. Once optimal clinical response has been achieved, the dosage should be reduced to the lowest possible amount of drug and to the longest possible rest period. The use of Rasuvo may permit the return to conventional topical therapy, which should be encouraged.
- RA: 7.5 mg once weekly of an oral or subcutaneous formulation (
- Adjust dose gradually to achieve an optimal response (,
2.2 Rheumatoid Arthritis including Polyarticular Juvenile Idiopathic ArthritisRecommended starting dose of methotrexate:
Adult RA:7.5 mg as a single oral or subcutaneous dose once weekly.pJIA:10 mg/m2once weekly.For patients switching from oral methotrexate to Rasuvo, consider any differences in bioavailability between oral and subcutaneously administered methotrexate [see
Clinical Pharmacology (12.3)].Dosages may be adjusted gradually to achieve an optimal response. Limited experience shows a significant increase in the incidence and severity of serious toxic reactions, especially bone marrow suppression, at doses greater than 20 mg/wk in adults. Although there is experience with doses up to 30 mg/m2/wk in children, there are too few published data to assess how doses over 20 mg/m2/wk might affect the risk of serious toxicity in children. Experience does suggest, however, that children receiving 20 to 30 mg/m2/wk (0.65 to 1.0 mg/kg/wk) may have better absorption and fewer gastrointestinal side effects if methotrexate is administered either intramuscularly or subcutaneously.
Therapeutic response usually begins within 3 to 6 weeks and the patient may continue to improve for another 12 weeks or more.
The optimal duration of therapy is unknown. Limited data available from long-term studies in adults indicate that the initial clinical improvement is maintained for at least two years with continued therapy. When methotrexate is discontinued, the arthritis usually worsens within 3 to 6 weeks.
The patient should be fully informed of the risks involved and should be under constant supervision of the physician.Assessment of hematologic, hepatic, renal, and pulmonary function should be made by history, physical examination, and laboratory tests before beginning, periodically during, and before reinstituting Rasuvo therapy [seeWarnings and Precautions (5.4)]. Females of childbearing potential should not be started on Rasuvo until pregnancy is excluded [seeContraindications (4)andWarnings and Precautions (5.2)].All schedules should be continually tailored to the individual patient. An initial test dose may be given prior to the regular dosing schedule to detect any extreme sensitivity to adverse effects.
Maximal myelosuppression usually occurs in seven to ten days.
)2.3 PsoriasisRecommended starting dose of methotrexate:
Psoriasis: 10-25 mg as a single oral, intramuscular, subcutaneous, or intravenous dose once weekly.For patients switching from oral methotrexate to Rasuvo, consider any differences in bioavailability between oral and subcutaneously administered methotrexate [see
Clinical Pharmacology (12.3)].Dosage may be gradually adjusted to achieve optimal clinical response; 30 mg/week should not ordinarily be exceeded. Once optimal clinical response has been achieved, the dosage should be reduced to the lowest possible amount of drug and to the longest possible rest period. The use of Rasuvo may permit the return to conventional topical therapy, which should be encouraged.
Rasuvo is an injection containing methotrexate at a concentration of 50 mg/ml available as a manually-triggered auto-injector that administers a single dose of methotrexate solution in the following dosage strengths:
- 7.5 mg
- 10 mg
- 12.5 mg
- 15 mg
- 17.5 mg
- 20 mg
- 22.5 mg
- 25 mg
- 27.5 mg
- 30 mg
- Pediatric use: Safety and efficacy of methotrexate, including Rasuvo, have not been established in pediatric patients with psoriasis. Safety and efficacy of Rasuvo have not been established in pediatric patients with malignancy ()
8.4 Pediatric UseThe safety and effectiveness of methotrexate, including Rasuvo, have not been established in pediatric patients with psoriasis.
The safety and effectiveness of Rasuvo 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 (14.2)].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 (6.1)].Rasuvo 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 (5.1)]. - Geriatric use: Use caution in dose selection ()
8.5 Geriatric UseClinical 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 (5.1),Drug Interactions (7.7)andUse in Specific Populations (8.6)]. 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 (5.1)]. - Lactation: Advise women not to breastfeed ()
8.2 LactationRisk SummaryLimited published literature report the presence of methotrexate in human breast milk in low amounts following oral methotrexate administration, with the highest breast milk to plasma concentration ratio reported to be 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 from methotrexate in breastfed infants, including myelosuppression advise women not to breastfeed during treatment with Rasuvo and for one week after the final dose.
Rasuvo is contraindicated in the following: