Case 1:14-cv-01498-JBS-KMW Document 28-5 Filed 07/11/14 Page 1 of 22 PageID: 174
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`Exhibit 1
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`DOSAGE FORMS AND STRENGTHS
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`HIGHLIGHTS OF PRESCRIBING INFORMATION
`Injection: Single-dose auto-injector delivering 0.4 mL of methotrexate in the following dosage strengths: 10 mg, 15
`These highlights do not include all the information needed to use OTREXUP™ safely and effectively. See full
`mg, 20mg, and 25 mg (3).
`prescribing information for OTREXUP.
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`CONTRAINDICATIONS
`
`OTREXUP (methotrexate) injection, for subcutaneous use
`Initial U.S. Approval: 1953
`
`WARNING: SEVERE TOXIC REACTIONS, INCLUDING EMBRYO-FETAL TOXICITY AND DEATH
`See full prescribing information for complete boxed warning.
`• Serious toxic reactions and death have been reported with the use of methotrexate. Patients should be
`closely monitored for bone marrow, liver, lung, skin, and kidney toxicities (5.1).
`• Methotrexate has been reported to cause fetal death and/or congenital anomalies and is contraindicated
`in pregnancy (4, 5.2).
`• 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) (5.1).
`• Hepatotoxicity, fibrosis, and cirrhosis may occur after prolonged use (5.1).
`• Methotrexate may cause interstitial pneumonitis at any time during therapy and has been reported at
`low doses. Pulmonary symptoms (especially a dry, nonproductive cough) may require interruption of
`treatment and careful investigation (5.1).
`• Diarrhea, ulcerative stomatitis, hemorrhagic enteritis, and death from intestinal perforation may occur
`(5.1).
`• Severe, occasionally fatal, skin reactions have been reported (5.1).
`• Potentially fatal opportunistic infections may occur (5.1).
`
`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).
`DOSAGE AND ADMINISTRATION
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`• 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:
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`• RA: 7.5 mg of an oral formulation once weekly (2.2)
`2
`• pJIA: 10 mg/m once weekly (2.2)
`• Psoriasis: 10 to 25 mg once weekly of an oral, intramuscular, subcutaneous, or intravenous
`formulation (2.3)
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`• Adjust dose gradually to achieve an optimal response (2.2, 2.3)
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`• Pregnancy (4)
`• Nursing mothers (4)
`• Alcoholism or liver disease (4)
`• Immunodeficiency syndromes (4)
`• Preexisting blood dyscrasias (4)
`• Hypersensitivity to methotrexate (4)
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`WARNINGS AND PRECAUTIONS
`
`• Organ system toxicity: Potential for serious toxicity. Only for use by physicians experienced in
`antimetabolite therapy (5.1).
`• Embryo-fetal toxicity: Exclude pregnancy before treatment. Avoid pregnancy if either partner is receiving
`Otrexup. Advise males to avoid pregnancy for a minimum of three months after therapy and females to
`avoid pregnancy for at least one ovulatory cycle after therapy (5.2).
`• Effects on reproduction: May cause impairment of fertility, oligospermia and menstrual dysfunction (5.3)
`• Laboratory tests: Monitor complete blood counts, renal function and liver function tests (5.4).
`• Risks from improper dosing: Mistaken daily use has led to fatal toxicity (5.5)
`• Patients with impaired renal function, ascites, or pleural effusions:
`Elimination is reduced (5.6).
`• Dizziness and fatigue: May impair ability to drive or operate machinery (5.7)
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`ADVERSE REACTIONS
`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.
`DRUG INTERACTIONS
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`• 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)
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`USE IN SPECIFIC POPULATIONS
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`• 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)
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`See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
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`Revised: 10/2013
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`FULL PRESCRIBING INFORMATION: CONTENTS*
`WARNING: SEVERE TOXIC REACTIONS, INCLUDING EMBRYO-FETAL
`TOXICITY AND DEATH
`1 INDICATIONS AND USAGE
`1.1 Rheumatoid Arthritis including Polyarticular Juvenile Idiopathic Arthritis
`1.2 Psoriasis
`1.3 Limitation of Use
`2 DOSAGE AND ADMINISTRATION
`2.1 Important Dosing Information
`2.2 Rheumatoid Arthritis including Polyarticular Juvenile Idiopathic Arthritis
`2.3 Psoriasis
`2.4 Administration and Handling
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Organ System Toxicity
`5.2 Embryo-Fetal Toxicity
`5.3 Effects on Reproduction
`5.4 Laboratory Tests
`5.5 Risks from Improper Dosing
`5.6 Patients with Impaired Renal Function, Ascites, or Pleural Effusions
`5.7 Dizziness and Fatigue
`5.8 Malignant Lymphomas
`5.9 Tumor Lysis Syndrome
`5.10 Concomitant Radiation Therapy
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`6.2 Other Adverse Reactions
`7 DRUG INTERACTIONS
`7.1 Aspirin, Nonsteroidal Anti-Inflammatory Drugs, and Steroids
`7.2 Proton Pump Inhibitors (PPIs)
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`7.3 Oral Antibiotics
`7.4 Hepatotoxins
`7.5 Theophylline
`7.6 Folic Acid and Antifolates
`7.7 Mercaptopurine
`7.8 Other Drugs
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.3 Nursing Mothers
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Females and Males of Reproductive Potential
`8.7 Renal Impairment
`8.8 Hepatic Impairment
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`14.1 Rheumatoid Arthritis
`14.2 Polyarticular Juvenile Idiopathic Arthritis
`15 REFERENCES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`*
`Sections or subsections omitted from the full prescribing information are not listed.
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`FULL PRESCRIBING INFORMATION
`
`WARNING: SEVERE TOXIC REACTIONS, INCLUDING EMBRYO-FETAL TOXICITY AND DEATH
`Otrexup 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), Otrexup 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, skin, and kidney toxicities. Patients should be informed by their physician of the risks involved and be under a physician’s care throughout therapy
`[see Warnings and Precautions (5.1)].
`1. Methotrexate has been reported to cause fetal death and/or congenital anomalies.
`Therefore, Otrexup is not recommended for females of childbearing potential unless there is clear medical evidence that the benefits can be expected to outweigh the considered
`risks [see Warnings and Precautions (5.2)]. Otrexup is contraindicated in pregnant women [see Contraindications (4)].
`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 Otrexup administration [see Warnings and Precautions (5.6)].
`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) [see Warnings and Precautions (5.1) and Drug Interactions (7.1)].
`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 Warnings and Precautions (5.1)].
`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 Warnings and Precautions (5.1)].
`6. Diarrhea and ulcerative stomatitis require interruption of therapy: otherwise, hemorrhagic enteritis and death from intestinal perforation may occur [see Warnings and
`Precautions (5.1)].
`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 Otrexup first and, if the lymphoma does not regress, appropriate treatment should be instituted [see Warnings and Precautions (5.8)].
`8. Like other cytotoxic drugs, methotrexate may induce “tumor lysis syndrome” in patients with rapidly growing tumors [see Warnings and Precautions (5.9)].
`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 Warnings and Precautions (5.1)].
`10. Potentially fatal opportunistic infections, especially Pneumocystis jiroveci pneumonia, may occur with methotrexate therapy [see Warnings and Precautions (5.1)].
`11. Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis [see Warnings and Precautions (5.10)].
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`1 INDICATIONS AND USAGE
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`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).
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`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.
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`1.3 Limitation of Use
`Otrexup is not indicated for the treatment of neoplastic diseases.
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`2 DOSAGE AND ADMINISTRATION
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`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 only available in doses
`between 10 to 25 mg in 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 10 mg per week, doses more than 25 mg per week, high-dose regimens, or dose adjustments of less than 5 mg increments.
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`2.2 Rheumatoid Arthritis including Polyarticular Juvenile Idiopathic Arthritis
`Recommended starting dose of methotrexate:
`Adult RA: single oral doses of 7.5 mg weekly using an oral formulation of methotrexate.
`2
`pJIA: 10 mg/m 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
`2
`2
`suppression, at doses greater than 20 mg/wk in adults. Although there is experience with doses up to 30 mg/m /wk in children, there are too few published data to assess how doses over 20 mg/m /wk
`2
`might affect the risk of serious toxicity in children. Experience does suggest, however, that children receiving 20 to 30 mg/m /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
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`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)]
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`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.
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`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 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 Otrexup may permit the return to conventional topical therapy, which should be encouraged.
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`2.4 Administration and Handling
`Otrexup is an auto-injector intended for subcutaneous use under the guidance and supervision of a physician.
`Patients may self-inject with Otrexup 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. A trainer device is available for training purposes.
`Visually inspect Otrexup for particulate matter and discoloration prior to administration. Do not use Otrexup if the seal is broken.
`1
`Handle and dispose of Otrexup consistent with recommendations for handling and disposal of cytotoxic drugs .
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`3 DOSAGE FORMS AND STRENGTHS
`Otrexup is an injection available as an auto-injector that administers a single 0.4 mL dose of methotrexate solution in the following dosage strengths:
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`• 10 mg/0.4 mL methotrexate
`• 15 mg/0.4 mL methotrexate
`• 20 mg/0.4 mL methotrexate
`• 25 mg/0.4 mL methotrexate
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`4 CONTRAINDICATIONS
`Otrexup is contraindicated in the following:
`• Pregnancy
`Otrexup can cause fetal death or teratogenic effects when administered to a pregnant woman.
`Otrexup is contraindicated in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the
`fetus [see Warnings and Precautions (5.2) and Use in Specific Populations (8.1)].
`•Nursing Mothers
`Because of the potential for serious adverse reactions from methotrexate in breast fed infants, Otrexup is contraindicated in nursing mothers [see Use in Specific Populations (8.3)].
`•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)].
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`5 WARNINGS AND PRECAUTIONS
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`5.1 Organ System Toxicity
`Otrexup 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), Otrexup
`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.
`Otrexup 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 Otrexup 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 Otrexup therapy is reinstituted, it should be carried out with caution, with adequate consideration of further need for the drug and increased alertness as to possible recurrence of
`toxicity.
`The clinical pharmacology of methotrexate has not been well studied in older individuals. Due to diminished hepatic and renal function as well as decreased folate stores in this population, relatively low
`doses should be considered, and these patients should be closely monitored for early signs of toxicity [see Use in Specific Populations (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, Otrexup should be discontinued until recovery occurs. Otrexup 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
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`drugs (NSAIDs) [see Drug Interactions (7.1)].
`Hematologic:
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`Otrexup can suppress hematopoiesis and cause anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, and/or thrombocytopenia. In patients with preexisting hematopoietic impairment, Otrexup
`3
`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/mm ) was seen in 2 patients,
`3
`thrombocytopenia (platelets <100,000/mm ) in 6 patients, and pancytopenia in 2 patients.
`Otrexup 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:
`Otrexup 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 Otrexup
`therapy, the drug should be used with caution.
`In rheumatoid arthritis, age at first use of methotrexate and duration of therapy have been reported as risk factors for hepatotoxicity; other risk factors, similar to those observed in psoriasis, may be present
`in rheumatoid arthritis but have not been confirmed to date. Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis in this population. There is a combined reported
`experience in 217 rheumatoid arthritis patients with liver biopsies both before and during treatment (after a cumulative dose of at least 1.5 g) and in 714 patients with a biopsy only during treatment. There
`are 64 (7%) cases of fibrosis and 1 (0.1%) case of cirrhosis. Of the 64 cases of fibrosis, 60 were deemed mild. The reticulin stain is more sensitive for early fibrosis and its use may increase these figures. It
`is unknown whether even longer use will increase these risks.
`Liver function tests should be performed at baseline at 4 to 8 week intervals in patients receiving Otrexup 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), Otrexup may be continued and the patient monitored as per recommendations listed above. Otrexup 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:
`Otrexup 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 Otrexup therapy. Immunization with live virus vaccines is generally not recommended. There have been reports of disseminated vaccinia infections after
`smallpox immunizations in patients receiving methotrexate therapy. Hypogammaglobulinemia has been reported rarely.
`Potentially fatal opportunistic infections, especially Pneumocystis jiroveci pneumonia, may occur with Otrexup therapy. When a patient presents with pulmonary symptoms, the possibility of
`Pneumocystis jiroveci pneumonia 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
`2
`methotrexate (1 gm/m ). 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 Otrexup 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:
`Otrexup 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:
`Otrexup 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.
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`5.2 Embryo-Fetal Toxicity
`Methotrexate has been reported to cause fetal death and/or congenital anomalies. Therefore, Otrexup is not recommended for females of childbearing potential unless there is clear medical evidence that
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`the benefits can be expected to outweigh the considered risks. Otrexup is contraindicated in pregnant women with psoriasis or rheumatoid arthritis.
`Females of childbearing potential should not be started on Otrexup until pregnancy is excluded and should be fully counseled on the serious risk to the fetus should they become pregnant while undergoing
`treatment. Appropriate steps should be taken to avoid conception during Otrexup therapy. Pregnancy should be avoided if either partner is receiving Otrexup; during and for a minimum of three months
`after therapy for male patients, and during and for at least one ovulatory cycle after therapy for female patients.
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`5.3 Effects on Reproduction
`Methotrexate has been reported to cause impairment of fertility, oligospermia and menstrual dysfunction in humans, during and for a short period after cessation of therapy.
`The risk of effects of reproduction should be discussed with both male and female patients taking Otrexup.
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`5.4 Laboratory Tests
`Patients undergoing Otrexup therapy should be closely monitored so that toxic effects are detected promptly. Baseline assessment should include a complete blood count with differential and platelet
`counts, hepatic enzymes, renal function tests and a chest X-ray.
`During therapy, monitoring of these parameters is recommended: hematology at least monthly, renal function and liver function every 1 to 2 months [see Warnings and Precautions (5.1)].
`During initial or changing doses, or during periods of increased risk of elevated methotrexate blood levels (e.g., dehydration), more frequent monitoring may also be indicated.
`Liver Function Tests
`Transient liver function test abnormalities are observed frequently after methotrexate administration and are usually not cause for modification of methotrexate therapy. Persistent