Otrexup

1 INDICATIONS AND USAGE Otrexup 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 Otrexup is not indicated for the treatment of neoplastic diseases ( 1.3 ). 1.1 Rheumatoid Arthritis including Polyarticular Juvenile Idiopathic Arthritis Otrexup 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 Otrexup 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 Otrexup is not indicated for the treatment of neoplastic diseases.

2 DOSAGE AND ADMINISTRATION Otrexup is for once weekly subcutaneous use only. Administer Otrexup 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 10 mg per week, doses above 25 mg per week, high-dose regimens, or dose adjustments of less than 5 mg increments ( 2.1 ). Starting doses of methotrexate: RA: 7.5 mg once weekly ( 2.2 ). pJIA: 10 mg/m 2 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 Otrexup is a single-dose auto-injector for once-weekly subcutaneous use only [see Warnings and Precautions ( 5.5 )] . Administer Otrexup in the abdomen or the thigh. Otrexup is available in the following dosage strengths: 10, 12.5, 15, 17.5, 20, 22.5 and 25 mg. Use another formulation of methotrexate for alternative dosing in patients who require oral, intramuscular, intravenous, intra-arterial, or intrathecal dosing, doses less than 10 mg per week, doses more than 25 mg per week, high-dose regimens, or dose adjustments between the available doses. 2.2 Rheumatoid Arthritis including Polyarticular Juvenile Idiopathic Arthritis Recommended starting dose of methotrexate: Adult RA: 7.5 mg once weekly. pJIA : 10 mg/m 2 once weekly. For patients switching from oral methotrexate to Otrexup, 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 Otrexup therapy [see Warnings and Precautions ( 5.4 )] . Females of childbearing potential should not be started on Otrexup 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: single weekly oral, intramuscular, subcutaneous, or intravenous doses of 10-25 mg. For patients switching from oral methotrexate to Otrexup, 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 shoul …

3 DOSAGE FORMS AND STRENGTHS Otrexup is an injection available as an autoinjector that administers a single 0.4 mL dose of methotrexate solution in the following dosage strengths: 10 mg/0.4 mL methotrexate 12.5 mg/0.4 mL methotrexate 15 mg/0.4 mL methotrexate 17.5 mg/0.4 mL methotrexate 20 mg/0.4 mL methotrexate 22.5 mg/0.4 mL methotrexate 25 mg/0.4 mL methotrexate Injection: Single-dose auto-injector delivering 0.4 mL of methotrexate in the following dosage strengths: 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg and 25 mg ( 3 ).

4 CONTRAINDICATIONS Otrexup is contraindicated in the following: • Pregnancy Otrexup 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 )]. Pregnancy ( 4 ) Alcoholism or liver disease ( 4 ) Immunodeficiency syndromes ( 4 ) Preexisting blood dyscrasias ( 4 ) Hypersensitivity to methotrexate ( 4 )

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, leucopenia, pancytopenia, dizziness, photosensitivity, and “burning of skin lesions” ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact Antares at 1-855-Otrexup (1-855-687-3987) 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 Otrexup 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/mm 3 ). Incidence 1% to 3%: Rash/pruritis/dermatitis, diarrhea, alopecia, leukopenia (WBC less than 3000/mm 3 ), 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. Rarel …

7 DRUG INTERACTIONS 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 Otrexup. 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) 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 Otrexup 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 Otrexup 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 Otrexup. 7.6 Folic Acid and Antifolates Vitamin preparations containing folic acid or its derivatives may decrease responses to …

8 USE IN SPECIFIC POPULATIONS Pediatric use: Safety and efficacy of methotrexate, including Otrexup, have not been established in pediatric patients with psoriasis. Safety and efficacy of Otrexup have not been established in pediatric patients with malignancy ( 8.4 ). Geriatric use: Use caution in dose selection ( 8.5 ). Lactation: Advise women not to breastfeed ( 8.2 ). 8.1 Pregnancy Risk Summary Based on published reports and methotrexate’s mechanism of action, methotrexate can cause embryo-fetal toxicity and fetal death when administered to a pregnant woman [see Data and Clinical Pharmacology ( 12.1 )] . In pregnant women with non-malignant disease, Otrexup is contraindicated. Consider the benefits and risks of Otrexup and risks to the fetus when prescribing Otrexup to a pregnant patient. 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. Data Human Data Published data from cases, literature reviews, and observational studies report that methotrexate exposure during pregnancy is associated with an increased risk of embryo-fetal toxicity and fetal death. Methotrexate exposure during the first trimester of pregnancy is associated with an increased incidence of spontaneous abortions and multiple adverse developmental outcomes, including skull anomalies, facial dysmorphism, central nervous system abnormalities, limb abnormalities, and sometimes cardiac anomalies and intellectual impairment. Adverse outcomes associated with exposure during second and third trimesters of pregnancy include intrauterine growth restriction and functional abnormalities. Because methotrexate is widely distributed and persists in the body for a prolonged period, there is a potential risk to the fetus from preconception methotrexate exposure. A prospective multicenter study evaluated pregnancy outcomes in women taking methotrexate less than or equal to 30 mg/week after conception. The rate of miscarriage in pregnant women exposed to methotrexate was 42.5% (95% confidence interval [95% CI] 29.2-58.7), which was higher than in unexposed 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]). Major birth defects associated with pregnancies exposed to methotrexate after conception were not always consistent with methotrexate-associated adverse developmental outcomes. 8.2 Lactation Risk Summary Limited published literature report the presence of methotrexate in human 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 including myelosuppression, from methotrexate in breastfed infants, advise women not to breastfeed during treatment with Otrexup and for one week after the final dose. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating Otrexup. Contraception Females Otrexup can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations ( 8.1 )] . Advise females of reproductive potential to u …

12.1 Mechanism of Action Methotrexate inhibits dihydrofolic acid reductase. Dihydrofolates must be reduced to tetrahydrofolates by this enzyme before they can be utilized as carriers of one-carbon groups in the synthesis of purine nucleotides and thymidylate. Therefore, methotrexate interferes with DNA synthesis, repair, and cellular replication. Actively proliferating tissues such as malignant cells, bone marrow, fetal cells, buccal and intestinal mucosa, and cells of the urinary bladder are in general more sensitive to this effect of methotrexate. The mechanism of action in rheumatoid arthritis is unknown; it may affect immune function.

11 DESCRIPTION Otrexup 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 Otrexup contains methotrexate in a sterile, preservative-free, unbuffered solution with a 27 gauge 1⁄2 inch needle for a single subcutaneous injection. Otrexup solution is yellow in color. Inactive ingredients include sodium chloride and water for injection, USP. The amounts of sodium chloride vary with the amount of methotrexate. Amount of methotrexate (mg) per 0.4 mL 10 12.5 15 17.5 20 22.5 25 Amount of sodium chloride (mg) per 0.4 mL 1.96 2.04 1.60 1.48 1.28 0.92 0.56 Hydrochloric acid and additional sodium hydroxide may have been added, if necessary, to adjust the pH to 8.0. Structure

10 OVERDOSAGE Leucovorin is indicated to diminish the toxicity and counteract the effect of inadvertently administered overdosages of methotrexate. Leucovorin administration should begin as promptly as possible. As the time interval between methotrexate administration and leucovorin initiation increases, the effectiveness of leucovorin in counteracting toxicity decreases. Monitoring of the serum methotrexate concentration is essential in determining the optimal dose and duration of treatment with leucovorin. In cases of massive overdosage, hydration and urinary alkalinization may be necessary to prevent the precipitation of methotrexate and/or its metabolites in the renal tubules. Generally speaking, neither hemodialysis nor peritoneal dialysis has been shown to improve methotrexate elimination. However, effective clearance of methotrexate has been reported with acute, intermittent hemodialysis using a high-flux dialyzer (Wall, SM et al: Am J Kidney Dis 28 (6): 846-854, 1996). Accidental intrathecal overdosage may require intensive systemic support, high-dose systemic leucovorin, alkaline diuresis and rapid CSF drainage and ventriculolumbar perfusion. In postmarketing experience, overdose with methotrexate has generally occurred with oral and intrathecal administration, although intravenous and intramuscular overdose have also been reported. Reports of oral overdose often indicate accidental daily administration instead of weekly (single or divided doses). Symptoms commonly reported following oral overdose include those symptoms and signs reported at pharmacologic doses, particularly hematologic and gastrointestinal reaction. For example, leukopenia, thrombocytopenia, anemia, pancytopenia, bone marrow suppression, mucositis, stomatitis, oral ulceration, nausea, vomiting, gastrointestinal ulceration, gastrointestinal bleeding. In some cases, no symptoms were reported. There have been reports of death following overdose. In these cases, events such as sepsis or septic shock, renal failure, and aplastic anemia were also reported. Symptoms of intrathecal overdose are generally central nervous system (CNS) symptoms, including headache, nausea and vomiting, seizure or convulsion, and acute toxic encephalopathy. In some cases, no symptoms were reported. There have been reports of death following intrathecal overdose. In these cases, cerebellar herniation associated with increased intracranial pressure, and acute toxic encephalopathy have also been reported. There are published case reports of intravenous and intrathecal carboxypeptidase G2 treatment to hasten clearance of methotrexate in cases of overdose.

16 HOW SUPPLIED/STORAGE AND HANDLING Otrexup contains methotrexate in a preservative-free sterile solution for a single subcutaneous injection. Otrexup is available in the following strengths and configurations. Otrexup (methotrexate) injection 10 mg/0.4 mL Carton of 1 NDC 54436-010-01 Carton of 4 NDC 54436-010-04 Otrexup NDC 54436-010-02 Otrexup (methotrexate) injection 12.5 mg/0.4 mL Carton of 1 NDC 54436-012-01 Carton of 4 NDC 54436-012-04 Otrexup NDC 54436-012-02 Otrexup (methotrexate) injection 15 mg/0.4 mL Carton of 1 NDC 54436-015-01 Carton of 4 NDC 54436-015-04 Otrexup NDC 54436-015-02 Otrexup (methotrexate) injection 17.5 mg/0.4 mL Carton of 1 NDC 54436-017-01 Carton of 4 NDC 54436-017-04 Otrexup NDC 54436-017-02 Otrexup (methotrexate) injection 20 mg/0.4 mL Carton of 1 NDC 54436-020-01 Carton of 4 NDC 54436-020-04 Otrexup NDC 54436-020-02 Otrexup (methotrexate) injection 22.5 mg/0.4 mL Carton of 1 NDC 54436-022-01 Carton of 4 NDC 54436-022-04 Otrexup NDC 54436-022-02 Otrexup (methotrexate) injection 25 mg/0.4 mL Carton of 1 NDC 54436-025-01 Carton of 4 NDC 54436-025-04 Otrexup NDC 54436-025-02 Store at controlled room temperature, 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). PROTECT FROM LIGHT. Handling and Disposal Handle and dispose of Otrexup consistent with recommendations for handling and disposal of cytotoxic drugs. 1