Rasuvo
Generic: METHOTREXATE
Basic Information
Manufacturer
Medexus Pharma Inc.
Product Type
HUMAN PRESCRIPTION DRUG
Route of Administration
SUBCUTANEOUS
FDA Set ID
d0075461-0e7e-4967-9c9b-d6440e912c0e
Indications & Usage
1 INDICATIONS AND USAGE Rasuvo is a folate analog metabolic inhibitor indicated for the: Management of patients with severe, active rheumatoid arthritis (RA) and polyarticular juvenile idiopathic arthritis (pJIA), who are intolerant of or had an inadequate response to first-line therapy ( 1.1 ) Symptomatic control of severe, recalcitrant, disabling psoriasis in adults who are not adequately responsive to other forms of therapy ( 1.2 ) Limitation of Use Rasuvo is not indicated for the treatment of neoplastic diseases ( 1.3 ).
1.1 Rheumatoid Arthritis including Polyarticular Juvenile Idiopathic Arthritis Rasuvo 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).
1.2 Psoriasis Rasuvo 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.
1.3 Limitation of Use Rasuvo is not indicated for the treatment of neoplastic diseases.
1.1 Rheumatoid Arthritis including Polyarticular Juvenile Idiopathic Arthritis Rasuvo 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).
1.2 Psoriasis Rasuvo 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.
1.3 Limitation of Use Rasuvo is not indicated for the treatment of neoplastic diseases.
Adverse Reactions
6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling.
Organ System Toxicity [see Warnings and Precautions (5.1) ] Embryo-Fetal Toxicity [see Warnings and Precautions (5.2) ] Effects on Reproduction [see Warnings and Precautions (5.3) ] Malignant Lymphomas [see Warnings and Precautions (5.8) ] The most frequently reported adverse reactions include ulcerative stomatitis, leukopenia, nausea, and abdominal distress.
Other frequently reported adverse reactions are malaise, undue fatigue, chills and fever, dizziness and decreased resistance to infection.
Common adverse reactions are: nausea, abdominal pain, dyspepsia, stomatitis/mouth sores, rash, nasopharyngitis, diarrhea, liver function test abnormalities, vomiting, headache, bronchitis, thrombocytopenia, alopecia, leukopenia, pancytopenia, dizziness, photosensitivity, and "burning of skin lesions" ( 6 ).
To report SUSPECTED ADVERSE REACTIONS, contact Medexus at 1-855-336-3322 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1 Clinical Trials Experience This section provides a summary of adverse reactions reported in subjects in clinical studies conducted with Rasuvo as well as with methotrexate injection and oral methotrexate.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug, and may not reflect the rates observed in practice.
Rheumatoid Arthritis The approximate incidences of methotrexate-attributed (i.e.
placebo rate subtracted) adverse reactions in 12 to 18 week double-blind studies of patients (n=128) with rheumatoid arthritis treated with low-dose oral (7.5 to 15 mg/week) pulse methotrexate, are listed below.
Virtually all of these patients were on concomitant nonsteroidal anti-inflammatory drugs and some were also taking low dosages of corticosteroids.
Hepatic histology was not examined in these short-term studies.
Incidence greater than 10%: Elevated liver function tests 15%, nausea/vomiting 10%.
Incidence 3% to 10%: Stomatitis, thrombocytopenia (platelet count less than 100,000/mm3).
Incidence 1% to 3%: Rash/pruritis/dermatitis, diarrhea, alopecia, leukopenia (WBC less than 3000/mm3), pancytopenia, dizziness.
Two other controlled trials of patients (n=680) with Rheumatoid Arthritis on 7.5 mg to 15 mg/wk oral doses showed an incidence of interstitial pneumonitis of 1%.
Other less common reactions included decreased hematocrit, headache, upper respiratory infection, anorexia, arthralgias, chest pain, coughing, dysuria, eye discomfort, epistaxis, fever, infection, sweating, tinnitus, and vaginal discharge.
Polyarticular Juvenile Idiopathic Arthritis The approximate incidences of adverse reactions reported in pediatric patients with pJIA treated with oral, weekly doses of methotrexate (5 to 20 mg/m 2 /wk or 0.1 to 0.65 mg/kg/wk) were as follows (virtually all patients were receiving concomitant nonsteroidal anti-inflammatory drugs, and some also were taking low doses of corticosteroids): elevated liver function tests, 14%; gastrointestinal reactions (e.g., nausea, vomiting, diarrhea), 11%; stomatitis, 2%; leukopenia, 2%; headache, 1.2%; alopecia, 0.5%; dizziness, 0.2%; and rash, 0.2%.
Although there is experience with dosing up to 30 mg/m 2 /wk in pJIA, the published data for doses above 20 mg/m 2 /wk are too limited to provide reliable estimates of adverse reaction rates.
Psoriasis There are two literature reports (Roenigk, 1969, and Nyfors, 1978) describing large series (n=204, 248) of psoriasis patients treated with methotrexate.
Dosages ranged up to 25 mg per week and treatment was administered for up to four years.
With the exception of alopecia, photosensitivity, and "burning of skin lesions" (each 3% to 10%), the adverse reaction rates in these reports were very similar to those in the rheumatoid arthritis studies.
Rarely, painful plaque erosions may appear (Pearce, HP and Wilson, BB: Am Acad Dermatol 35: 835-838, 1996).
6.2 Other Adverse Reactions Other adverse reactions that have been reported with methotrexate in oncology, RA, pJIA, and psoriasis patients are listed below by organ system.
Alimentary System: gingivitis, pharyngitis, stomatitis, anorexia, nausea, vomiting, diarrhea, hematemesis, melena, gastrointestinal ulceration and bleeding, enteritis, pancreatitis.
Blood and Lymphatic System Disorders: suppressed hematopoiesis, anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, thrombocytopenia, agranulocytosis, eosinophilia, lymphadenopathy and lymphoproliferative disorders (including reversible).
Hypogammaglobulinemia has been reported rarely.
Cardiovascular: pericarditis, pericardial effusion, hypotension, and thromboembolic events (including arterial thrombosis, cerebral thrombosis, deep vein thrombosis, retinal vein thrombosis, thrombophlebitis, and pulmonary embolus).
Central Nervous System: headaches, drowsiness, blurred vision, transient blindness, speech impairment including dysarthria and aphasia, hemiparesis, paresis and convulsions have also occurred following administration of methotrexate.
Following low doses, there have been occasional reports of transient subtle cognitive dysfunction, mood alteration or unusual cranial sensations, leukoencephalopathy, or encephalopathy.
Hepatobiliary Disorders: hepatotoxicity, acute hepatitis, chronic fibrosis and cirrhosis, hepatic failure, decrease in serum albumin, liver enzyme elevations.
Infection: There have been case reports of sometimes fatal opportunistic infections in patients receiving methotrexate therapy for neoplastic and non-neoplastic diseases.
Pneumocystis jiroveci pneumonia was the most common opportunistic infection.
There have also been reports of infections, pneumonia, Cytomegalovirus infection, including cytomegaloviral pneumonia, sepsis, fatal sepsis, nocardiosis, histoplasmosis, cryptococcosis, Herpes zoster , Herpes simplex hepatitis, and disseminated Herpes simplex .
Musculoskeletal System: stress fracture.
Ophthalmic: conjunctivitis, serious visual changes of unknown etiology.
Pulmonary System: respiratory fibrosis, respiratory failure, alveolitis, interstitial pneumonitis deaths have been reported, and chronic interstitial obstructive pulmonary disease has occasionally occurred.
Skin: erythematous rashes, pruritus, urticaria, photosensitivity, pigmentary changes, alopecia, ecchymosis, telangiectasia, acne, furunculosis, erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome, skin necrosis, skin ulceration and exfoliative dermatitis.
Urogenital System: severe nephropathy or renal failure, azotemia, cystitis, hematuria, proteinuria; defective oogenesis or spermatogenesis, transient oligospermia, menstrual dysfunction, vaginal discharge, and gynecomastia; infertility, abortion, fetal death, fetal defects.
Other rarer reactions related to or attributed to the use of methotrexate such as nodulosis, vasculitis, arthralgia/myalgia, loss of libido/impotence, diabetes, osteoporosis, sudden death, lymphoma, including reversible lymphomas, tumor lysis syndrome, soft tissue necrosis and osteonecrosis.
Anaphylactoid reactions have been reported.
Organ System Toxicity [see Warnings and Precautions (5.1) ] Embryo-Fetal Toxicity [see Warnings and Precautions (5.2) ] Effects on Reproduction [see Warnings and Precautions (5.3) ] Malignant Lymphomas [see Warnings and Precautions (5.8) ] The most frequently reported adverse reactions include ulcerative stomatitis, leukopenia, nausea, and abdominal distress.
Other frequently reported adverse reactions are malaise, undue fatigue, chills and fever, dizziness and decreased resistance to infection.
Common adverse reactions are: nausea, abdominal pain, dyspepsia, stomatitis/mouth sores, rash, nasopharyngitis, diarrhea, liver function test abnormalities, vomiting, headache, bronchitis, thrombocytopenia, alopecia, leukopenia, pancytopenia, dizziness, photosensitivity, and "burning of skin lesions" ( 6 ).
To report SUSPECTED ADVERSE REACTIONS, contact Medexus at 1-855-336-3322 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1 Clinical Trials Experience This section provides a summary of adverse reactions reported in subjects in clinical studies conducted with Rasuvo as well as with methotrexate injection and oral methotrexate.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug, and may not reflect the rates observed in practice.
Rheumatoid Arthritis The approximate incidences of methotrexate-attributed (i.e.
placebo rate subtracted) adverse reactions in 12 to 18 week double-blind studies of patients (n=128) with rheumatoid arthritis treated with low-dose oral (7.5 to 15 mg/week) pulse methotrexate, are listed below.
Virtually all of these patients were on concomitant nonsteroidal anti-inflammatory drugs and some were also taking low dosages of corticosteroids.
Hepatic histology was not examined in these short-term studies.
Incidence greater than 10%: Elevated liver function tests 15%, nausea/vomiting 10%.
Incidence 3% to 10%: Stomatitis, thrombocytopenia (platelet count less than 100,000/mm3).
Incidence 1% to 3%: Rash/pruritis/dermatitis, diarrhea, alopecia, leukopenia (WBC less than 3000/mm3), pancytopenia, dizziness.
Two other controlled trials of patients (n=680) with Rheumatoid Arthritis on 7.5 mg to 15 mg/wk oral doses showed an incidence of interstitial pneumonitis of 1%.
Other less common reactions included decreased hematocrit, headache, upper respiratory infection, anorexia, arthralgias, chest pain, coughing, dysuria, eye discomfort, epistaxis, fever, infection, sweating, tinnitus, and vaginal discharge.
Polyarticular Juvenile Idiopathic Arthritis The approximate incidences of adverse reactions reported in pediatric patients with pJIA treated with oral, weekly doses of methotrexate (5 to 20 mg/m 2 /wk or 0.1 to 0.65 mg/kg/wk) were as follows (virtually all patients were receiving concomitant nonsteroidal anti-inflammatory drugs, and some also were taking low doses of corticosteroids): elevated liver function tests, 14%; gastrointestinal reactions (e.g., nausea, vomiting, diarrhea), 11%; stomatitis, 2%; leukopenia, 2%; headache, 1.2%; alopecia, 0.5%; dizziness, 0.2%; and rash, 0.2%.
Although there is experience with dosing up to 30 mg/m 2 /wk in pJIA, the published data for doses above 20 mg/m 2 /wk are too limited to provide reliable estimates of adverse reaction rates.
Psoriasis There are two literature reports (Roenigk, 1969, and Nyfors, 1978) describing large series (n=204, 248) of psoriasis patients treated with methotrexate.
Dosages ranged up to 25 mg per week and treatment was administered for up to four years.
With the exception of alopecia, photosensitivity, and "burning of skin lesions" (each 3% to 10%), the adverse reaction rates in these reports were very similar to those in the rheumatoid arthritis studies.
Rarely, painful plaque erosions may appear (Pearce, HP and Wilson, BB: Am Acad Dermatol 35: 835-838, 1996).
6.2 Other Adverse Reactions Other adverse reactions that have been reported with methotrexate in oncology, RA, pJIA, and psoriasis patients are listed below by organ system.
Alimentary System: gingivitis, pharyngitis, stomatitis, anorexia, nausea, vomiting, diarrhea, hematemesis, melena, gastrointestinal ulceration and bleeding, enteritis, pancreatitis.
Blood and Lymphatic System Disorders: suppressed hematopoiesis, anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, thrombocytopenia, agranulocytosis, eosinophilia, lymphadenopathy and lymphoproliferative disorders (including reversible).
Hypogammaglobulinemia has been reported rarely.
Cardiovascular: pericarditis, pericardial effusion, hypotension, and thromboembolic events (including arterial thrombosis, cerebral thrombosis, deep vein thrombosis, retinal vein thrombosis, thrombophlebitis, and pulmonary embolus).
Central Nervous System: headaches, drowsiness, blurred vision, transient blindness, speech impairment including dysarthria and aphasia, hemiparesis, paresis and convulsions have also occurred following administration of methotrexate.
Following low doses, there have been occasional reports of transient subtle cognitive dysfunction, mood alteration or unusual cranial sensations, leukoencephalopathy, or encephalopathy.
Hepatobiliary Disorders: hepatotoxicity, acute hepatitis, chronic fibrosis and cirrhosis, hepatic failure, decrease in serum albumin, liver enzyme elevations.
Infection: There have been case reports of sometimes fatal opportunistic infections in patients receiving methotrexate therapy for neoplastic and non-neoplastic diseases.
Pneumocystis jiroveci pneumonia was the most common opportunistic infection.
There have also been reports of infections, pneumonia, Cytomegalovirus infection, including cytomegaloviral pneumonia, sepsis, fatal sepsis, nocardiosis, histoplasmosis, cryptococcosis, Herpes zoster , Herpes simplex hepatitis, and disseminated Herpes simplex .
Musculoskeletal System: stress fracture.
Ophthalmic: conjunctivitis, serious visual changes of unknown etiology.
Pulmonary System: respiratory fibrosis, respiratory failure, alveolitis, interstitial pneumonitis deaths have been reported, and chronic interstitial obstructive pulmonary disease has occasionally occurred.
Skin: erythematous rashes, pruritus, urticaria, photosensitivity, pigmentary changes, alopecia, ecchymosis, telangiectasia, acne, furunculosis, erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome, skin necrosis, skin ulceration and exfoliative dermatitis.
Urogenital System: severe nephropathy or renal failure, azotemia, cystitis, hematuria, proteinuria; defective oogenesis or spermatogenesis, transient oligospermia, menstrual dysfunction, vaginal discharge, and gynecomastia; infertility, abortion, fetal death, fetal defects.
Other rarer reactions related to or attributed to the use of methotrexate such as nodulosis, vasculitis, arthralgia/myalgia, loss of libido/impotence, diabetes, osteoporosis, sudden death, lymphoma, including reversible lymphomas, tumor lysis syndrome, soft tissue necrosis and osteonecrosis.
Anaphylactoid reactions have been reported.