RASUVO

Rasuvo contains methotrexate, a folate analog metabolic inhibitor. Chemically, methotrexate is [N-[4-[[(2,4-diamino-6-pteridinyl)methyl]methylamino]benzoyl]-Lglutamic acid. The structural formula is: C 20 H 22 N 8 O 5 M.W.= 454.45 Rasuvo contains methotrexate in a sterile, preservative-free, non-pyrogenic solution for a single subcutaneous injection. Rasuvo is an isotonic, clear, yellow to brown solution. Rasuvo contains the following inactive ingredients: sodium chloride 0.4% w/v; water for injections, sodium hydroxide and, if necessary, hydrochloric acid are added to adjust the pH to approximately 8.5. Chemical Structure

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.

Rasuvo is for once weekly subcutaneous use only. Administer Rasuvo in the abdomen or thigh. ( 2.1 ) 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 ) Starting doses of methotrexate: RA: 7.5 mg once weekly of an oral or subcutaneous formulation ( 2.2 ) pJIA: 10 mg/m2 once weekly ( 2.2 ) Psoriasis: 10 to 25 mg once weekly of an oral, intramuscular, subcutaneous, or intravenous formulation ( 2.3 ) Adjust dose gradually to achieve an optimal response ( 2.2 , 2.3 ) 2.1 Important Dosing Information Rasuvo 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. 2.2 Rheumatoid Arthritis including Polyarticular Juvenile Idiopathic Arthritis Recommended starting dose of methotrexate: Adult RA: 7.5 mg as a single oral or subcutaneous dose once weekly. pJIA: 10 mg/m 2 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) ]. 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/m 2 /wk in children, there are too few published data to assess how doses over 20 mg/m 2 /wk might affect the risk of serious toxicity in children. Experience does suggest, however, that children receiving 20 to 30 mg/m 2 /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 [see Warnings and Precautions (5.4) ]. Females of childbearing potential should not be started on Rasuvo until pregnancy is excluded [see Contraindications (4) and Warnings 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 Psoriasis Recommended 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. 2.4 Administration and Handling Rasuvo is a manually-triggered auto-injector intended for subcutaneous use under the guidance and supervision of a physician. Patients may self-inject with Rasuvo if a physician determines that it is appropriate, if they have received proper training in how to prepare and administer the correct dose, and if they receive medical follow-up, as necessary. Rasuvo is injected once weekly . The patient must be explicitly informed about the once weekly dosing schedule. It is advisable to determine an appropriate fixed day of the week for the injection. Visually inspect Rasuvo for particulate matter and discoloration prior to administration. Do not use Rasuvo if the seal is broken. Handle and dispose of Rasuvo consistent with recommendations for handling and disposal of cytotoxic drugs 1 . 2.5 Pregnancy testing Verify the pregnancy status of females of reproductive potential prior to initiating treatment with Rasuvo [see Use in Specific Populations (8.1 , 8.3) ]

Rasuvo is contraindicated in the following: Pregnancy ( 4 ) Alcoholism or liver disease ( 4 ) Immunodeficiency syndromes ( 4 ) Preexisting blood dyscrasias ( 4 ) Hypersensitivity to methotrexate ( 4 ) • Pregnancy Rasuvo can cause embryo-fetal toxicity and fetal death when administered during pregnancy. [see Warnings 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 [see Warnings and Precautions (5.1) ]. • Immunodeficiency Syndromes Patients who have overt or laboratory evidence of immunodeficiency syndromes [see Warnings and Precautions (5.1) ]. • Preexisting Blood Dyscrasias Patients who have preexisting blood dyscrasias, such as bone marrow hypoplasia, leukopenia, thrombocytopenia, or significant anemia [see Warnings and Precautions (5.1) ]. • Hypersensitivity Patients with a known hypersensitivity to methotrexate. Severe hypersensitivity reactions have been observed with methotrexate use [see Warnings and Precautions (5.1) and Adverse Reactions (6.1 and 6.2) ].

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.

Aspirin, NSAIDs, and steroids: concomitant use may elevate and prolong serum methotrexate levels and cause increased toxicity ( 7.1 ) Proton pump inhibitors: concomitant use may elevate and prolong serum methotrexate levels and cause increased toxicity ( 7.2 ) 7.1 Aspirin, Nonsteroidal Anti-Inflammatory Drugs, and Steroids Nonsteroidal 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. 7.2 Proton Pump Inhibitors (PPIs) and H2 Blockers Use caution if high-dose methotrexate is administered to patients receiving proton pump inhibitor (PPI) therapy. Case reports and published population pharmacokinetic studies suggest that concomitant use of some PPIs, such as omeprazole, esomeprazole, and pantoprazole, with methotrexate (primarily at high dose), may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. In two of these cases, delayed methotrexate elimination was observed when high-dose methotrexate was co-administered with PPIs, but was not observed when methotrexate was co-administered with ranitidine. However, no formal drug interaction studies of methotrexate with ranitidine have been conducted. 7.3 Oral Antibiotics Oral antibiotics such as tetracycline, chloramphenicol, and nonabsorbable broad spectrum antibiotics, may decrease intestinal absorption of methotrexate or interfere with the enterohepatic circulation by inhibiting bowel flora and suppressing metabolism of the drug by bacteria. Penicillins may reduce the renal clearance of methotrexate; increased serum concentrations of methotrexate with concomitant hematologic and gastrointestinal toxicity have been observed with high and low dose methotrexate. Use of Rasuvo with penicillins should be carefully monitored. Trimethoprim/sulfamethoxazole has been reported rarely to increase bone marrow suppression in patients receiving methotrexate, probably by decreased tubular secretion and/or an additive antifolate effect. 7.4 Hepatotoxins The potential for increased hepatotoxicity when methotrexate is administered with other hepatotoxic agents has not been evaluated. However, hepatotoxicity has been reported in such cases. Therefore, patients receiving concomitant therapy with Rasuvo and other potential hepatotoxins (e.g., azathioprine, retinoids, and sulfasalazine) should be closely monitored for possible increased risk of hepatotoxicity. 7.5 Theophylline Methotrexate may decrease the clearance of theophylline; theophylline levels should be monitored when used concurrently with Rasuvo. 7.6 Folic Acid and Antifolates Vitamin preparations containing folic acid or its derivatives may decrease responses to systemically administered methotrexate. Preliminary animal and human studies have shown that small quantities of intravenously administered leucovorin enter the CSF primarily as 5-methyltetrahydrofolate and, in humans, remain 1 to 3 orders of magnitude lower than the usual methotrexate concentrations following intrathecal administration. However, high doses of leucovorin may reduce the efficacy of intrathecally administered methotrexate. Folate deficiency states may increase methotrexate toxicity. Trimethoprim/sulfamethoxazole has been reported rarely to increase bone marrow suppression in patients receiving methotrexate, probably by decreased tubular secretion and/or an additive antifolate effect. 7.7 Mercaptopurine Methotrexate increases the plasma levels of mercaptopurine. The combination of Rasuvo and mercaptopurine may therefore require dose adjustment. 7.8 Nitrous oxide The use of nitrous oxide anesthesia potentiates the effect of methotrexate on folate dependent metabolic pathways, resulting in the potential for increased toxicity. Avoid the simultaneous use of nitrous oxide and methotrexate. 7.9 Other Drugs Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by certain drugs, such as salicylates, phenylbutazone, phenytoin, and sulfonamides. Renal tubular transport is also diminished by probenecid; use of Rasuvo with this drug should be carefully monitored. Combined use of methotrexate with gold, penicillamine, hydroxychloroquine, sulfasalazine, or cytotoxic agents, has not been studied and may increase the incidence of adverse effects.

Store at controlled room temperature, 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). PROTECT FROM LIGHT.